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TABLE OF CONT_EI'~-S- .... Letter of Intent " 1-2 Table of Contents ............ : : ................... " ........... . ..... .... 3 Scientific Rationale ............... : ..................... i ....i~ ..... 4-6 Preliminary Program :- . 7-8 Alphabetical List of Proposed Speakers and Chairs .......................... 9-10 References • ~ ..... ' .................. • .................. -~...i. :.". • • 11-12 Biographical Sketch - Michael .H.-Smolensky, Ph.D .......................... 13-14 Biographical Sketch - Francesco Portaluppi, M.D ...... ~.. .............. , ..... 15-I6 Academy Background ............................................. . . 17-18 Board of Govemord . .............................................. 19-22 Project Budget ............................ 23 Budget Justification .......................... ...... ~ ................ 24 501(c)(3) Form ... ........... ......... ~ .... :. ........... ~i. 25 Current Annual Report ............ i ~ ...... ~ ....~.... ~ . ... .... ~ ~ . . . ~ . ! 26-38 (3)

TIME.DEPENDENT STRUCTURE & CONTROL OF ARTERIAL BP INTRODUC'rlON: Cardiovascular diseases constitute the leadin.g causes of dea-th~ff-~a~ United States: far beyond the ~number of deaths due to cancer, Approximately one.half the-cardiovascular, deaths is a consequence of high blood pressure (BP) (1).~ Thus, hypertension constitu'tesa significant medical and. social problem. !t is the subject of an extensive amount Of basic research devoted to mechanisms as well as clinical trials of medications devoted to its control. Although meaningful advances have oc.eurred in understanding the physiology of BP regulation by neural, cardiovascular, renal, and hormonal mechanisms, our work is far from complete. Research into themeehanisms of BP maintenance in health and disease states such as hypertension is .also being strongly pursued. On the other hand, the facets and mechanisms 6f BP regulation in relation to time, especially in relationship to parahologieal and therapeutic implications, have received comparably little scientific attention until recently. It, has become increasingly evident, especially through the applieation of ambulatory BP monitoring technology (2), that BP varies in a time-dependent fashion; the temporal organization of BP variability .encompasses a number of factors and mechanisms with specific time courses. Most scientists have focused on .circadian (24- hour) and to some extent seasonal components of BP variability. Others have been concerned with ultradian components having periodicities of less than 24 hours (4-6). Recently, there has been an appreciation of the analogous temporal structure of cardiovascular ~funetions as it relates to temporal patterns in pathological cardiovascular events (for review see ref. 7). In this regard, there has been a surge of scientific interest in.the field of medical chronobiology as it pertains to cardiovascular disease, including hype~___.m~.on. Moreover, there is growing appreciation for the role of circadian and other rhythms on the pharmacokinetics (chronokinetics) and pharmacodynamics (chronesthesy) of antihypermnsive medications. Intriguingly enough, the time course of drug absorption and distribution need not coincide.withthe time course of drug effects on. BP (7). This phenomenon, which is referred to chronesthesy, infers that drug effect is not simply a result of drug concentration per se: it can be dependent on a set of mechanisms which are also variable in time and which-determine therapeutic results. A fascinating newfield of research known as chronopharmacology (the study of biological rhythms and medications) has great clinical relevance, considering the aforementioned medical and social impacts of hypertension and cardiovascular accidents which all exhibit very .specific time patterns. The investigation of BP regulation and. the underlying mechanisms must include the role of biological rhythms. and other temporal factors which are influential. The results of such studies have clinical implications, especially in regard to the optimization of therapeutic interventions by timing antihypertensive medications to circadian or other biological rhythms .(chronotherapeutics). Complete understanding of the chronobiologic and other mechanisms of BP rhythms in essential or secondary hypertension .is still sought. Interest in the chronotherapy of hypertension is only in its infant. The conference which is being held. in Ferrara, Italy September, 1995 is intended to stimulate multi-disciplinary scientific inquiry into the ehronobiology .and chronotherapy of hypertension. ~The proceedings of the New York Academy of Sciences conference, "Time, Dependent Structure and Control of Arterial Blood Pressure" is anticipated to have broad appeal since the subject matter explores topics of certain interest to both basic and applied scientists - physiologists, pharmacologists, clinicians, epidemiologis~, biostatisticians, drug delivery and other pharmaceutical scientists plu.~.~egu!at0ry personnel. CONFERENCE TOPICS AND ISSUES: Five important topics and issues are to be addressed in depth at during the conference.

