Efficacy and tolerability of multiple doses of MK-996, an angiotensin II (AII) receptor antagonist, compared to enalapril and to placebo in mild to moderate hypertensive patients

160A ASHABSTRACTS

C21 Comparisonof Vaacular Responses to Converting Enzyme InhibitionV.rsul AnglotonslnII AntagonismIn Pressure Overload Hypertrophy, DEReed, OM Brown,8 J Cody'. ThG OhioState University, Columbus,OH Thecontributionofbradyklnin(BK) 10 thevascularresponseof c<'nvClrtlngen;ymoInhibnion(CEI)halS receivedrenewedInterest, asBK enhancescellularpathwaysofvasodilation.We hypothesizedIhatgreatervasodilation.and iTIc:ressoofcardiac outpUIwouldbeobservedwnh CEI, comparedtoangiotensinII anlagonlsm, despilesimilarbloodpressurereduction. 16wk spontaneouslyhypertensiverats (SHR) were prospoct:valy Irealedwnhorallosartan(30mglkg),enalapril(1 Omg Ikg), or placebofor3months. Aftertrealment,hemodynamicsobtained withlowJevelinhaledhalothane,andsamplingraleof 1kHz, were aorticvolumelricflow(peak: PkF; mean: MAF; mVmin),highfidelity (Millar)aorticpressure(mean: MAP, mmHg),and heartrate (HR, bpm). Tolalperipheralr;~~(1 (TPR, unns)andtolalarterial compliance(TAC, I1VmmHg)componentsofvas<:ulartonewere derivedfromanalysisofdignizedwaveforms. TAC was determined froma modifiedWindkesselmodel,assumingexponentialtilof the non·linear pressure-volumerelationindiaslole,using area under thepressurewaveform,and strokevolume(SV, ml)fromthe aortic flowwaveform. Inage matchednormalrats, TPR was 0.46±.14, aOO TAC was 5.74±2.1 . ANOVA, wilhgroupmeanvaluGsare: N:: HR MAP PkF MAF TP8 SV TAC Placebo16416148# 572 1081 .46# 0.26# 1.58# losartan12 402 94Jno630]ns140]noO.70jns 0.35]n6 :;1. 82Jns Enalapril13 398 94 704 144 0.68 0.34 3.39 (Hp<.OS, pfscebovs losartsn, pfacebovsena/april; ns:=not significant,/osBl1anvsena/april).Wilhcomparablebloodpressure reduction, losartanand enalaprilsignificantlyimprovedthe resistanceand capacitancecomponenlsofvasculartoneinthe SHR, a"houghnot ~o normal. Differencesofpeakflowand capacilanceforthetrealmenlgroupswere observed,butwere not significant. KeyWords: angiotensinII, losartan,vascularcompliance

AJH-APRIL1995-VOL.8, NO.4,PART 2

C22 IN VIVO STUDY OP THE DURATION OP INHIDITION OF TISSUE ANGIOTENSIN CONVERTING ENZYME IN THE MICROCIRCULATION OP SPONTANEOUSLY HYPERTENSIVE RATS (SHR). E, %:ayt andXHou, LEM et INSER~ U141, Hop.F.Wldal,Paris,France. We compared 3 angiotensinconvertingenzyme (ACE) inhibitorsfor the duration of their inhibitory effect on tissueACE at the microvascularlevel. During2 weeks, 67 SHR were treated by gavage with equl-hypotenslve doses of Trandolapril,Perinctoprll,and Enalaprll (l.e, ::1.6, 2, and 10 mg/kg.day respectively). A control groupdid notreceivedACE inhibitor.Then, we used an originalpreparationof intravital mtcroscopy in isolated Krebs-perfusedrat cremaster muscle whichallowedustoexclude circulatingACE and todeterminein vivo the activity oftissueACE at the microvascularlevel. This was attempted byadministratingtopically AngiotensinI (Om and 0.1 nmol/ml AI) on themuscle and by measuring the arteriolarvasoconstriction due to theconversionof AI in All by tissue ACE in themicrocirculation . Duration ofthe Inhibitory effect of the 3 ACE inhibitorswas studied bycomparing arteriolarvasoconstrictions obtainedwhen AI was administered at 3h, 7h, 24h and 48h after the last doseof ACE Inhibitor. At 3hafter the lastdose, the vasoconstrictions in responseto AI did not differbetween the groups,and the degree of Inhibition was greater than 60% fer the 2 doses of AI and in allarterioles studied. At times 7h to48h, vasoconstrictionsin Trandolapril treated rats were smaller (p
C23

C24

SIGNIFICANCE OF PLASMA RENIN ACTIVITY ON CARDIOVASCULAR STRUCTURE AND FUNCTION CHANGES WITH FOSINOPRIL ANTIHYPERTENSIVE TREATMENT.

