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pyridine in virro and on the N-osidatioo of pyridine and 3<hloropyridine are now reported. According to the data, pyridine-Nozidase activitl, is found mainly in the hepatic and pulmonary tissue microsomal fractions of various eaperimcntal animals. The level of enzyme activity is not neceuarily the same In a1I spccies, however, as shown by the fact that it propeaively declined as rabbits, mice, guinea-pip and rats were substituted for hamsters. Ra1a and mice also showed a sea diRereocs. The speciflc kinetic data (K. and V.„) for the N-oaidation of pyridine, 3-methylpyridine and 3-chloropyriline in various species and orgaos are reported. Gorrod, I. W. and Damad, L. A. Xcnob/ork. 9( 4):209-21 fi, 1979. From the Department of Pharmacy, Chelsea College. University of London, London. TNP. EFFECT OF VARIOUS POTENTIAL INHIBITORS, ACTIVATORS AND INDUCERS ON T11E N-0XIDATION OF 3-SUBSTITUTED PYRIDINES IN VITRO In their continuing series of eaperimenta on the Noaidalioa of 3-sub- slituted pyridines, the authors now present evidence indicating that this type of naction le medlated by a cytochroma P-450 aystem, which is different from eytochrome P-446 and from the flavoproteio<ontaining amine ozidase. The Noadation of pyridine, 3-mclhylpyridine and 3<hbropyridine was inhibited by SKF 525A (2-diethylaminoethyl-2,2diphenylvakrNe) and DPEA (2-4- dich{oro-6-phenylphenoayethylamine). These compounds also inhibited Ihe C-oaidatioo of 3-methylpyridine. Various other nitrogenous substrales, io- cludin6 noclylamine, also inhibited the Nosidation of these three pyridines. When microsomal fractions were incubated with NADPH In a carbon mon- oside almosphere, the N-oxidation of aM three substrates and the C-ozidalion of )-methylpyridine were inhibiKd. In additioe, any treatment of microsomes that reduced eytochrome P-430 concomitantly decreased the Nosidation of the pyridines. Pretreatment of rabbils with phenobarbilone signi/lcantly increased N-osidatioa of the pyridines !n virro, while pretreatment with 3-methykholan- threne had no appreciable effect. EsaenliaBy the same results had previously blen obtained with hamsters and guinea pip. Pyridine-Nozidase, therefore, is clearly similar to the group Ila Noaidase rather than to the tertiary amine osidase. Tlase data support the view that factors olher than the subslrate: dissociatioe eonslant, such as nuckophilicity and nitrogen atom hybridizalion, are among thoee that determine the differentiation of the variaus enzymatic N-osidative processes. Gorrod, l. W. and Damani, 1.. A. Xtnobiorica 9(4):219-226, 1979. Frnrn the Ikparrment of Pharmacy, t'helsea College. Univeniiy of l,nndon, I ondon c T71E EFFECTS OF CYTOCIIROME P-430-44t1 INIIIBITORS ON TIIE BINDING OF BENZO(a)PYRFNE AND DERIVATIVES TO DNA UPON MICROSOMAI. ACTIVATION Whik the rok of cytochrome P-430-44tl-dependent oaidalive pathways in the carcino~enicNy o/ benzo(a)pyreoe (BP) is well krrown, the ideetifkuioe of 6-hydrotymelhyl-BP as a carcinogenic metabolite of BP and the aubaeqrreot determination that the arylhydroaymethyl synthetase «actiws in indepeadcsl of cytochrome P430 indicates that oon-cytochrorne P430-44t{ pathwaya may also be involved in the formation of prodmate carcinogens. This study ea- amines the possible role of tae<ytochrome P-J30-448 pathways i. Ihe covalent binding to DNA of BP aod of the 6-aubslituted derivalives of BP, 6-methyl-BP, 6-hydrozymethyl-BP, and 6-formyl-BP. Resulta show that liver microsomal preparuions from rau prelreated with 3-methykholaolhrene I. the presence of NADPH have an increased capacity to form acliw metaboGta (rom BP and from the 6-substituted BP derivativea. Two different typea of cytochrome P-4S0-44t inhibilon..-tupthollevoee and 1-beozylimidazole, show greater than 80% inhibition of the binding of BP to DNA. I. the presena of these inhibilora, 6-hydroaymethyl-BP, 6-methyl-BP and 6-/ormyl-BP show varying degrees of inhibition o( binding to DNA, depending upoa the iabibilor used. Also, it can be seen that potyRuanylie acid is the most eQective wrb- strale for the binding of each activated polyewekar aromatic hydrocarboe; polyadenylic acid and DNA show essentially equivalent binding. Ttr.r.fora, the data presented in this paper clearly demonstrate that microsanal prepara- 3 from methykhdanthreoe-pretrealed rau, in the preaeoce of NADPH, ate 6-substituted derivetiva of BP b InNaboliles which oovalently, bbind lo DNA In the prsance of two diQerent inhibiton of cytochrom. P-430-44t, under coodilions whereby activation of BP prr re is inhibited. T1se metabolic rowea of the activatiow of dre 6-subsUtuted BP derivatives are not yet know.. Liu. W-1. and Sloawe, N. N. Xrnobloaka 9(l):163-171, 1979. OtA.r a.pporet American Caacer Society. From the Department of Biochemistry. Univer/Ny of Teneessee Center for the Health Sciencea, Memphia- EFFE('TS OF A CYTO(.'HROME P-4301NHIBITOR ON COVALENT BINDINO OF (rHIBENZO(a)PYRENE IN NILCEL.L. FRACTIONS Does 1-benzylimidazok (81), a potent inhibitor of eytochrome P-470 hydrosylatioo reactiona, inhibit the covalent binding of ('lllbeezo(.)pyKrM (BP) to both the nuclear and tytoplasrqic fractions of Nil eelh7 Eaperimeou show that incubation of lirst cycle celb with 81 for 24 hours inhibits 70% of the eovaknlly bound cytoplasmic BP. In the nuclear fractioe. BI inhibiu 33% of the BP binding. In the second eyck. BI activity seems to concentrate in the nuckus, since the addition of more BI to the p.eviously treated nuclear (rae- lions does not further increase its inhibitory effect on 8P binding In the cyurplasmic fractions, however, 81 inhibits 47% of the BP binding aad additional 1rcalment causes 70% inhibition. Inlereatintly, there Is evidence, IB 19

according to aoother report, that benr]midazde derivatives covaknlly bind to nuckic acids. Sloane. N. N.. Chu, L. N. and Amo., H. IRCS Medicd Srknce 7:t1, 1979. Other wpportr American Cancer Sockty. From the lkpartment of Microbioloby ud Medh:al Qeoetks, Harvud Medical School, Boston. REACTIVE ANTIBODIES IN THE BRONCHIAL WASIUNOS OP LUNG CANCER PATIENIS Tumor-rcactive snlibodks have bee. wooerfuly isolated from cluales of lung csrcinomas and from their eAusions in the p..t. To esplore the woleat and the specificity ot immunopobulau (rb) in broechial wuhinp, specimem were obtained from 26 patients with various types ot lung eaneer, 11 patienU with non-neoplastic pulmonary diseases, and 10 hmp with no evidence of lung disease. Fspressed as Ib/potasaium ratios, statistically sipniflcanl increases in 1S levels were found in imflammalory diseases and even higher increases In lun6 carcinomas. The iwlation of I6 from bronchial washinp was a:hieved by dissociation of immune completey at low plt, neutralization and subiepuent purification by anion eschange chrornatography. The isolated immunogtobulins were tested in indirect immuno/luorescence against luna cancer cells of various histologic types in tissue cultures and fresh suspemions. Positive cytoplasmic fluorescence was obtained with cells of adenocarcinomas and spuarrwus-ceU