." " I) A~al,vsts of" the ~mporal sh'-~cmre or'. BP v~abH~: &is portion o~ ~e con~r~n~ d~s wi~ definitions md ~p~s of BP ~mpom] palms md ~c relative con~budon of d~ferem ~y~ .~ Mere. An~] (~,9) md h~ (10.11) models w~l] be presen~d. 2) M~ch~s~ of ~mpoya] BP pa[~c~ md v~Hi~.-~m do we ~~ow md ~at ~ould we ~yMms. N~w dm ~om ongo~n~ studies will ~ presen~d to begin ~ ~drcss Me con~bm~on of c~rc~m md o~r ~mpo~ p~ of blood flowm. BP v~i~Hi~, over ~e :~hour ~d o~cr time ~c~ (.12.13). Also, M~ con~ibmion of "clmsi~" erenin-mgio~min-aldo~rom, ~i~ol) ~ w~ll m novel ho~oml endo~elial fairs .(~ial ~iur~tic ~pfide, ~]ckonin gene-rel~d pepfide, opioids, endo~elim~ ni~c oxide) md ~ir ~y~ will ~ ~x~in~d highlighting findings of ~ mos~ ~m studies (I~19). Pi~lly, ~ role of ~xog~nous b~havio~ fa~ on e~ogeno~ BP p~ w~II ~ ~dr~ (19). ' " 3) ~e p~ophysiology ofBP v~i~ili~ - ~ do we ~ow ~ ~m ~ould w~ investing. will discuss ~ av~l~le epid~miolo~i~I ~vid~n~ ~i~ su~ges~ ~ ~ ~~ of BP (~ oppo~ levels) ~ prognosfi~ly impo~. ~is is p~b~l~, even ~ou~ ~II unproven, given ~. r~lmionships be~e~n ~ ~y~ in BP md ~ ~diovm~l~ oven~ (for ~vi~w s~ r~f. 20).~ kecent ~ will~ be ~r~s~d- on ~ p~olog~l co~s .(~di~ ~r~b~, r~) of no~ ~ ~r~d BP ~y&~ ~t-~). wo ~mpo~ ma~rs wall b~ ~dr~ss~d: (a) ~r ~Jhyp~miv~ ~enr should be progr~med in time m achi~v~ higher l~vels of m~dica~ion in ~e morning for ~s~nfi~ h~nsion md in ~ ~vening for s~cond~ h~ns~on ~d ~) ~e~r a goal of ~ent should ~ ~s~ng ~ BP circadlm ~y~m in prim~ md s~cond~ fo~s of hy~nsion, 4~ Chronoph~acology md ~rono~e~utics of BP - ~m do we know md what should" we investigate. ~er~ is convincing evidence now, bo~ from smdi~ on mi~s md hu~s, ph~macokine~ics of medications used for BP control ~xhibk ~minis~ion-tim~-dependenc~es ~2~). Much less dam ~e av~Iable (rod ~y ~. all ve~ rec~nt) on ~e time-depend~n~ of d~g effe~ on ess~mial md second~ fo~s of humm hype~nsion ~9-31). ~e f~w ~ials fo~sing on ~ time-dependent differences of amihypen~nsives have usually ~n limited in design to a comp~ison of morning vs. evening ~e rationale md me~ods of chrono~e~u~ic ~i~s for h~e~ion will b~ dis~ssed.. ~e ~cial issues m b~ addressed ~e: how do~s ~ ~nt m~gement of hype~mion affe~ BP rhy~ms? How ~ ~e BP rhy~ms b~ modified ~n a ~me-sp~dfi~d.~ner? Is m indiv~du~i~d chrono~empy ofhype~nsion possible? Is i~ ,d~sirable. md when? Wl~ r~g~d m ~ lm~r issue, n~w d~ will b~ presumed from ongoing studies of a new evening once-a-day calcium chmn~l mmgonis~ m~di~fion ~d~r ~ial ~ ~e Uni~d Sm~s ~32). 5) ~e role of 24-hour ~rial ~bulam~ BP monitoring in ~e ~valuation of mfihyp~nsiw m~dica~ions. ~is se~ion of ~ conferen~ ~dresses endpoint blood, pressure p~eters md statistical me~ods for BP dam malysis md ime~remtion. ~e p~rspectives of ~e ph~mi~l indust~ md regulam~ agencies (for example, ~e Food ~d Drag Agen~ in ~e USA md compile ones in ~urope) reg~ding ~e chronobiology of hypertension md ~e chronoph~acology ~d chrono~mi~ of antihypen~nsives will be ~dre~sbd~in d~mil. • FORMAT OF THE CONFERENCE: The conferen~ will be divided into five separa~ sessions to cover the above topics. ,Neural mechanisms of" BP rhythms will be discussed in Session I instead~of Session II only for practical reasons, i.e, to leave adequa~. =ime for be. evening poser sess.ion~s).. A call for abstracts will be issued for this purpose, and submission from young investigators new to the field will be encouraged. Prominent scientis~ from the five comin~nL~ (7. 