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I 1 3. _f, li IJ: ;' 7. Gir* a 6rtef Statement of your Workinp Hypothesis: tao. 626 - • 'cF. .9~ U.S.A. Activated: 7/1/66 CF. #3l+4 - 1962-164 COtdPARE: 3955 - 1957 #i6o - 1957 #213 -1959 - 1961 #301 -1961 - 1962 •r deiined vithout

t`d) A d ( d' B: : con PPen e : F' 9 P6Ys+ml Focilties Available (Where Other Shan Administering Organization Indiwte GeograP hicn! location ) ~ ew York University Researeh Laboratories, Goldwater Memorial Hospital,. Welfare Islanrl, N.Y. ... --Vascular•Research, Laboratory, New York University Medical Qenter, 550 First Ave., N.Y. l."b~c.-..:._a.::.....' - • , .. . . .- ;.~ _ ~ "L~'irY-^,~. •.a. ~~ ~:'~ ~ . •r ~'. Detoib of Ex erimenlal Des~ ( and Procedures ~P° Attach rate Po ts ~"' `~ r. . .• ~,v {N. v n: The method to be used in this study is di°_ferential venous occlusion Ple thYsmoBraPhY. ar.^4:.s: . ' .. ¢ ~, Plethysmographlc measurements of the foot and^ca.lf are taken, those of the foot being -Far_iepresentative of skin blood flow while measurementa•of the calt are representative of e cle blood flow. The calf and foot are placed in the appropriate plethysmographic L"f'* ; ~*l~nusucite chambers. The chamEers are then made airtight with vaseline and foam'rubber. Volume chenges of the ldmb are caloulated from the effect of a kaowa volume, namely ;; { 5 nl air ia~ected into the chamber, has oa the deflectioa of the recorder. On the =`°= =~recording a time-scale permits measuret>~at of tlie distaace equivalent to 10 seconds ti . fi~;on the base line. At this point a perpendicuLar is erected. Hlood Yiow in ml/mfnute n''in 100 cc of tissue is calculated from the Pormula: _ ., . . ~9~,. .:.. . ... .. . . .. _- _ .. .- . _ .. . • _. k€:= 600 x. L_ Blood Flow c t. °~ tt ~y K z V r<ml~ per minute per 100 mll of tissuej: the perpendicular rise of the slope in >ffi, during 10 seconds. K is the call- ; bratioa constant of the recording apparatus in >an deflection per ml of change in ~alume. V is the volume of the enclosed ca1P or foot in ml which is deterratned by ~ iNi: `. ,.r- ~ the water displacement overflnw.method. ;. • wyZ: Y: ,, ._~- .,, ..n. . . . _ .. . . ,. .. .. .... ... . ' ' _.. ~. 11. biopraphical sketches of all principal and professional personnel (append) K t' t Appended D !' ., . .. 12 L9st of publications: (Five most recent as pertinent) (append) Appended 0 ® T `_

R: REDACTED MATERIAL . Estimated Fulu re Requirements: , , vr...: Salaries Consumable Suppl. Other Expenses Permanent Equip. Overhead Total Y.ar 2 _ Year3 -. : Siqnature ' <<- 7 / ~- ~'%lSl It is understood that the applicant and instilutional officers le applying for a grant liare read and found;acceptable tbe•Council's "Statement•af Policy Containing Conditions and Terms Under Which,Preject Grants Are Made:' otr.d-.r.,a.6 688-3500 Ext 50T % r , Telephone Signature' .`, ~ twinns o(f~.. of iM t.»~~wio. ) ,Telephone l