earcinomas of the lung but not with normal lung eells It seems, Iher,efore, that together with the infiltralion of lymphocytes .nd plasma eella in the tumor tiaues, the formation of spccdkaily reacli.e antibodies represents a parl of the immune response to the growth of lung cancer. The accessibility of bronchial washings makes the estimation of their lung<ancer-reactive 1S relatively easy and raises the possibility of Ihis measurement's eventual conversion into a screening test. Paluch. E. and IoarliLn, H. L. Inrcrmrlond Journal o/ Cancer 2)(1) :42-16, 1979. From the Departments of Pathology. Columbia University College of Phy- skians i Surgeons and Lenox Hill Hospital, New York. HEREDITARY CANCER: ASCERTAINMENT AND MANAOEMENr Heredilary, cancers and precancerous diseases have several eharacteristica-- early pe of onsN, bilateral cancer oecunesses in paired orbans, increased occurrence of nwhicentric cancer, and segregation patterns consistent with autosumal dominant inheritance-that distinguish them from other cancer patlerna /heu cMractenstKs can be used as familial cancer selection criteria when rdentdkd in sr.larcd patienls and nuclear family cancer clusters Familial muluple . Lnawna~~~~s pA>P^is of the colon (fPC). which is frequently cited as the cla.+wsl poui.,t>pc ol a hereditary cancer-prcdisposing disxttder, is eum- I i ined in this paper. The historical perspective provided by FPC and depicted la a table here provides an excellent example of the advances in cancer epidemiology and characterization of hereditary precascerous discase(s). Receotly, a Seredi- Iary. premelanoaic cutaneous phenotype (characlerised by multiple large moMs, irregularly shaped, reddish-brown to pink ia color, and with evidence o[ pijmaa- tary leakage) has been iden/i0od. This cutasrcan peeeancer phenotype, which is transmitted in a manner consistent with ae autowmal dornieaot moda of b- heritance, has had the acronym FAMMM, for Familial Atypieal Multiple 111otr Melanoma Syndrome, ascribed to it. Multiple endocrine adeootnato.is (MEA) has also been described as a familial entity. The Cancer Rebistry-baseA probrns which is dealt with here has clearly demonstrated t6a man.er in which a carefully obtained famiy (niNOry can lead to the recppiilioo of patients with exceedingly high cancer risks. Lynch, N. T. er d. CA-A Cawrrr Iorrnd /or CUn/c{aws 29(4):216-212, 1979. Other .upport: Amerkao Cancer Society, Nebraska aod Iowa Divisions. From the Department of Proventive Medicine/Public Health and the Oncology Clinic, Creighton University School of Medicine, Omaha. FAMILIAL FACTORS IN BLADDER CARCINOMA An increasingly valid overview of cancer etiolopr has beea made poa. sible by highly accurate verification of cancer p.lhotogy at all anatomk dtea, and by a meticulous recording of peneabtr, associated diseases and k.ows environmental exposures. While carcinoma of the bladder (s the most coremos malignancy of the urinary tract, surprisingly liltk is known about bost factors in such cases. In this sludy, two families prone to transiliona1 cell carciooma of the bladder were investigated. It is reasonable to wume that members ol the subject families may be snore suseeplibk to various espowrea to cu- einogens, a concept that supports a genetie<nviromnenlal interaction hypotheais for cancer etiology. Identification of hibh-risk individuab should prompt spec cilk surveillance programs instituted sibnifkanlly earlier for such person. Ihan for the general population. Such programs should include urinalysis at regular inlervals to detect mkroscopic hemaluria or pyuria and sedimentary tumor cells. In addition, cancer control measures should consider preventive programs aimed al the avoidance of carcinogenic exposures such as eipretlie smoking by high-risk relatives of cancer-affected probands. The etiology of familial bladder cancer may be a complex one, possibly Involving other associated malignancies arn//ur certain other non ncoplaslk ulmenls, in addition to spe- cifk carcinogenic esposures. Detailed reporting of /amilies prone to this dr- order, including cunsideration of all the potentially important associated /aclors, is seriously needed in order to understand it more fully. Lynch, H. T, cr al. The Iournal o/ Urology 122(1):I3/-161, 1979. From the Departments of Preventive Medicioe/Public Hedth, Urology and Biochemistry. C'rcighton University School of Medicine, Omaha. 21 • 2O

COORDINACY OF LYSOSOMAL ENZYME EXCRETION IN IIUMAN URINE Whether or not the high levels of urinary jlucuronidase observed in blad- der cancer patients are a cause or a consequence of the disease could cooceiv- abiy be resolved by determining whether individual variation in the excretion of this enzyme is genetically determined. It ao, whether bladder cancer patients have a jienetic predisposition toward bigh enzyme excretion could be estab- lished by measuring enzyme excretion in their progeny. New aasay procedures utilizing fluorometrk substrales were Ihereforn developed, in order to measure A-glucuronidaae. S-tialactosidase, sip-Salaelaidase and A-helosaminidase eacre- tion. 77rc assay conditions for a-glucurooldafe eliminate the previously trouble- some problem of interference by both low and high molecular weiilht inhibi- tors. The urinary kvels of the four lyaoaornal enzymes vary coordinately, that is, although their absolute levels (unha/mg crestinine) vary during the day, and from one day to the nest, the ratio of one enzyme to the other remains relatively constant. The lack of oornlalion between their plauna and urioe levels and their high enokeular wdghl, both suggest that thew urinary encyrnn do not derive trom gkMeerular fUtretbn. That then is also no eoord)nacy with lactate dehydrotenase, nsoreover, suggests that they do aot corne from eafoli- aled cells. 11 is proposed that they stem from lysoaornes extruded by epithelial cells into the lumen of the proabnal lubuk. Total enzyme excretion abo varies considerably, as shown in a population of 125 healthy adults. However, both total enzyme escretion and coordinacy ratios follow logarithmic distribution, suggesting that lhey are the resultants of many tacton, each having a relative or proportional effecl on enzyme eacretion. ralten. K. and Petenon, 1. The /owrna1 o/ Clinical I nvesrigarion 61 :711-762, 1978. OOther support: National Institutes of Health. From the Departmcnt of Mokcular Riobgy, Roawell Park Memorial Institute, SuRab. 