0f~26 young and 3 women inves:igamrs) have agreed, m contribute oral presemations and manuscripts to the proceedings. The proposed agenda of the September, 1993 meeting is appended..The proceedings and postsrabstracts will be publishcd in a future volume of the Annals of the New. York Academy of Sciences distributed worldwide to over 700 institutional libraries and also offered to the Academy's 35,000

member.~. "l-he volume is inmnded to serve both as a compendium of the present knowledge and sr.imutu~ for RELATED N~.ETINGS: ...... To our knowledge, during the last {'1992) and the Sixth .(199~,) Inmrnmional Conference of Chronopharra~ology and Chronothempeudcs which took place at the~ Amelia Island Plantation Confer~nce Center, near .lm:~onville, Florida. under the.auspices of the Inmmational Society of Chronobioiogy, addressed the chronopharmacology and ~chronoff~empy of antihyperrensive medications to a limi~d degree. Only marginal consideration .wa.~ given to the issues of BP rhythms and their control. The Society for Research on Biological Pdiythrm has also been gathering in Am*-tia Island for it~ biannual meeting, in 1992 and 1994, focusing mainly on non-.clinical aspecr.~ of chronobioto.gy.- The meetings of the societies of hypermnsion and related fields, do include BP monitoring and/or BP control: however-~ the conference we propose is unique in its being focused not .only on BP monitoring and BP variability, but on the specific matmrs and mechanisms relating to the chronobiology and ehronotherapeuti:s of BP and hypertension. In conclusion, no other meeting ,or session held. during the last .three year5 (or scheduled for next year) has addressed the conference .topic. Hence, researchers from various discipiin~s concerned with BP regulation and hypertension should .find this conference unique~ and of great scientific interest. (6)

TIME-DEPENDENT STRUCTURE & CONTROL OF ARTERIAL BP DAY 1 8:30 - 8:40 AM 8:40 - 8:50 AM 8:50, I2:30 AM Se.rsion 1: 8:50 AM 9:20 AM 9:50 AM I0:20 AM - 10:40 AM I0:40 : I1:i0 I 1:40 I:2:10 -i2:30 PM 12:30 - 2:00 PM 2:00 - 4:20 PM Session Prelimirmry Program. Greetings Introductory Remarks (F Portaluppi-Ferrara, Italy) Blood pressure ~yrdam$ and their neural control ,Session Chairs: G Parati (Milano, Italy) and .1 Waterhouse (Manctaester; England) High-frequency components of blood pressure variation (M Pagani-Mitano, Ultradian rhyr&ms of blood pressure associated with sleep and wakefulness ('EB: Raffery-Harrow, England) Circadian and infradian rhyuhms of blood pressure (G Comelissen, Minneapolis, MN) Intermission Nettral mechanisms of blood pressure rhythms (G :Parati-Milano, Italy) Ne~amtransmitr.e.r syster~ and blood pressure rhythms 0'P. Chatmers' Bedford Park, Atmtralia) Signal tramdtmtion in animal models ofnormotension and hypertension (K Witte-Frankfurt, Germany). .. General Discussion Luncheon : . Vascular. renal, endocrine, and behavioural mechanisms of blood pressure Session Chairs: TG Picketing (New Yolk, USA) and A Ange|i (Torino, Italy) Vascular mechanisms ofblood pressure rhythms (E Casigtia'Padova, Italy) : (7)