THE COUNCIL FOR TOBACCO RESEARCH - U.S.A. Application For Research Grant • • . Give a Brief Statement of your Working Hypothesis: the effects of cigarette smoking on the cardio-vascular system show• some essential similarities to the pharmacologic effects of nicotine. have the same effects on~various physiologic parameters. There is like- wise no definite proof that these effects aree dlze to nicotine. However, There is no proof that cigarette smoking and tobacco smoking in general The pharmacologic action of nicotine consists.of a primary transient stimulation and secondary more persistent depression of all sympathetic and parasympathetic ganglia. This includ'es the adrenal medulla and epinephrine is thereby discharged. Nicotine and tobacco smoking have also been shown to exert an antidiuretic action This effect is thought to be the result of stimulation and of the supraoptical-hypophyseal• system iaith the subsequent release of posterior pituitary anti-diuretic hormones. Nicotine also markedly stimulates the central nervous system which is particularly evident for the respiratory and vasomotor centres of the medazlla. Due to the multiple sites of action one may encounter initially a slowing of the heart rate due to,stiYmulation of the central vagal nuclei and cardiac.vagal ganglia. Later owing to the stimulation of sympathetic ganglia, and the central vasomotor centre, tachycardia: and a peripheral vasoconstriction ma.y become prominent. may dil"a.te. .After the stage of sympathetic ganglionic stimulation is eucceeded by paralysis, smaller vessels of the periphery, especially those of the skin, These responses shbuld be studied to ascertain-the presence or absence of an increased catecholamine activity in the systemic blood vessels of patients with hypertension and'the presence or absence of a basic abnormality in catecholamine metabolism in primary hypertension. Such findings in untreated patients with primary hypertension should be compared to findings in patients•iireated with various drugs to lower blood pressure. Also the effect of cigarettee smoking on the treatment of hypertension with diuretics should be studied. 4r

TFID+:COUNCIG.FOR TOBACCO RESEARCH - U.S.A. Application For Research Grant :Dr. Walter Redisch `'New York University School of Medicine New York University Research Service ' 8. Details of Experimental Design and Procedures: (cont'd) When measuring blood flow through the calf (i.e. muscle vascular bed) two pressure cuffs are applied to the extremity to be measured. The distal tocclusion) cuff is inflated to 270 mm Hg, the one proximl to the plastic case (collecting cia•ff )• to the individual'sc diastolic blood pressure minus 10, mm Hg. When measuring blood flow to the foot (i.e skin vascular bed), only the collecting cuff is used which is inflated to the individU•al's diastolic blood pressure minus 10 mm Hg. Following sudden• occlusion, the linear portion of the rising slope of the recorded curve is used to calculate the rate of flow according to the formula mentioned above. All experiments of course will be d'one in a constant temperature laboratory, .t at temperatures of 20 and 28°C . Humidity will be held constanti at 50- In order to avoid environmental influences, patients izb basal state will be brought to the constant temperature laboratory where they will rest on a bed while quasi-continuously the skin temperature on both big toes and the .right middle finger are recorded using.a six ehannel Speedomax. A patient is considered to be adjusted to-the environment of the room when the skin temperature of his toes and fingers has come down to constant room~ temper- ature and stayed there for thirty minutes. In,patients whose skin temperature does not come down•to room temperature despite prolonged exposure, maintenance of a constant skin temperature of toes and fingers for 30 minutes is con- sidered.to represent adaptation. For smoking, our standard proceduxe will be used, subjects will be instructed and supervised to smoke at the rate of one inhalation every thirty seconds for six minutes (total of twelve inhalations). • •

THE COUNCIL, FOR TOBACCO RESEARCH - U.S.A. Application For Research Grant r. Walter'Redisch New York Univers3,ty School of Medicine .;.New York University Research Service 12. Publications Fontana, V.J., Reddsch, W, Nemir, R.,. Smith, M.K., DeCrinis, K. and 'Sulzberger, M6B. J. of Allergy, 30: 241, 1959. Studies.in Tbbacco Hypersensitivity. Tobacco;Hypersensitivity: Peripheral Circulatory Implications. Walter Redisch, M.D. Presented at the New York Acader{y of Sciences,, March 25, 1960. Annals, N.Y. Acad. of Sciences go,: Art._ 1, 142-l44, Sept. 27, 1960. -Vascular Responses. to Smoking Tobacco Compared with Responses to Skin Testing of Tobacco Extracts. DeCrinis, K., Redischy W., Fontana, V., Lewis, A., Sulzberger, M.B. and Steele, J.M. Annals Int. Med. 52: No. 5, 1960. Charles C. Thomas, Publisher, Springfield, Illinois, pp. 352, 1962. Studies on Effects of Catecholamines Upon Ektremity. Blood Flow in Man. Redisch, W. Metabolismus Parietis Vasorum!- Praha Diebus - 4- 9 September 1961. Evaluation of Vascular Responses to Cigarette Smoking. Redischy W., Messina,. E.J., Terry, E.N., Rouen, L.R. and Steele, J.M6 Submitted for publication, 1967, Angiology. (Accepted 7/27/67) A Manifestation of Diabetic Microangiopathy in Nailfold Capillaries. Terry, E.N., Messina, E.J., Schwartz, M.S., Redisch, W. and Steele, J.M~ Diabetes, in press. Tobacco Allergy and Vascular Responses-. Redisch, W. Reprinted from BOOK - TOBACCO AND HF.I4LTH, James and Rosenthal, et al.. Blood Flow- Measurements in Response to Bamethane Sulfate in Man. 01 Terry, E.N., Messina, E.J., Redisch, V. and Steele, J.M. w Angiology 18: 161-173, March 1.96,. C.11 EP ?3