11. T/re Respiratory System DEFENSES OF THE LUNG: A DYNAMIC OVERVIEW . Lung defenses include a number of inlerrelated nonspeciflc ewd specific systems, from the nose and mouth to Ihe alveolar-eapi0ary parenchymal Inter- face. '1'hese are intended to isolate or eachrde noaioua inhalanta from the deli- cate mucosal and/or epithelial cellular membrann, either throulh mechankal barriers (e.g., mucus) or by physical removal mechanisms (e.l., sneezing, coughing. reflett bronchospasm, mucociliary escalalor, or macrophage removals). Within the lung, substances can be detoxifkd locally by interacting with anti- microbial protein secretiorn, with airway and/or vascular enzymatic mech- anisms, or with the complex airway and parenchymal immune defense systems. lhii e.temive review empha+irrs the importance of interactions between ciliary (uncnon sr>,f mu.rn anJ between mscrophsges and other lung cells. llre role I of the various mucus constituents in airway defense responaea, however, re- mains to be fully clari(kd. It is apparent that pulmonary alveolar macrophaolu may have the potential for many functions in addition to that of primary alveolar defense against microorganisms. They may also have a key role in the pathogenesis of various inflammatory destructive and fibrotk lung dreasea. Furthermore, it is recognized that while mucus-producing cella and plujocyles are crucial to the defense of the lung, they may also harm the host. Broader comprehension of these integrated defenses (and potentially injurious macb- anisma) should further clarify the pathogeneais of lung diaeaae and lead to improved treatment. Croas, C. E., Kaiw, T. and L..t,1.A. In: C1ark, M. A. (ed.): lrln.owory Dtreasr.: DtJenu MecAan(snv and ropa- larlonr at R64. Tobacco and NedrA RneareA InrNrrtr Sympos/re.-2, l edng- 1on, Kenlucky: University of Kentucky Printing Serviees, 1979, pp. 14-59. Other wpportr Primata Center Ilw Grant eed Ewvironmental Protectio. Agency. From the University of California Sclsod of Medicine and the California Pri- mate Research Center, Davis. LUNG HOST DEFENSES: A STATUS REPORT The lung has a complex and ealensive system of defenses that work. tirelessly to purify inspired air and keep pulmotaary (iaaue free of iefectio.. Since the major components of this system have been identified and well de- scribed, present research is focusing om the eoardination of these parta or on the integrated function of the whole syatem, particularly on the cellular iater- acliorn, generation of local inMnune «spoesea, and nnpUfyinR-inhibitory faa ton regulatinR inRammatiow. A tab/e of httrR host defenses b airway challenge presented here lists 11 surveillance mechanisna and two augmenting mecha- aisms,-iniliation of 6emune responses (humoral antibody and cellular) and generation of an inflammatory response (infiu: of polynarphorysckar Rraw- locytes, eosinophils, aod 7 lymphocytes). Colkaivey, the ekments of this de-ense ayslem work smoothly and continuously. Increaaiagly, however, ea- amples of isolated immune deficiencies are being found which are associated with recurrent pulmonary infections. Complement factor deficiencies (C,), abnormally functioning cilia (Kartagener's ayndrome), absence of immuno- globulin (IgA), and abnormal kukozytea, all seem to predispose to lung i.- fections. These sekctive deficiencies aetve as splendid probes for asseaaing tl.e Importance of individud components in lung defense. However, the fact that lung function can be maintained in the face of one or more of these dcbckn- cies serves to dramatize the overall ydaptability of the lung defense system. Reynolds. H. Y. C/irst 73(2):219-242, 1979. Other support: National Institutes of Health. From the Pulmonary Section. Ikpastment of Medicine, Yak University School of Medicine, New Haven, ('onn. 23 22

VASOACTIVE SUBSTANCES AND THE LUNGS: MOLECULAR MECHANISMS There is uo question that gas esch•nhe ir the lungs' primary function and that interference with this process is the m•ior determinant of mortality in the microembolism syndromes. A variety of other metabolic reactions conducted by the lung., however, may well contribute to the clinical eapression of sy- dromes and may play a role in the development of pulmonary and systemic vascular drsfurxtion. For esample, lung endothelium has a signi6cant role in the regulation of circulatory contx•IrNio•w of kinins, angiotensins, prosta- =landins, and adenine nuckolides. Other mechanisms are still unckar, however. 7 he importance of pulmonary endolbelirw in the inhibition of microthrornbi formation and the role of other cell types i• such activities remain unknown. Still other questions that are posed an: ts the aMi-•ssretNing aSen1, pros- lacyclin, made by the endothelial ce1Mt Ca• these celh inactivate the pro- aggregatory faclor, ADP? What is /he importance of pulmonary angiolerain converting enzyme In the development of renal dysfunction in the delayed microemholism syndrome? Would know• inhibilors of this enzyme alkviale or eliminate renal InsufRcieacyT Ecaminatioo of what happens 7o the "oon- ventdatory" functions of the lung during the development and course of the early microcmbolism or delayed microernbolirm syndrome could be informa- li.e. It may help define the humor•1 meehanisms through which microemhol- ized lunp affect renal function •nd, perhaps, slso the processes through which permeability factors are teneratcd. Ryao, 1. W. and Rr.n, U. S. In: S.Ideen, T. (ed): The MkrormAdinn Srndro.ne, Stockholm: Aheqvist A Wikull /nlernalional, 1979, pp. 213-221. Other sMppsrtr U. S. Public Health Service and the Hartford Foundatioa. From the Department of Medicine. University of Miami School of Medicine. Mismi, Fl•. VASOACTIVE SUBSTANCES AND THE LUNGS: CELLULAR MECHANISMS This review summarizes what is known about the nonventilatory functions of the lung. UUrntructursl studies demonstrate various specialized structures and microenvironments suitable for the processing of vasoactive substances. While many of the known "para endocrine" functions of the lunp can be attributed to the activities of the endotheli•1 celts, their functional limit in the processing mechanism of Mrrnwnes, prohormones and other escitatory sub- stsnces, or in the synthesis of vasoactive compounds is unknown. l7rcre are, moreover, pulmonary subslances such as thrombosants, which are released by the intact lung but are not produced in large quantities by endothctial cells. Consequently. it ir eksr that more remains to be learned abont !.pecifk mela- 1Jhc at iwaws 4•f puln.un.ry enduthebsl cells and even mure alrwl such ae- 1t.sly in od.rr pulm..n.# y ..uulu tell typcs a Rr.n, U. S. and Rran,1. W. In: Saldcen, T. (cd.): The Mknoenrbl4n. Sywdrowre. Stockholm: Akaq.lrl & Wiksell Intern.tional, 1979, pp. 22)-272. Other support: U. S. Public Health Service and the Hatt(ord Fouedatio•, From the Department of Medici•e. University of Miami School of Medici•e. Miaml, Fta. SYNTHESIS OF PROSTAOLANDINS BY PULMONARY ENDOil1EL1AL CELLS Although it ha. beew known that lunp rekaae relatively IarRe quantities of prostaplandin-rclatcd wbstantea following embo*atioa or induction of u.- phrl•sis, nothing ia known of the oellalar eilea of spethesis of the .ubMa•cea released by the lunps and nothing in knows of bw tA• prwt•Rl.ndin-relatcd substaaces gain access to the vascular space. 1s this attempt to deterei•o whether pulmonary e•dotheli•1 eells contribute b 1!r eRlut of proet•pla•di•- «lated subetanees, cultured bovine pulmonary arterry esdothelial eells wen i•- cubaled for two houn with 1-r'C-ar•chidonk acid in mediurn 199. A bkr•k, containing rrC-•r•chidoaic acid i• medium withoat «lle, was dso incubated. The diiference chromatoprnn obtained by eublracyinR the blank c.p.m. /ram those of !he esperiarcnt•1 showed at least .it s4C-lsbekd emtaboliw, but .