2:30 PM 3:00 PM 3:30 PM 4:00 - 4:20 PM 4:30 - 6:30 PM DAY2 8:30 AM - 12:30 PM Session II1: 8:30 AM 8:55 AM~ 9:20 AM 9:45 AM 10:10 - 10:30 AM 10:30 AM 10:55 AM 11:20 AM 11:45 AM 12:10 - 12:30 PM 12:30.- 2:00 PM 2:00 ~- 4:00 PM Session IV: 2:00 PM 2:25 PM 2:50 PM 3:15 PM 3:40 - 4:00 PM 4:00 - 4:20 PM 4:20 - 6:20 PM Session V:~ Renal-hemodynamic mechanisms of blood, pressure rhythms (J Cambar- Bordeaux, France) Endocrine mechanisms-of-l~tood pressure rhythms (F Poi~aluppi-Ferrara, Italy) Behavioral mechanisms of blood pressure rhythms (TG Pickering-New York, General Discussion Poster Sessions (8) Pathophysiology of blood pressure rhythms Session Chairs: Y Imai (Sendai, Japan) and F Portaluppi (Ferrara, Italy) Relationships of .the circadian rhythms of thrombotic,' ischemic, hemorrhagic.~ and .arrhythmic events to blood, pressure rhythms~ (R Manfredini-Ferrara; Italy) Relationships of cardiac function and stnacture to blood pressure rhythms (D Rizzoni-Brescia, Italy). . Relationships of cerebrovascular function and structure to blo0~d pressure rhythms (Y Imai-Sendai, Japan) . Relationships of renal ~nction to blood~pressure rhythms (j Staessen: Leuven, Belgium) Intermission ...... Aging ~and blood pressure rhythms (E O'Brien-Dublin, Ireland) Pregnancy and blood pressure rhythms (F Carandente-Milano, Italy) Blood pressure rhythms in sleep disorders and dysaut0nomia (P Cortelli- Bologna, Italy) Blood pressure rhythms in transplanted patients (G Degaute-Bruxelles, Belgium) General Discussion Luncheon Chronopharmacology and chronotherapeutics ofhypertension Session Chairs.~ Talma Rosenthal (Tel Aviv, Israel) and MH Smolensky (Houston,'TX) Chronopharmacology of hypertension (B Lemmer-Frankfurt, Germany) Analysis of blood pressure ~rhythms for drug. efficacy evaluation (G German6-Roma, Italy) Drug, effects on BP rhythms in .essential hypertension (T. Rosenthal-Tel Aviv,. Israel) Drug effects on.. BP rhythms in secondary hypertension (M Middeke- Mfinich, Germany) General Discussion Intermission The role of arterial blood.pressure monitoring (ABPM) in the evaluation. of antihypertensive medications: procedural, statistical :and regulatory issues Session Chairs: R Lapicky (FDA, Rockville, MD)and. B Lemmer .(Frankfurt, Germany)

4:20 PM - 4:45 PM 5:10 PM 5:35 PM 6:00 - 6:20 PM 6:20 PM - 6:30 PM Chronobiologic perception .. of the role and Smolensky-Houston, TX) Validation and statistical 4ssues" on the role and need of ABPM (Industry Speaker to be determined) Pharmaceutical industry perception of the role and need of ABPM (Industry Speaker to be determined) Regulatory perception, of the role and need of ABPM.('R Lai~icky- Rockville, MD) General Discussion Closing Remarks (F Portaluppi-Ferrar. a, Italy) need of ABPM (MH Alphabetical List of Proposed Speakers and Chairs The following speakers are women: Franca Carandente, Germaine Cornelissen and Talma Rosenthal. .. ~ . The following speakers.are young investigators (35 or younger): Edoardo Casiglia, Pietro-Cortelli Giuseppe German~, Roberto Manfredini,~ Massimo Pagani, Damiano Rizzoni, Klaus Witte. 1) 2) 3) 4) Alberto Angeli, MD, PhD - Dept. of Internal Medicine, University of Torino Ospedale S. Luigi Gonzaga,. 1-10043 Orbassano (TO), Italy Jean Cambar, PhD - Groupe d'Etude de Physiologie et de Physiopathologie R6nales 5) 6) 7) 8) 9) 10) 11) Facult6 de Pharmacie - 3 Place de la Victoire, F-33000 Bordeaux, France Franca Carandente, MD, PhD - Chair of Chronobiology, University of Milano Istituto di Anatomia Umana Normale, via Mangiagalli 31, 1-20100 Milano Edoardo Casiglia, MD -. Institute of.Clinical Medicine, University of Padova v. Giustiniani 2, I~35128 Padova, Italy • John P. Chalmers, MD .