EFFICACY AND TOLERABn..ITY OF MULTIPLE DOSES OF MK·996, AN ANGIOTENSIN n (AU) RECEPTOR ANTAGONIST, COMPARED TO ENALAPRIL AND TO PLACEBO IN MILD TO MODERATE HYPERTENSIVE PATIENTS. J,T, Lap~. J. Toh. B.A.SofTer, A.I. Goldberg,C.S. Sw.; . 1 lorthe M!{·996 Investigators,McrckResearch Laboratories, West Point,PA. A randomized,double-blind, placebo-controlledparallelc1inicallrialwas performed ~o evaluate the tolerabilityand lIDtih}llertensiveeffects of MK·9% (MK). lID AlI receptor antagonist (AT Iwith subnanomolar potency),comparedtoenalapril(E) andto placebo(P) inpatientswithmild to moderateessentialh}llertension(sittingdiastolicbloodpressure(SiDBPJ 95·115 mmHg). FollowingII J.week washout/placebobaseline period (DL). quaIiJYingpatientswere randomizedtoaS-day once-dailytreatment with MK(25, SO, 100 or200 mg), E (20 mg) orP. SittingsystolicBP (SiSBP) and SiDBP was measured predoscat hours -I, .a.S and 0, and postdoseat hours0.5. 1,2,3.4,6,8 and24 on the lastday ofBL(Day .1) and treatmentDays I and 5. Preliminarydata are presented liom ISJ completed patients (mean age S5 years; 72% male; 8l'Ya Caucasian, 2% Oriental,17% Other)enrolledal18 domesticsites. M.eanchmgcsfi'lJnDly.1 inSiSBPlSiDBPalhaJrsO(hoor24,Dly4P,4,6, 8 B1¥124mDly5me shmwin ~ tablebelow:

OP Vyssoulls,:, EA Karpanou', AA Paleologos, CS Tselika, PK Toutouzas. AnlihypertensionCenter, Departmentof Cardiology,UniversityofAthens,Athens,Greece, To evaluate the effect of plasma renin activity(PRA) on the leftventricular(LV) and aortic root (AD) structuraland functionalchanges after 6 monthsof fosinopril20 mg dally antihypertensivemonomerapy, 115 pat/entswithessential hypertensionwere studied. At baseline, 33 patientshad PRA <1 ng/mVh .40 had 1·3ng/ml/hand 42had>3nglmlfh. Blood pressure wasnormalised(168/104 to 137187 mmHg) with aconcomitantmodestbradycardia(-3.9%) in all 3 groups. LV dimensionsdecreasp.d significantly(·1.2 s ·3.3%, p<.OOOl) but similarlyIn the 3 groups(p-NS), while interventricularseptalthicknessdecreased accordingto prelreatmentPRA values (-8.4, -10.6, -12.1%, p...004). Thus.LV mass indexdecreased(148 to 126g/m2• p<.OOl) in parallel to PRAlevels (-11 .7. -14.9, ·17%, p...OOO4 and r• .40, p<.0001). LV systolic wall stress fell (-19.5%), LV ejectionfraction increased (2.9%) and totalperipheral restlstancesfell (·6.6%)significantly[pc .000l) with no among groupsdillerences. AD elasticpropertiesimproved, as aorticdist6nsibiUty(1.85 to 2.76 cm2/dyne, p< .0001), uniiormlyin th 3PAA groups. It Is concluded~llat pretreatmentPRA valuessignificantly affect LV hypertrophyregressionmagnitudoafterfosinopril anti- hypertensive therapy, while the PRA role in the functionalLVand AO changesinsmall. KavWords: Plasma renin activity, Iostnoprll, left ventricularhypertrophy.aorticdistensibilitr

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Thellltih)pCl'lensiveeffectsofallMKgroupson SiDllP at peak(hour6) were. clinicallymeaningfuland appeared tobe dose related; however, at trough (24 hourspostdose),clinicallysignificantreductionsin SiSBP and SiDBP were observed only in the MK·200 group. Heart I1Ite was unaffected, There were no senous clinicalor labvl'atoryadverse events in any MKgroup. 'jliemost frequentAE in any treatmentgroupwas dry mOl ,~nose in"(15%) oftheMK·200·treatedpatients. In this study, 5-day trea.ment with MK was welt tolerated. MK-2oo produced clinically meaningfulreductionsin SiSBP and SiDBP throughoutthe dosinginterval' loow,;ver,the magnitudeofresponsewas less than E. '

Key Words: Angiotensinnreceptorantagonist,ACE inhibitor.mildto moderatehypertension