• peak corresponding to ar•chidowic acid. PbE,, • major tneuboWe, /ornnA at a r•w of 0.33 as" of cell protei•/2 hows. POS, showed up m• second metabolite. Having established th•t pulmonary artery endotbelial celk+ i• cu{- ture are capable of inet•bolisini aradddonie acid to yield POE and related wbstaeces„ a search was slarted for sikU of We fatty acid eyc1o-osy8eaase. Among attempts reade lo 1•calize nAotfsdi•1 eyclt..oargenaae using combi•ed ttarphok>tk and biochemical IecMiques, both ekctro• microscopy and nrto- radiopraphic audies wer• do•e. The results of ther studia ahow that bovi•e pulmonary artery endotbe4al eells are e•p•ble of forming proet.pla•di•a ana related substances Irom 1-r4C-arachidoe•1e Ibr•ugh the action of •n e•spme system situated on the endoplasmic retie.hw.. P(1Es i. a major metabolite, and a substance which cochronutographo with R-keto-POFr., a breakdow• product of PUI,, is dro formed in highly variable qw•tities. While these ra- wlts indicate that pulmonary endothelial eeqk c•o account for p.rt of tbo etllua of prostaglandin-like substances from eabotiud or ao•phylactk lunp, they provide no information on the cellular origins of thrombo:ane A,, likely to be a primary medi•tor of •n•phylaui., or of other subuanea which may occur in lung venous eAlue•u bt much higher eoneentraliona than those of POEr. ~ Ryan, l. W., Rysn, U. S., llablisto•, D. and Martiq L. Trauarrbns of rhe Assorl.ulon o/ Arnrrk.w pApskbnr aei:74)-730, 1978. PtbeT support: U. S. Public Health Service and the Hartford Foundation. From the Ikparrment of Medicine. University of Miami School of Mediciae, Miami, Fla. :4 25

ISOLATION AND CULTURE OF ENDOTHELIAL CELLS FROM THE LUNOS OF SMALL ANIMALS Th. object of this study was b obain pulmonary esdotheliar eet6 from small a.imale commonly used 1o stud7 the metabolic tales of ho -rrwnes and other eacitatory subrtances, and to fLd a iray of coNectin6 thesi cdts from th. pulmonary vasculature. Teeh.auq rred for isolNing and culturing endo- thelial cells from the lungs of rabbitR fltrfnea piP and rats aru deacribed. Retrograde perfusiom of blooddra hrys with buffered aaline .olution cootab- In6 colla2enase was used to eolket t!e oeflr, which were then char rcterized by light microscopy, electron mictoeoopy of tldn sections ud wrfrce replicas, and by the presence of antiotesiteo.verting enzyme (ACE). The ACE was assayed with 'H-bensoyl-Phe-Ala•Pro sa We wbstrNe, and IocalireG by Indirect immunnAuorescence, using guinea p4 qdolbelial te1N incubated with rabbit .ntlbodin to 6uinca pi6 hm6 ACE followed by 6oat anti-rabbit globulins con- jutated to Auorescein. The Iechniqw described here allows the use of small animals for convenience. It can also be used os larger animala, however, and even humans from whom pulnwwary l,ndothadum may ona day be obtainable by open biopsy. Habli.tow, D. L., Whitaker, C., Hart. M. A., Ryaw, U. S., and Ryan. 1. W. AnKrkan Reritw o/ Rtrpiratory Disease 119(6):e3)•i6~, I979. Oth.r wrportr U. S. Public Health Service aed the Hanford Foundation. From the D.partment of Medicin.. University of Miami School of Medicine, Miami, Fla. AGE-RELATED CHANGES IN ELASTIC FItiERS AND ELASTIN OF LUNG Numerous physiologic studies of Ilumm lungs show decreased elasticity with aging, but the morphologic and chemical bases of these changes In both the elastic Iiwm .nd the orpnization of the elastic tiber network are not clear. The effects of age on the hrnp of .n inbred strain of mice (tiA1.t!/e) were studied (I) to determine the .Iterations in the morphometrically estab- lished total elastic Aber length (TFL) and the chemically measured elastin content in nonemphysemalous aging hmp; and (2) to correlate TFL and el.stin content with static compliance of excised lunp as a function of aging. According to the resuhs: (1) static compliance Increased with age; (2) TFL increased with lung expansion in ap- and sea+natched mice, indicating an aaial extension of elastic fibers (but in aging lungs fiaed at a distending pres- sure of I S cm 11 ,0, l FL did not change significantly in spite of an age•related increase In lung volume); and (3) both lung collagen and elastin content de- creased with age, she tatter indicating a loss of elastic Nben. The virtual absence of p.eudoelastin fihers in the lungs of aging mice, as determined by histochemical technipoes, may account for the differences in elastin content of aging human and rnmne lungs. Additional studies of the pseuduelastin eon- lent oi human and animal lungs are indicated. Ranga, V., Ki.onrrmnn, !., Ip, M. P. C., and Sorensen, ). I American Review ol Rrsoiratory D/sraa 11i(3):)69-176, 1979. OtAer.rrprtr Natlon.11m1itute of Ea.iro.mestal Health Sciences. From the Division of Pathology Researeh, Dep.rtmente of Patbolop. St. Luke's Hospital and Case Western Raerve Universily, Cleveland. EFFECT OP TOBACCO SMOKE ON THE METASOLISM OF RAT LUNG The composition and metabolic activity of rat hteti parenchyma Jter 30 days of in vivo espowrre so cigarette unoke was i.Malipled. University of Kentucky research cigarettes (brand IAI, 25 mR tar, 0.3 mR aiootisro; ..d brand 1 R 1, 30 m6 tar and 2.2 mR .iootia.; wei6ht eapte.red per cigarette) in a Wahon smoking machMe wsre used for one rnontlr ow two scheduhy: one cigarette twice daily or three eipretles hvke daihr (7 ptiQs/dprette). Oan group of aeirnals served s Intaet eootroY, while another control group was introduced Into the machine but aot exposed to Mrwk.. AR uimalr wa. wel6ht-matched at the beginning of tM eaptximed and had free aocets to food and water. At the end of th. 30 days„ Ipe weiRA1 pis was noted i. the machine control rats (2!%). th. IAlpposi0 group (I0l6 ), and th. IRI- eapoaed rata (26-10% ) tha in the intact eoatrok. Study of the eAeet of cigarette smoke on the uptake amd metabolism of sH-pahnital., a11-kudee, Ur'C-glucose and r'C-tlucoe.min. I. hmg slioa showed that .either p.ImNate uptake .or phoaplwlipW aynthesis was dke1N4 E+tposure to IAI eipr.tlse increased sCO kvds by 25% ard Mpid leoorporatioe of glucose by 30%. The IRI brand had no eRect on Rlucosm metaboliarr, but lowered prolsi" nrnth.sis by 30%. Both braaAr, horrev.r, tatreA a two-toW ixrss. In glyco- protein synthesie, which wr probably rdaled bo hi6her productio: of nwcus after exposure to amoke. H.w»osA, AI., Shechier, Y. and Hamosh, P. ArcAires o/ Ewvlrewiwrearat HedtA )1(1) :17-27, 1979. From the Department of Physiolm and fliopAya{o. Georgetown University Schools of Medicine and Deetistry, WaahinRlottr D.C. NEUTAOPHII. LYSOSOMAL ELASTASE ACTIVITY IN NORMAL SUt!)ECTS ANI) IN PATIENTS WITH CHRONIC OOSTRUCTIIVE PULMONARY DISEASE The degree of circulating posymorplwmrckar, h:ukocyte lywaornd elaalw activity was determined in asymptomatic aduUe with normal lung funtlitrok is patients with chronic obstructive lung disease (COPD) and in alphao-an8- trypain-0dlcient individuals with and without evidenee of COPD. The resulting data were analyzed for any relationship between the presence and severity of COPD nd newrophil lysosomal elntase t?onoedratqra. In addition, the eo- zyme's activity was repeatedly determined at 1 to 12 month Intervals i, a population of normal subjecls and in a group of COPD p.tienta. No diller- ences (n neutrophil lysosomal elastase activity between smokers and nonsmoken 26 27*