- Department of Medicine, Flinders Medical Center Bedford Park, S. Australia 5042 Germaine Comelissen, PhD -. Chronobiology Labomtoires, 5-187 Lyon Labomtoires 420 Washington Avenue, S.E., Minneapolis, MN 55455, U,S.A; Pietro Cortelli, MD - Institute of Neurology, .University- of Bologna via Ug0 Foscolo 7, I'40100 Bologna, Italy Jean-Paul Degaute.- Hypertension Clinic, University of Bruxelles H6pital Erasme,808 route de Lennik, 1070 Bruxelles, Belgium.. Giuseppe Germanb - Internal Medicine,. University "La Sapienza" I Clinica Medica, Policlinico Umberto I, viale del Policlinico, 1-00161 Roma Yutaka Imai, MD - Second Department of Medicine, Tohoku University School of Medicine Seiryo-Cho, Aoba-ku, Sendai 980, Japan_ . ~ _ Dr. Raymond Lapicky • Food and Drug Administration/C.eder/ODE1/HFD-110 5600 Fisher Lane, Rockville, MD.20852, U.S.A. • ~ ~ - ,~o,,th~-Un, v,~ ~,.~ Bj6m Lemmcr, L,,D, .Ph Zentrum der Pharmakologie~ I.W. ~ .- -, : .... :,r., Theodor-Stern,Kai 7,D-60590 Frankfurt/M, Germany Roberto Manfredini, MD, Institute of Internal :Medicine,: University of Ferrara S. Anna Hospital, Corso Giovecca.203, 1,44100 Fe.rrara, Italy:. 13) (9)

14) 15) 16) 17) 18) 19) 20) ~ 21) 22) 23) 2~) 25) 26) Martin Middeke, Reha-Zentrum Spreewald Klinik ffir Herz- Kreislauf- und Stoffwechselerkrankungen.- D-03096 Burg, Ge.r~any Eoin T O'Brien, MD - Blood Pressure Unit, Depaf't~6~~ of Cardiology Beaumont Hospital - 9 Dublin, Ireland Massimo Pagani, M.D. -Internal Medicine, University of Milano Ospedale L. Sacco,~ 1-20157 Milano, Italy Gianfraneo Parati, MD -, Scientific Institute S. Luca Hospital, Centro Auxologico Italiano • via Spagnoletto 3, 1-20149 Milano, Italy Thomas G Pickering, MD, PhD - Cardiovascular Center, The. New York Hospital Cornell Medical Center- 525 East 68th Street, New York, NY 10021, U.S.A. Francesco Portaluppi, MD - Hypertension Unit, Internal Medicine, University: of Ferrara via Savonarola 9, 1-44100 Ferrara, Italy. Edward B Raftery, MD - Department of Cardiology .and Clinical Research Center • Northwick Park Hospital, Harrow, Middlesex, United Kingdom Damiano Rizzoni, MD - Internal Medicine, University of Brescia Ospedale Civile di Brescia, Piazza Spedali Civili .1, 1-25100 Brescia, Italy Talma Rosenthal, MD - Chorley Hypertension Unit, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel. Michael .H Smolensky, PhD- school of Public Health, University of Texas Hermann~Center for Chronobioogy, 6410 Fannin,-Suite 833, Houston, TX 77030, U.S.A. Jan A Staessen, ~MD, Department of Pathophysiology, Catholic University of Leuven U.Z. Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium ~ Jim M Waterhouse, PhD - Dept. of Physiological. Sciences, University of Manchester Stopford Building, Oxford Road, M13 9PT Manchester, United Kingdom Klaus Witte, MD - Zentrum der Pharmakologie, J,W. Goethe-Universit~t: Theodor-Stern-Kai 7, D-60590 Frankfurt/M, Germany References The Fifth .Report of .the Joint National Committe~ on Det~tion, Evaluation, and Treatment of High Blood Pressure UNC V). • Arch Intern Med 1993; 153: 154-83, Picketing TG. Ambulatory. Monitoring and Blood Pressure Variability. Science Press, London, Cornelissen G, Haus E,.Halberg F. Chronobiologic blood pressure assessment from womb to tomb. In: Touitou Y, Haus E,-eds: BioIogic Rhythms in, Clinical and Laboratory. Medicine. Berlin: Springer-Verlag, 1992: 428-52. . Pagani M, Furlan R, Dell'Otto S, et al. Simultaneous analysis of beat by beat systemic arterial pressure andheart rate variabilities in ambulatory patients. J Hypertens 1985; 3(Suppl 3):$83-5.