R: REDACTED MATERIAL CURRIv'ULUM VITAE • -:.Marital Status: . ' Former Appointments: Present Appointments: Walter Redisch, M.D., F:A.C.P., P.R.S.A . ~ Demonstrator, Dept. of Physiol., German University of Prague Fellowship, Heart Station,, Vier.na University Fellowship, Dept. of Internal Medicine, Franz 1921-33 1927 Joseph's Hospital, Vienna 1929 Fellowship, Dept. of Internal Medicine, University of Tuebingen, Tubingen, Germany 1924 University iss't., Dept. of Cen._and E:~. Path. and Clin:. Propedeutics, GerLlan Uriiversity Med. School of Prague and•Univ. Hospital Associate Professor of Clinical Medicine, New York University School of Medicine, New York, t~TY Research Associate, New York University Research Service, Goldwater Memorial Hospital, New York, NY (Director, Dr. J. Murray Steele) Visiting Physician, New York University Medical . Research Division, Goldwater Memorial Hospital, New York, NY : Associate Visiting Physician, . New• York, NY ., Bellevue Hospital, 1923-32 Associate Attending Physician, University Hospital, New Yor::, NY Physician-in-charge, Vascular Section, New York University Cardiovascular Clirtic; Bellevue Hospital. Physician-in-charge, Medical-Surgical Vascular Group; New York University Medical Center (Surgeon-in-charge, Dr. Roy Clauss)• Member, Advisory Board', Council on,Circulation, A.H.r.. A C 0 Consultant, Vascular Disease, St. Michael's Hospital, Newar::, New Jersey. 0) ~ ~

R: REDACTED MATERIAL - CurricUuiu Vitae W~Llter Redisch, M.I}. / -2- Participe.ted in a project for the United States Navy of the Office of Scientific Research and Development under the directicn of Dr. Steele Major, USA Medical Corps 1°irst.t on- New Guinea and then,Chief of Medical Service, Regional. Hospital, Ca:ap Shelby., Mississippi ~ .During 37 months of imr service on official leave of absence frozi the Universit f. ACTED ACTED l i 1943-46.

PRESENT APPOIN2MENTS : MD!BER OF: R: REDACTED MATERIAL CURRl_'.ULUM VI'rAE Erwin N. Terry, M.D. L R- Vienna, Austxia Tel-Aviv High-Schooi of Cotmnerce; Palestine 1940 No. 7 Formation College - 1945-46 Medical Faculty of the University of the Saar 1951-56 Major, British Army and Israel Defense Forces 1941-46 Moniteur, University of Saar, Department of Psychiatry -1954-56 • Civilian Contract Physician, P.A.C. Hospital,, U.S. Air Force in Germany 1956-61 Associate Medical Director, C.H. Boehringer Sohn, Ingelheim/Rhein, Germany .1961.-63• Medical Director, Pharma Research Canad;a;, Ltd., Pointe Clair, Qitebec 1963- - Research Fellow, New York University Research Service, Goldwater Memorial Hospital, Welfare Island, NY, NY 1964- ACTED PMACOTED1 , • !