were noted ie either normal subjects or patients. Siknifkanlly greater degrees of enryme adivity, however, were found in patients with Pi M phenotype and COPD, suggesting that circulating dastaae activity may be involved in the mechanism that damages lung elastin and, thus, ie the pathogenesis of pul- nae.ry emphfsenu. Rodrigues:, 1. R., Sesh, 1. B., Radio. A.. Lie, 1. S., Mandl, 1., and Tr.Jwo, G. U. Anwrk.w Review of Respiratory D/arosr 119(7) :409-417, 1979. Othor w".rtr U. S. Public HeaM1 Senioe and the Stony Wold-Herbert Fund. From the Departments of Medkir and Obstetrics and Gynecololy. Columbia Univenity College of Physici.r i Surkeorrs, New York. ELASTOLYTIC ACTIVITY OF ALVEOLAR MACROPHAGES IN NORMAL DOGS AND HUMAN SUBJECTS Uneertainty remains as to the precLo kver and variability of alveolar mscrophade elutase activity aemng earoal stobjectsboth smokers sed rws- smoken. Is addition, the capacity of hunus alveolar macrophakes to grow aod divide /n vitro has never been defined. This study measures cleanse acliv- ity in freshly Iavated human and dos alveolar macrophages from normal sub- (ecu, in order to determine its magnitude ssd variability. There seemed to be no relationship between a history of smoking and cleanse activity. /n rlrro, the macrophagcs released measurable and similar levels of elastase into the culture medwm over a period of three months. The cells underwent mitosis and demonstrated phakocylosis. Synthetic sile-speci0c elastase inhibitors (chlora methylketones) btally suppressed elastaae activity. According to these dats, both canine and human alveolar macrophates from normal subjects show ape- cilk elastase activity regardless of the smoking history. This activity appears to be generated continuously by the maerophages themselves rather than in- corporated from external eouneL Green, M. R., Lin, J. S.. 8erma., L. it., Oanan, M. M., Cerrets, 1. M., Maodl, 1., and Torlwo. G. M. Jownd oJ L.Aorerory.nl Clinical 6felk4w 94(4):31l-362, 1979. Other anrprts U. S. Public Health Service and the Stony Wold-Herbert Fund. From the Departments of Medicine and ObNetrics and Gynecology. Columbia University College of Physicians A Surgeons. New York. I UNO INJURY INDUCED BY LEUKOCYTIC PROTEASFS Human polymorphonuckar neutrophilic kukocytes (PMNs) contain lar9e amounts of neutral proleases. Inslillation of one of these. elasuse, in the purJ'ied form. rnto dog lunts ro rivo prodraes degradation of elastic fibers and orher atvcolar scpral cwnponents and leads to anatomic changes similar to I those found In human pulmonary emphyepna. Cigarette smoking may 1e1er- (ere with the regulation of PMN elastae activity by alveolar antiprotesses. This is supported by the observation that the oxidizing activity of tobeooo sreoke inactivates .r-proldnne iwhibilor M drro. Low levels o( elaaolptic proleases are also secreted by snaerophalles. Cultured mouse sn.crophatia aa- posed so cigarette unoke for a short period of tMse demonstrate an hxreased rate of cleanse accretion. This enzyme is not Inhibited by .,-proteinass W hibitor or by .; macroff{ob.alin. This unusual property of wmerophage ehstase may facilitate the breakdown of elastht o.er a prolonged psriod of time is spite of very low levels of enzyme. A unified hypothesis o( Me role of cleanse in the patholenesis of puhvwn.ry emphysema is proposed whereby two diQer- ent puhways for the production of hmd injury by cipeNts amoke ara envi- sioned. One of these is mediated by PMN dastase and the other by aucrophage elasta+.. Future research should resolve which pathway ia the key determinant of lung injury in the smoker snd how it eam be blocked. J.nol. A. er ed. American Journal o/ tuAoWq 97:111-I16, 1979. ~ Other ar".rtt National Heart, LunR and Blood lartitule. From the Department of Patholop, State University of New York d Stony Brook, Stony Brook. CIGARETTE SMOKE INHALATION DECREASES a,-ANTiTRYPSIN ACTIVITY IN RAT LUNG , Aqueous extracts of cigarette snake ineqivale human ..entitrypsim b rirro, suggesting a relationship belween eiprctte smoking and pulmosry emphysema. lhe experiments reported here were intended lo determine whether cigarette smoke inhalation aho inaetiratea lung ar-antitrypsin in vivo. Results show that brief inhalation exposure (thres to sia puQs of cigarette smoke) of rats significantly decreases the cleanse inhibitory capacity (EIC) per milligram of .,-anlitrypsin In lung lavage fluid. This loss in EIC could be reversed by a reducing .teat, suggesting that osidation of the Inhibitor in the lung by some cigarette smoke component mi6ht be the responsible mechanism. That o:one-tolerant animab .re not a0eeled by cigarette smoke supports this hypothesis. Human serum obtained inunediately after smoking also shows a decrease in FIC. It may be that transient imbalance between lung proteasee and their inhibitors caused by smoking injures the alveolar walls and that repeated imbalsnces of this type slowly deform the alveoli, eventually leading to disease in wn.e chronic smokers. JanoO. A. er d. Science 206:1111-1114,1979. Other e.r'prts U. S. Public Health Service and the [kpartment of F.nerar. From 1he Ikpartment of Patholonr, State University of New York at Stony Brook. Stony ttrook; and the Medical Depsrtment, Brookhaven National tabo- ratory, Upton. N. Y. 28 29

STUDIES ON ELASTASE SECRETION BY CULTURED MURINE MACROPHAGES !n the shdies reported here, mouse peritoe,eal exudative macrophages (PEM), cultured ie the presence of aqueoru dgarette smoke e:tracts, increased their production of elastase in a way that was dose and time dependent and could be inhibited by cycloheaimide. On the other hand, untreatrd mouse alveolar macrophsges secreted elastase at a rase equivalent to that shown by smoke-treated PEM and could not be further stimulated by ,hort-Ierm exposure to aqueous smoke extracts. Even psaler baseline elaslase .ecre/ion vras sbown by exudative alveolar mscrophallas oblained from mice previously -raccinated with complete Freund's adjuvaet. Wben the susceptibility of macrophage elas- tase 1o inhibition by endogenoau aMiproteases was tesled, h was seen that macrophage elastne was only poorly inhibited by a,Pi (human) : though it was definitely inhibited by both PiMM and PIZ sera. Is other work, the ef- lects of purified a,M on the eladolytic activity of mare macrophnle condi- tioned medium were examined. The rewib clearly denwnstrale 11at under , conditions suflicient to inhibit porcine Paecreatie elWase, the m.erophaje enzyme was not Inhibited by a,M frorw either hunun or mouse ma:rophaRes. Although these results do not explain the Iwhibition of m.crophage clauase by PrZ serum, they do show that macrophase elsuse ia tewre resist,mt to 04 major endogenous inhibilors than are other .eulyd protenes of lAalocytie cells. This suggests /hat, in