~ Mancia G. Autonomic modulatibn of the cardiovascular system during sleep. N Engl I Meal 1993; 328:3a.7-9. - Sta~ssen JA, Fagard R, Tfiijs L,-et al. Fourier analysis.of blood pressure profiles. Am J Hypertens 1993; 6:184S,187S. (10)

I0. 11. 12. 13. 14. i~. 16. 17. 18. 19. 21. 22. 23. 24. Lemmer B. Cardiovascular chronobiology and chronopharmacology. In: Touitou Y, Haus E, eds. Biologic Rhythms in Clinical and Laboratory Medicine. Bedim Springe.r~Verlag, 1992: 418-27. - ........ " Lemmer B, Mattes A, BShmn M,, Ganten D. Circadian blood pressure variation intransgenic hypertensive rats.. Hypertension 1993; 22:97-101. Sasaki S, Yoneda Y, Fujita H, et al. Association of blood pressure variability with induction of atherosclerosis in cholesterol-fed rats. Am J. Hypertens 1994; 7:453-9. Degaute JP, an de Borne P, Linkowski P, et al. Quantitative analysis of.the 24-hour blood pressure and heart rate patterns in young men. Hypertension 199i; 18:i99-'210. Portaluppi F, Cortelli P, Avoni P, et al. Diurnal blood pressure Variation and hormonal correlaEes in fatal familial insomnia. Hypertension 1994; 23-569-76. de Leeuw PW, Gaillard CA. Circadian changes in the circulation. HighBIood. Press 1992; 1:245-7. Casiglia E, Palatini P, Baccillieri MS, et al. Circadian rhythms of peripheral resistance. A non- invasive 24-hour .study in young normal volunteers confined to bed. High Blood .Press 1992;~ 1:249-55. Portaluppi F, Trasforirfi G, Margutti A, et aL Circadian rhythm of ealcitonin gene-related peptide in uncomplicated essential hypertension. J Hypertens 1992; 10:1227-34. Por~.tuppi F, Vergnani L, degli Uberti EC; Atrial natriuretic-peptide and circadian blood pressure regulation: clues from a chronobiological approach. Chronobiol Int 1993; 10: 176-89. Portaluppi F, Vergnani L, Margutti A, et al. Modulatory effect of the renin-angiotensin system on the plasma levels of calcitonin.gene-related peptide in normal man. J Clin Endocrinol Metab 1993; 77: 816-20. Calhoun DA,-Zhu S, Wyss JM, et al.- Diurnal blood pressure, variation and dietary salt in spontaneously hypertensive rats. Hypertension-1994; 24:1-7. Bianchi S, Bigazzi R, Baldari G, et al. Diurnal variations of blood pressure and. microalbuminuria in essential hypertension. Am J Hypertens I994; 7:23-9. James GD, Pickering TG. The influence of behavioral factors on the daily variation of blood pressure. Am J Hypertens 1993; 6(6 Pt 2):S170-3. Purcell .I-I/, Gibbs JS, Coats AJ, et al. Ambulatory blood pressure monitoring and circadian variation of cardiovascular disease; clinical and research applications. IntJ Cardiol 1992; 36:135- 49. Verdecchia P, Schillaci G, Guerrieri M, Gatteschi C, Benemi0 G, Boldrini F, Porcellati C. Circadian blood pressure changes and left ventricular~ hypertrophy in essential hypertension. Circulation 1990; 81:528-536; Rizzoni D,.Muiesan ML, Montani G, Zulli R, Calebieh S, Agabiti-Rosei E. Relationship between initial cardiovascular~ structural changes and daytime and nighttime.blood pressure monitoring. Am J Hypertens 1992; 5:180-186. Kuwajima I, Suzuki Y, Shimoswa T, Kanemaru A, Hoshino S, Kuramoto K. Diminished nocturnal decline in blood pressure in elderly hypertensive patients .with left ventricular hypertrophy. Am Heart J 1992; 123:1307-13.11.