Comprehensive Report : Walter Redisch, H.D. - . • , , . Go].dwater Memorial Hospital New York University Research Service ;'Research Associate . ;Associate Professor of Clinical Medicine, New York University School of Medicine. BLOOD FLOW STUDIES ]N HYPERTIlNSIVE SMOKERS ,.,,•.,:, . ,:: •.,, .:. `;This laboratory has studied vascular responses to cigarette smoking in•man sInce Z955• There have been 4 phases of the investigation so far. 1955 - 1959 In cooperation with Drs. Ma.rion Sulzberger and'Vincent Fontana it, was first ascertained that in healthy volunteers the percentage of subjects with strongly tobacco• extract had:, no decrease in peripheral blood flow• in response to smoking•. : on significant correlation,: 90%• of those who did not react to skin testing with ;~extremity measured by plethysmography were then ascertained in 80 healthy subjects and correlated to other hemodynamic parameters as well as to the results of testing- ,:for skin sensitivity to tobacco. extracts. Comparison with• skin, testing revealed ,, -` to cigarette smoking. The effects of cigarette smoking•on blood flow in the lower the percentage of subjects who showed a significant•decrease in blood flow response positive reactions to skin testing with tobacco extract was about, the same as 1~9 - 1962 .,'5ince b]•ood flow responses to smoking in the lower extremity seemed erratic, that some test subjects showed unequivocal increase in total flow, it, soon ;'~'::became evident that it was necessary to employ some acceptable means of separately • most obvious errors. . following permits,a rough estimation of skin and muscle flow by correcting for the : ence between skin-mass/muscle mass•ratio!in the foot and in the leg. The formula ,.;'.estima.ting skin flow and muscle flow. A method of differential plethysmography 'has been developed in our laboratory on the basis of the rather constant differ- Pf - Pi Ut a = 1-Cf-cl ~ F= Flow Rate V= Volume ~ P = Perfusiion, Rate ~ L= Leg F' = Foot S= Skin M= Muscle C= Correction Factor - Fl + Ff = F c.c./min.) V1+Vf =V ~c.cj p = v (c.c./100, c.c./min•.~ }.~ O Ps = Pf + Cf,& Cf = o'. 20 Q Pm=P]1-ClA C1=026 ~ Of course, all experiments are done in the Constant Temperature Laboratory; . the ones reported here were done at 25°C and 55% humn•di'try.

In order to be reasonably sure that the differences be meaningful, we • • considered as significai.it only changes of more than 1 1/2 ml. per 100 m-l. of . aissue~min. - . ,4,, At the present time 34 subjects have been.tested:,with this method. There '~ were 25,males and nine females.. Their ages ranged from 24 to S7 years with an •arteriosclerosis, while the rest had no demonstrable vascullar disease. Nine of the group were significantly sensitive to one or more specific tobacco extracts. Skin and muscle flow responses•of these 9 subjects were tested for the smoking of tobacco types to.wYiich their skin was sensitive. :.. average of 56.3. Seven of the 34 subjects exhsbited evi.dence of obliteratz.ve Skin I+'1ow. Mu.scle Flow ase No Change Increase Decrease No Change Increase Total Allergic J 1 0 2 3 4 No OAS 8 7, 1 0 2 2 ~+ .OAS 1 - 0 0 0 1 0 - In response to smoking,. in eight of these nine tobaeco-sensitive persons a significant decrease in skin blood flow was observed. One•he.d a decrease not significant according to our criteria and was therefore listed as showing "no change't; none had an increase in skin flow. Skin• Flow - Nfuscle Flow Decrease No hange Increase Decrease No Chan e Increase Total Non- ' A1Ll.er ic 2 2 1 8 2 12 11 No OAS l9 1 10 8 2 9 8 OAS 6 1 0 0 3 3 In contrasty of the 25 subjects who•were skin negative, eight showed an increase in skin flow•, 15 had no change and in only two a significant decrease in skin flow was observed. There was no, conclusive trend in mw.scle flow changes i,n, either group-. The df,fiierences in skin flow responses are-h2ghlyy significant. 3) 1962 - 1964 ' The study now turned to patients with,non-gangerous occlusive athero- sclerosis. sclerosis. 22 patients were sttudied'in more than 100 experiments. The results