dgarette smoten, 1be macrophage en:;ime could play an important role in lung injury. Whi1e, R., White, 1. and /ano#, A. INSERM t4:1S9-16S, 1979. Other a.rr.rrr National Heart. Lung and Blood Institute. From the Depertment of Patholop, Sute University of New York at Stony Brook. Stony Brook. ALBUMIN MICROSPHERES AS CARRIER OF AN INHIBITOR OF LEUKOCYTE ELASTASE: POTENTIAL THERAPEUTIC AGENT FOR EMPHYSEMA Succinoyt-Ala-Ala-Pro-Va1CH,C1 has been showa to be one of the more potent inhibilors of human kukoc7te elatae, an enzyme that has been im- plicated i. king tissue injury leading lo emphysema. While this inhibitor seeau to cAer promise as a Iherapewie apn1, (ts eAecdvenea would probably be greatly enhanced il it could be targeted directly to tM /unRs. In this paper, the sequence of reactions involved i. the covalent .ttachmtnt of the inhibitor to human albumin mkrotpheres with extended side ehains Is described In detail. The insertion of side arnw of various lengths showed that ma.imum enzyme Inhibition was obtained when the paar arm was al least 24.7 A in length App.o.imetety, 10 mokcules of the inhibitor could be attached to each mulecule of ./bum.n, wah derrvalured rnierospheres were cap.bk of InhMb!ting .ppruamatcly one mok of els.r.ae per mok of .Ibumin, which n comparable w rhe inhiblory .crrvrry uf ., antitryprrn Etperoments in vivo in which rats I were in~ected inlravenoudy with radiolabeled mkroipheres to which 16e I.- bibitor h.d been attached showed a rapid and eaclusive uptake by the luop. About 40-50% of the injected microspheres subsequently remained in 1ba lungs with a hdf-life of approximately 17 days. Although these studies wera specifkally designed to asseas the feasibility of altRhinR an elastue Inhibitor to a carrier that could be targeted so the lunp, the broeder implicalions of this approach deserve careful consideration. Martodam, R. R.. Twunasi, D. Y., Gcncr, /. E., Powen, J. C.. Nisbino, N., and Krejcaret, G. • Proceedings o/ the National Academy of Sckncer o/ the United St.as o/ Amerka 76(S):2128-21I2, 1979. Other at pr.rt r NationallnuNutes of Health. From the Department of 6iochewriqry. College of Biological Scienoes. Unt- versily of Minnesoia, SI. Paul; Department of Cheraislry, (korga Institute of Technolop. Atlanta; and the Nuclear Medical LaborNory, 3M Company. St. Paul. I QUANTITATIVE CHARACTERISTICS OF THE FEYRTER CELLS At ID NEUROEPriHEL1AL BODIES OF THE FETAL RABBIT LUNG IN NORMOXIA AND SHORT TERM CHRONIC HYPOXIA This report attempts to estimate the number of single Ferrter (APUD) cells ud neuroepitheH.l bodies (NEes), or grouped Feyrter eelly is the lungs of 26-, 27.5- and 29dars feluses dueMg aotrnosia and short-term chronic hypoxia. The possibility that these cell numbers vary in fetuses from short- term chonically hypoxic mothers was also i.vestisaKd. The nast sisnilkan/ variation was found between the 26- and 29-dar fe/use., the marked decline in the apparent number of lhese «Ms suggesting a response to increased bypoa- ernia. The lunp of fetuses from shor/-1erm, ehronicaly hypoxic nathen, fur- thermore, contained fewer of lhess eells thaw those of feluses from nornrozie mothers. These observations apee with the resuUs of previous studks in short- lerm. chronkally hypoaie neonN#1 rabbils, and suggest that induclion of br- poaia in the mother increares hypo.enua in the fetus, thus stimulating tbe secretory activity of Feyrter cells ud NEM. This in turn eupporu the hypotb- esis that the Feyrter cells and the NESs may play a role in the mechanism of hypo.emic pulmonary vasoconsltiction in Ihe fetus. In addition, the oMerva- tinm on letuses of normoak rabbib provide base line data on the chroeoio{kal imporlance of these cells. Hernandet-Va.wret, A., WIN, I. A.,and Quay, W. d. Celt and T/rrrc ['uhrre 159:179-1 t6, 1972. Oflr.r .u'rortr University of Wisconsin College of Agricultural and U/e Sciences. 1'rom the Dep.rrment of Velerinary Science and Nnuoerwlocrine Section. War- man Center on Menlal Retardation and Human laevcloprnent. University of Wiseomin. Madieon. 30 31

HUMIDITY AND THE ANESi71ET1ZED PATIENT This study attempts b corrslaN the eybmorpbdogic chan=es caused by a)ack of moisture Ia anesthetic pw with the incidence and severity of poN- opcrative complications. A point soocin8 system wr tned to aaseas theae changes in 202 patients who breathed either dry or humidified psa for a period of 223 t 71 mia. Results abow that pouoperative pulmonary complka. tiorr increase .bng with damage 1o Ib cBiated epitbelitun. 71w incidence of theas cornplicatbns was reduced, htwe.er, a Ibo humidity of ehe administered gases rose from 0 to 32.5 me H,O/L Ro1h btwt low aed the incidence of poM- operalive shivering wer. aho higher r 1V moisture conlenl of the anesthetic dropped. It appears lhat the u.s of dry a.albetk pnes for operations laaing longer thaa one bour may be h.nafui. The Weal level of humidification aoema 1o be that which returns to tha ptket tM e:act amount of watcr lost during eapiration (.u per saturation humidity M 72'C). Ttiis has three arhanlaAes: it (1) decreaea damage to the tracheal nwoaea; (2) lowers the pottoperative eomplicaliona rate; ud (3) vlrtu.lly e0rwi..lea poatanesdretk shiverinA (thia ia not desirabk, howevrr, in the presesoe e/ tubsisaat hyperpyrsxia, whea beat loss should be increased by all possible eeaes). Some improvemeatb In the design of anesthesia appuatus that would 1.ke the control of humidity output into account are suggested. CAalon, !. et d. Anrit/ierldopy 30:193-195, 1979. From the Department of Anatbealology, New York University Medical Cen- ter, New York. . 111. He.rt and Clrer/.tiow EFFECT OP DILTIAZEM. A CALCIUM ANTAOONIST, ON MYOCARDIAL ISCHEMIA Diltitaem hydroehloride. a potent eakiwn aotaBonist, was a+.ses+cd for its elRcacy ie reducing the effects of myocardW Ychemia. Melabol c/wctioe wilhie both behemk auid aoalachew+k titrue was analyzed a.d compared iN two groups of dop: Orvup I was sacriboed atkr 60 minuks cd regional bchemia without receiving tay of the dru8; Oroup 11 wn given diltiaus after t0 mi.utes of iachemia a.d sacriboed 30 ati.utes later. DiNiveat ditniM- Wred the injurious effects of i.cbetnia In several ways. it (1) reduced the de- ereaw is adenosina-S'-Iriphophate by baH; (2) decreased the Inaibition of anaerobic Alycolysb; (3) lowered 1inue lactic and free Iatty acids kvela; and (4) Improved the eontractitity of Alyoerinated heart muscle fiben. MNo- chondrial (unction, however, was wt dleeled. Mitodwndrial oaygen uptake, respiratory control Red eakium ion bindio8 were equatly reduced in both groups. It Ia neverthekas clear that even if iu benefkid action does not ealend to all the pathways of myocardial t»etaboliarn, dihia=em bas the capacity to minimize the adverse effects of acute ischemia. Wnshasr, R, Ashikawa, K and siny, R. J. The AnKrkan lorrnd o/ Cardioloty 47:1177-1143, 1979. 