~ Palanin P, Penso M, Racioppa A, Rugno E~ Guzzardi G, Anaclerio M, Pessina AC. Clinical relevance c~f nighttime hlood.pres.~ure and of daytime blood pre.s.~re~ variability, Arch I~ter Med 1992; 152:1855-1860. . (11)

25. 26. 27. 28. 29; 30. 31. 32~ Del Rosso G, Amoroso Ji Santoferrara A, Fiederling B, Di Liberato L, Albertazzi .A. impaired blood pressure nocturnal decline and ,target organ damage in .chronic renal failure.... J Hypertens 1994; 12(Suppl 3):S15. - Lemmer B, Nold G, Behne S, et al: Chron0pharmakinetics and cardiovascular .effects of ,nifedipine, Chronobiol Int i991; 8:485,94: Mattes A, Lemmer B. Effects of amlodipine on circadian, rhythms in blood pressure, heart rate, and motility: a telemetric study in rats. Chronob~ol Int 1991.; 8:52638; Witte K, Weisser K, Neubeek M, et al. Cardiovascular effects, pharmacokinetics, and converting enzyme inhibition of enalapril after morning versus evening adm.inistration. Clin Pharmacol Ther 1993; 54:177-86. Palatini P, Racioppa A, Raule G, et al.- Effect. of timing of administration on the plasma ACE • inhibitory activity and the antihypertensive effect of quinap~l. Clin Pharmacol Ther 1992; 52:378-83. Palatini P, Mos L, Motolese M, et al. Effect of evening versus morning benazepril on 24-hour blood pressure: a comparative study with-continuous intraarterial monitoring; J Clin Pharmacol Ther Toxicol 1993, 31.:295,300. Potaluppi F, Vergnani L, Ambrosio MR, et al. Effect of isradipine sustained release on the circadian pattern of blood pressure in hypertension-due to Chronic :renal failure. Am J Hypertens 1993; 6(5 part 2):99A, abs. 1262. Weber MA,. Anders RJ,. Maclntyre JM, Smolensky MH. Antihypertensive efficacy of delayed release verapamil gastrointestinal therapeutic system (GITS) during the acceleration period (04:00, 10:00) following nocturnal administration. Sixth International Conference ofchronopharmacology and Chronotherapeutics, Amelia Island, Florida, . July 5,9, 1994~ Abstract Book, p. IIIb-10. (12) BIOGRAPHICAL SKETCH Give the following information for the kay personnel and consultants and collaborators. Begin with the principal investigator/program director, Photocopy this page for each person. NAME j POSITION TITLE Micha~l H. Smolcnsky[ Professor of Environmental Sciences EDUCATION fBegin with baccalaureate or other initial professional education, such ~~g, and include ~ostdoctoral training.I INSTITUTION AND 'LOCATION DEGREE University of Illinois, Urbana, Illinois University of Illinois, Urbana, Illinois University of Illinois, Urbana, Illinois M.S. Ph.D. YEAR CONFERRED FIELD OF STUDY 1964 1966 1971 Zoology Physiology Physiology RESEARCH AND pROFESSIONAL EXPI~RIENC~: Concluding wi~ pmunt position, list. ~ c~g~al o~er. =m~us .e~y~t. o~e" nM ~. Key ~l ~e ~ p~ll ~i~r I~ a~y o~r ~i~s ~ pa~e ~ .~ I~n~f~ de~t or exec~n oft~ pfo~. Key peyotl ~a.y w~ ~o. ~1 ~u~s ~ doc~al or o~r pm~oSs~i.deor~s, b~ ~ ~m p~s w~ ~o ~i~s ~ ~ masters or