The Council for Tobacco Research -' "-were by and large identicali with those in healthy subjects. The last phase of the project was devoted to a critical re-evalnzation.-'~.; .The following conclusions were reached: pletnysmography "opthalmic artery pulsensor", capillaroscopy and'photography and skin sensitivity testing for tobacco extracts, the following conclusions seem justified: : On the basis of studies carried out using segmental venous occlusion .1) Vascular response to•cigarette smoking in the lower extremity differs in skin and muscl:e. A decrease in skin perfusion-is generalhyy accom- panied. by an increase in muscle perfusion and vice versa. 2) Changes in relationship between,skin and muscle perfusion depend ever muscle perfusion is increased in response to cigarette smoking at 20 C, it will decrease at 25°C inresponse to-the same stimulus. Whenever skin perftasion is decreased at 20°C following cigarette smoking, it will show an increase in response to cigarette smoking 25 C. o en- ,.responses to cigarette smoking are quantitatively at their lowest. ',;quantitatively and qualitatively on environmental temperature. 3) At "neutral" temperatures between 22.5°C to 23.5°C., vascular 5) There is almost constant relationship between skintand muscle • perfusion in vascular responses to smoking in.the lower extremity. As a rule, increase in one is accompanied by a decrease in•the other and vice versa. of the rapid rate, at whichrthey occur. 6) Microcirculatory changes in response to tobacco-smoking are dynamic in nature. The anal,ysis of these changes require microcineamatography because 7) s`Opthalmic artery pulsensor" studies do not seem to be of value in assessing the response to smoking. 8) Skin sensitivity reaction to tobacco extracts may be dependent to, a very large extent on preparation and composition of the extract. ~ 0 ~ ~ ~ + = ~

. Total Essay of Proposal BLOOD FLOW ST7DIES IN HYPERTENSIVE; SMOKERS No-reference could be found to a studyy of effects of cigarette smoking on blood:- The effects of cigarette smoking on the peripheral circulation have been •studied extensively in healthy subjects and in patients with arteriosclerosis. ;:flow in patients with hypertension, untreated or under treatment with variouS substances. recently it was thought that cardiac output and stroke volume in primary hyper- tension are within normal limits. There was little or no evidence for over- activity of the sympathetic nervous system, vasoconstrictive reflexes remaining at normal levels. In the majority of cases catecholamine excretion, as a measure of sympathetic activity, was found to be within normal limits. be due to an increased peripheral resistance in the circulatory system. Until .. In primary hypertension, the elevation of blood pressure is considered to In the early labile stage of primary hypertension, some moderate elevati,on of catecholamine excretion ha•s beenishown in some cases. This elevation was particularly evident during peak elevations of blood pressure. The whole concept of peripheral vascular resistance is ill defined. It, has been shown that circulation in various organs or vascular beds may respor_d differently to a different stimulus. It has also been demonstrated that the ststus of a particular vascular bed, prior to stimulation, will influence the subsequent response. Observing vascular responses in one vascular bed does not necessarily permit the prediction of similar responses in other areas This concept of variability of vascular response in differing vascular beds would appear to contradi,ct the concept of increase in total peripheral vascular resistance in essential hypertension. amine metabolism. Though it would appear that overall synthesis of catecholamines and their release from storage by neurone discharge as judged by urinaryy catechol- amine excretions is normal, it has been shown that systemic blood vessels of subjects with hypertension are more reactive to catecholamines suchas Nore- pinephrine than, those of normals. Mis then,, would suggest that the Norepine- phrine released in response to nerve discharge is modulated dYfferently. It has also been suggested that a defect of the storage mechanism of Nbrepi,nephrine, in primary hypertension one is basically dealing with an abnormality in catechol- A number of drugs currently in use to•lower blood pressure affect catechol- 'aaiine function in one way or another. Thus the question has been, raised whether being smaller in hypertension compared to the normal, would lead to a greater response to infused or endogenous Norepinephrine as well will be absorbed, leaving more available for vasoconstriction. A third possibility to explain the increased vascular reactivity in primary hypertension has been suggested, • namely insufficient tissue binding of exogenous or end•ogenous~ norepinephrine C thus leading to~an exaggerated vasoconstrictor response. Q W The pharmacologic action of nicotine consists of a primary transient• ~ stimulation and secondary more persistent depression of all sympathetic and ~ _ parasympathetic ganglia. This includes the adrenal medulla and epinephrine ~ a.