0t6er au'porrt Tbe Hoover Fouadatioa From the Huntington Institute of Applied Medical Research aod the Califor.ia Institute of Technology. Pasadeoa; and the University of Southern Califor>tla, Laa Angeles. INHIBITION OF CHOLESTEROL UPTAKE BY THE ARTERIAL WALL IN THE INTACT ANIMAL 1t has previously been demoastr.led that 7-ketocbolaleroi, a t.oi-physb- bgic cholesterol aaabg, Inhibits the /n r/tro uptake of cholesterol by perfused human tad animal arteries. This report pre.eets evidence indicating Ihal 7- ketocholesterol effectively inhibits cholesterol uptake by the arterial wall In vivo u well. Isolopaa blood preincubaled with the sterol was infused Into in/act rabbila along with some of the anLwab' own plasma codainhg radio- active cholesterol used as a lraoer to measure arterial uptake during two successive Infusions. Thu., each rabbit served in i1s own eo.tral. le the presence of 7-ketoclak.lerol, the mean cholesterol uptake by 1he carotid and femoral arteriet was 11 t 3 amoln/ R tiswe an oppored to 3) t 3 enroks/R amue without it. Tbe tnean blood 7-kelocholalarol oonce.tratiaa ranAed from 34 to 87 aepks/ml. Preliminary In wbro esperitneats abowed that preiecu- bation of plasma -with particulate 7-kelochokslerol also inhibited cholesterol uptake by perfuaed pig eoroo.ry arteries eves whes /his particular fraction was removed before perfu.ioa. Tha 7-kdoelakslerd bindo to the plasma lipa proteins and bas an evee hiAhec aAl.ity, for red blood cells. dlnp. R. I.. Sarma,l. S. M. n.d Chn, 5.1. I Arrery 3(/) :14-28, 1979. ~ ~ OtRer wrrertr The Hoover Foundation. From the Huntington Institute of Applied Medical Research and Huntington Memorial Ho.pital, Pasadena; the Division of Chemistry and Chemical Er Bineering, California Institute of Techaology, Pasadena; ..d tAe University of So ybern California, Los Angeles. SERUM CHOLESTEROL ESTERIFICATION IN HYPERTHYROIDISM AND HYPOTHYROIDISM Changes In the level ted compoailios of plasma lipoproteir h.ve bee noted in cases of thyroid dysfunction. This study atteppts to determita tha effects of altered lipoproteiw metabolism found iM thyroid disease on kcilhYt:- eholederd acyllransferase (I.CAT) activity. T/r rate of serum ehokNeroi esterifkalion was measured i. 20 4scallhy bumaw wbjeels withou/ a fanJly history of lipid or thyroid disorden and used as caMrd data. When thesa were compared to values obtained in 17 hyperthyroid and 10 hypothyroid h- dividuals, there were no signi/kant diRerenbes in the cholesterol esteriAcaliow rates, but highly signifkant (p<0.001) differences were found in the fractional tales. 7hese were higher than normal in the hyperthyroid group and lower than .ormal in thc hypothyroids. TAerapy did not seem to have any consistent eRects on the cholesterol eslerification rate. Thia either increased or decreased 32 33 •

I as patients became cuthyroid, reprdkss of their original status (i.e., hypo- or hyperthyroid). The fractional esterifkatioe rates, however, did show a clear trend during therapy, always increasing or decreasing in hypothyroid and hypenhyroid patients, respectively. Lacko. A. O., Muks, A. D., Ruteeber6. H. L„ and So/o0, L. A. Hormone ewd hlet.bolk ResercA 10:117-131, 1976. OIAa ur'prtt Administration o. Ati.B. From the Department of Mediciee, Tem#l. U.iversity Health Scknoe. Ceeter, Philadelphia; and Tesu College of Osuopahie Medkiee, North Te:as State Uaivenity, Deebe. INTEGRATED CAROTID CHEMORECePTOR AND PULMONARY INFLATION REFLEX CONTROL OF PERIPHERAL VASOACTIVITY IN CONSCIOUS DOGS With 14 mongrel dogs in the corrcious s1.1e r experimental subjects, the Iateraction of carotid chenwreceptor a.d pulmonary laeatioa reAe= eootrol of vascular mpn.nes is the aseaeateric, resul, and iliac beds was examined by eomp.ring respooses to chemoreceptor stimulatio. (ielracarotid ia' ioo o( nicotine or cyanide) during spontaneous and controlled respiration. ~s were dso studied in the eoescioru state after (1) bets receptor blockade with pro- prarwlol, (2) cholioergic blockade with atropiee. (3) bistaminergic biockade with tripekmamiee, and (4) alpha receptor bbckada with pbeetolamise. Also, to e:areine the effects of c'henareceptor atinulatioo in the absence of changes in ven/ilnios and secondary refk>< effects of pulmonary infiatioe, 11 dogs were sludied during succinykholine infuiion with controlled ventilation. Results showed that rHrKarotid administration of aieotiee or cyanide in the intact conscious dog elicited a biphasie cardiovascular rsspoese. The Mt phase was charaderited by bradycardia, as iecre,ae in re jaaal resisla.on, and ae in- erease in depth and rate of respiration. The seeord phase followed the rn- prralory changes aad was characterized by tacbyeardia and a decrease in regional resistaaoes. Alpha-blockade with pheBldami.a nearly abolished the early vasocosstrictios and 1.1er vasodilalio.. When tha ehanoreeeptor-iodured increw in respiration was prevented. or after bilal.ral va6olomy. there vru significantly more vasocomtriction in all three beds eed no later vasodeatios. lUere(ore, io the coescious Baimd, carotid cheworeceplor stimutuio. resups ie a bipbasic vascular respos.e, while the pulmonary in0ation re/kses are sufM ciestly powerful to atteouate the initial v.soooastricbr resporne and to reverse the coeulridion to a later period of ieteese vasodilatioe. Rutherford. 1. D. and Yuwrr, S. F. Circulation ReuarcA Il ( 2):20Q201. 197t. Other arrprt 10. S. Public Health Service. From the Department of Medicine. Harvard Medical School and Peter B:et Brigham l/ospNal; the Ikpartment of t:ardioloty, Chitdres's Hospital Medi:al ('enter, Boston; and New Nngland Regeonal Primate Research C'enter, Southboro, Mars. 14 CONTROI. OF THE MYOCARDIAL CONTRACTILE STATE BY CAROTID CHEMO- AND BARORECEPTOR AND PULMONARY INFLATION REFLEXES IN CONSCIOUS DOGS This study examines the extent to which the carotid c6ernoteoeplor reas= re6ulates myocardial cootractiNty in conscious doa aad, Nlempta b Ideaihr the eateat to which these effects would be modiAed by Ibe ooeooedtaM b- ' creaae in respiration aod ~tinwlalio. o( pulmonary idlatioa aRere.b. Catheten were Implanted in the left atrium and eorta of 19 dogs, and ths eaperiwteefla were conducted three weeks to two monthe postoperNively, whew ebe do6s were again vigorous and healthy. Cber.oreoep/or atimulation wae aecooplia6ed by lejectioe of nicotine (0.2 pg/kg) or sodium qaride (2.0 r3/kt) irto the (.lracarotid catheter. Theaa two qenla used for Miewlatie6 1he carotid esemo- roeepbr relks isduced similar e/fena e. heart rNe, LV ..d arterial preaauna and dr/fr. B.roreceptor un{oadieR was .ccornpli.hed by ieBati.6 the hydrau- lic occhrders implanted on thm eonreos carotid arterirs. Dogs wese aYo adsdied in the co.scious state after: (a) cloli.er& blockade with atropiee; (b) beta adrenergic receptor blockade with proprawolol; and (c) eorobined eholimrgie and beta adrenerpc blockades. The adequacy of beta receptor bbekade wr tested with i.oprotoreool and that of cholieeritie blockade wr te.ted with a¢tytcfaiine. In .urnmary, rauNs showed that the carotid ckKmoreceptor re- Bez in conscious dop, when ainwlated, elicits a si6nibcaet increre I. ruyoe.rdial contractility mediated throu6h beta adre.n6ic mechaai.ms. This increase in contractility is attenuated by secondarY stimulation of