s Blood ?low Studies in Hypertensive Smokers ;is thereby discharged Nicotine and tobacco smoking have also-been shown to release of posterior pituitary anti-diuretic hormones. Nicotine also markedly stimulates the. central nervou's, system which is exert an•antidiuretic action. This effect is thought to be the result of stimulation of the supraoptical-hypophyseal system with the subsequent .: become prominent. central vasomotor centre, tachycardia and a peripheral vasoconstriction may vagal ganglia. Ia.ter owing to stimulation of sympathetic ganglia, and the .the heart rate due to stimulation of the central vagal nuclei and cardiac ;_-Due to-the multiple sites of action one may encounter initially a slowing of = particul:arly evid'ent for the respiratory and. vasomotor centres 'of the medulla. . 'After the stage of sympathetic ganglionic stimu]lation is succeeded by may dilate. . paralysis, smaller vessels of the periphery, especially those of the skin, ,..pressure. Also the effect of smoking on the treatment of hypertension with diuretics shoul.d be studied. Such findings in untreated patients with primary hypertension shoul(lbe com- pared to findings in patients treated with various drugs to lower blood .'blood vessels of patients with hypertension and the presence or absence of : a basic abnormality in catecholamine metabolism iniprimary hypertension. These combined effects of nicotine should be studied:,to ascertain the presence or absence of an increased catecholamine activity in the systemic It is suggested that the effect of cigarette smoking be studied an.dd compared in the following groups: 1) patients with primary hypertension who have not been treated before and are not being treated while the study is in progress 2) patients with primary hypertension treated. with reserpine 3) patients-with primary hypertension tkeated with thiazide ~~ patients with a primary hypertension treated with a reserpine thiazide combination 5) patients with!primary hypertension treated with guanethedin 6) normotensive subjects • a Es.ch group to consist,of 5 subjects Essential hypertension for the purposes of this study Ls.defined as a sustained diastolic pressure of 100: mm Hg.or higher without detectable underlying cause.

_ ,`,.. . . . . Blood ~'low Studies in Hypertensive Smokers y The method used in this study is differential venous occlusion plethys- ,:~.... mography. _ Plethysmographic measuTements.of the fot.ad ca73 are taken, those of the- , • PPro- • - . :,.... . reDresentative of muscle blood flow. The calf and foot are placed in the a foot being representative of skin blood flow while measurements of the calf are ~~ ', with vaseline and foam rubber. Volutne changes of the limb are callculated from ''..priate plethysmographic lucite chambers. The chambers are then made airtight :•.• tissue is calculated from the formula: • measurement of the distance equivalent to 10 seconds on the base line. At : this point a perpendicular is erected. Blood flovin ml/minute i,n 100 cc of on the deflectionlof the recorder. On the recording a time-scale permits the effect of a known volume, namely 5 ml air injected into the chamber, has ' (00 x L _ Blood Flow K x V (ml, per minute per 100 ml of tissue) L is the perpendicular rise of the slope in mmy during.10 seconds. K is the calibration constant of the^recording apparatus in mm deflection per ml of change in volume. V is the volume of the enclosed calf or foot in ml which-is determined by the water displacement overflow method. When measuring blood flow through the calf (i e. muscle vascular bed) two pressure cuffs are applied toathe extremity to be measured. The distal (occlusion) cuff is- infliated to 270 mm Hg, the one proximal to the plastic case (collecting cuff) to the indi;vidtzal's diastolic blood pressure minus 10;mm Hg. When measuring blood' flow to the foot (i e. skin vascular bed) only the collecting cuff is used which is inflated to the individual's diastolic blood pressure minus 10 mm Hg. Following.sudden occlusion,, the linear portion of the rising slope of the recorded curve is used to calculate the rate of flow according to the formula mentioned above. All experiments.will of course be done in a constant temperature roomy at temperatures of 20 and 28oC. Humidity to•be held constant at 55%, A In order to. avoid environmental influences°, patients will be brought to the constant temperature laboratory where they will rest on a bed while quasi- continuously the skin temperature on both big toes andithe right middle finger are recorded using a six channel Speedomax. A patient is considered to be adjusted to the environment of the room when the skintemperature of his toes and:,fingers has come down to constant roomitemperature and. stayed there for thirty minutes. Inpatients whose skin temperature does not come down to. room temperature despite prolonged exposure;. maintenance of a constant skin temperature of toes and fingers for 30 minutes is considered to represent. adaptation. Walter ReB:isch, M.D. New York University School of Medicine.

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