pulmonary inflalion reflexes. Aaordia6ly, wpep the hyperventilation that occurs with carotid chemoreceplor stimulation is prevented, the isotropic respnre Is significantly 6reater. Fisally, (or an equipreaaor sespore, the caro/id cbnsro- reeeptor reAea elicited a greater increw in contractility tha* did the carotid b.roreceplor reflex. Yaner. S. F. and Ruthertord, l. D. lownl o/ Cpstr.f lnreitl`arlon 61(6):1593-1601, 1978. Oth.r arrprir U. S. Public Hedt6 Servies. Frwa the DepartmeN of Medieiee, Harvard Medical School and Peter B.M Bri6ham Hospital; the DeparuaerN of Cardioloq, Childrenl. Hospital Medical Center, Boston; and New England Regional Primate Research Ceeter, South- boro, Mw. THE RELATIONSHIP OF REGIONAL CORONARY BLOOD FIAW TO MITOCIIONDRIAL FUNCTION DURINO REPERFUSION OP THE 1S('l1EMIC MYOCARDIUM , The purpose of this inveNiptioa was to relate changes In reRioaaa ooro.ary blood flow to the type and degree of biochemical disturbances that occurred during oc~haion of branches of the left anterior descending coronary anery and during reperfusion of the occluded area. To make these nwasuremenls, two groups of dogs were estsblished: group 1. moderate ischemi• before retlow, and group 11, severe ischemia prior to reAow. Using labeled microsphores, regional coronary blood flow was determined before liption, alter 60 mia. of 35 I

1-h , . . ischemia, and a(ter 15 min. of refbw. Hearts made ischemk for 60 min. hut not reperfused served as controls. aroups I and 11 were distinguished by several fealures. Oroup 11 showed a marked exacerbation of biochemical damage on reperfusias of the ischemic region (reduced levels of ATP, im- pairment of milochoodrial oxygen consumption and mitochrondrial calcium binding). Thia was accompanied by dgnificant aubendocardial hyperemia. Reperfusioo in group 1, on the other band, partially reversed these changes. Milochondrial calcium uptake aad ozidadve pbosphorylatioe (ADP/O ratio) were nol aAecled in any group. Tbeae data illustrate that the degree of bio- chemical damage following reperfu.iost of Ihe iachcmic myocardium is de- Iermined by the degree of isdsemia, sid suggest that interference with ATP productioe by the mitochroodria is aot responsible for the damage. Weiahaar, R., Tachurtscheotbakr, O. V., A.hiRawa, K., and Sinr. R. l. Cu.Jlofory 64 : )10. )64, 1979. Other erpport: The Hoover Fouodalioa From the Hualinpon Institute of Applied Medical Research aod Huntington Memorial Hoapilrl, Pasadena; and the University of Southern California, Los Angeles. TIIE EFFECT OF ALCOHOL ON TIIE HEART lo this very thorough review, the effects of skobol on the beari are examined In several different ways. The ftve maio sections of this paper are devoted to: (1) Historical Considerations; (2) Clinical Features; (3) The Acute Effect of Alcohol on Coronary Flow and Myocardial Performance; (4) The Acute Effect of Alcohol on Cardiac Melabolism, and (5) Correlation of Function and Structure. From a clinical standpoint, alcoholic cardio- myopathy cannot be differentiated from other myocardial diseases unless a history of akoholism b documented. The dinkal course of the disease depends on the duration of iaeAriety, aod abstiaenoe /rom ethaool is the most imponaot therapeutic consideration. lienwdyoamk studia show that the changes in- duced in animala aad men by prdooged perioda of ethanol administration do not differ from those observed is other types of eardioreyopathy. However, akohol allecta other ordaro, primarily Ibe li.er, and the bemodyoamic changes depend on the absence or presence of hepatic disease. The changes Induced by ethanol oa cardiac metabolism and fuaetion result tran its toxic action on the myocardial cell. However, all Ihe ooted changes ioduced by this agent an iodiuin6uishabk from other eardiomyopathia. In man, leakage of enzymes as well as of potassium and phosphate from the hean is observed. Ethanol also causes diminution of respiratory function of mitoehotdria and reduced activity of iruramitochondrial isocilraN dehydrojeoase. 11 dimirinhes calcium uptake and binding by the aarcoplasmk reliculum. 11 is also likely that i1 damages the contractile proteins. Most Irnportantly, a close correlation exists between function and structural ehanpes induced by ethanol. OveraN, much evidence exists that alcohol aQects a8 aubcdlular Mructurn, rewlting in their bio- chemical and biophysical malfunction. Bint. R/. and 1 illmanns, H. 36 I In: Lieber, C. S. (ed.): MdaWk Alpects o/ Akolioltsm, Laecaater, England: MTP Press Limited, 1977, dsapt. 4, pp. 117-134. Other support: U. S. Public Headh Service, Tbe Hoover Fouodatioo, and the Norris Fouodation. From the Huotingtoo Memorial Hoepild, Huntington Inslaule of Applied Medical Research and the Califoraia lns1ilule of TocbrwlOpy. Paudena; ad the University of Soulbero Cdiforoia, Los Aagek.. THE EFFECT OF ALCOHOL ON ACTIVE AND PASSIVE STIFFNESS, AND ON ISOMETRIC CONTRACTIONS OF OLYCERINATED HEART MUSCLE IN RATS Accordin4 to the eaperimew reported hen. the beuta of rata exposed b alcohol show several ooncurreal changes: shorteaisid velocity at zero bad (V..), total torce (P,) aod maaisaf rate of Ietrioa developmesM (dp/d1..) were all reduced. Tbe lirae oeeded to reach peak 1e..iow (1.) remained tbe same. As was found with fresh papitl.ry nMnele, the el.stkity module of active plyceriaated mu.de iacrea.ed lo proportioa to luad. 'ibere was rd- t.ilkmt elevation also in the t1iQ.esa of the seria elastic eksmeM. Ilo.re.er, no significant difference in res/i.d statu pessive tNiAaiesa waa observed betweeo rata exposed to alcohol asd the .os><paed controls. Other yet unpublfsYed results also indicate aorm dsnya io dn neliw aliAneas of infarcted beart mmck. The «lalio.ship ot aM Iheac data to the developmea of snyocudial failure rem.ros to be ioreslipMed. Maruyama. Y., etnr, R. /., Sarns., l. S. M. and Weishaar. R. lepestze Htart lorrwa/ 19(4):S1)-321, 19711. Other arpperts U. S. Public Health Servia` The Hoover Foundatio., and The Wright Foundation. From the Iluntingtoo Institute of Applied Medieal Research and HuatiWoo Memorial Ilospilal, Pasadeaa, Cal.; ud the University of Southern Califorda, Los Angeles. EFFECT OF ALCOHOL ON THE CONTRACfILE AND ELASTIC PROPERTIES OF GLYCERINATED HEART MUSCLE FROM RATS The effect of chronic alcohol coroumptiow on (1) the contractility and (2) the active and passive ali0nesa of the rat hearl muscle was examined because i1 had been fell thal changes io these p.ramelen might herald Ihe development of alcoholic cardiornyopathy io eaperimenld animals. In the lesu reported here, passive kngth•temion relationship in testing uale, iaoroetric contraction and isotonic quick «kase, and sti/fnesa of series elastic ekmenl (ataive stiRness) were measured in glyeerinaled heart muscle 1lbera obtained from 13 Sprague•Dawky rals maintained on alcohol tor an average period of five weeks and from 12 correspondind controls. Results show that is the hearts of rats exposed to akohd, the series elastic, as well as contracuk, elements are impaired. The rate of increase of active stdlnesa with tension 37