C) Mcmilln Press Ltd, 1994 Br J PhrmcoL (I994), 112, 837 842 '" Mcmilln Press Ltd, 1994 Lck of correltion of hypotensive effects with prevention of crdic hypertrophy by perindopril fter ligtion of rt coronry rtery Kiyoshi Chib, Schiko Moriym, Yutk Ishigi, Akiko Fukuzw, Kiyoshi Irie & 'Toshiro Shibno xplortory Reserch Lbortories II, Tokyo R&D Center, Diichi Phrmceuticl Co, Ltd, 1-16-13, Kit-Ksi, dogw-ku, Tokyo 134, Jpn 1 The present study ws designed to test the hypothesis tht beneficil effects of ngiotensin converting enzyme (AC)inhibitors re independent of fll in blood pressure in rt experimentl hert filure following coronry ligtion 2 The nimls were ssigned rndomly to six groups; shm opertion, controls subjected to coronry ligtion (control), coronry ligtion plus chronic tretment with AC inhibitors t non- nd hypotensive doses; perindopril (2 or 2 mg kg- ' dy-') or enlpril (2 or 2 mg kg- ' dy- ') for three weeks strting one week fter the ligtion 3 Systemic blood pressure ws mesured every week during the experiments At the end of the tretments, crdic function nd hert weight (n index of myocrdil hypertrophy) were determined In the other nimls, AC ctivities in plsm nd tissues including hert, kidney, lung nd blood vessels were mesured 4 In the controls, crdic AC ctivity, weight of right ventricle nd left ventriculr end-distolic pressure (LVDP) were higher compred to those in the shm-operted nimls four weeks fter the coronry ligtion However, AC ctivities were not chnged in plsm, kidney, lung nd ort by ligtion of the coronry rtery 5 The chronic tretment with perindopril t dose of 2 mg kg-' dy-' inhibited the increse in AC ctivity in crdic tissue nd suppressed the right ventriculr hypertrophy without ffecting systemic hemodynmics In contrst, enlpril t dose of 2mgkg-' dy-', but not 2mgkg'1 dy-', prevented the development of the right ventriculr hypertrophy nlpril t 2mgkg-' dy-' lso lowered systemic blood pressure 6 There is no significnt correltion between systemic blood pressure nd right ventriculr hypertrophy t the end of the tretment with perindopril (r = 6) or enlpril (r = 1) 7 These findings demonstrte tht perindopril, n AC inhibitor, prevents crdic hypertrophy without ffecting systemic blood pressure in the rt with hert filure fter coronry ligtion, nd suggest tht selective ugmenttion of AC ctivity in crdic tissue is involved in the progression of hypertrophy in this model Keywords: Angiotensin-converting enzyme; blood pressure; crdic hypertrophy; coronry ligtion; enlpril; perindopril Introduction xperimentl myocrdil infrction following ligtion of the coronry rtery results in compenstory hypertrophy in the non-infrcted myocrdium In the rt model of myocrdil infrction, ngiotensin converting enzyme (AC) inhibitors, such s cptopril nd enlpril, prevent the progression of crdic hypertrophy, though the exct mechnism of this prevention is uncler (Pfeffer et l, 1985; 1988) The increse in pre- nd fterlod ginst the hert my fvour the growth of myocytes Indeed, AC inhibitors re potent vsodiltor gents nd re likely to ttenute the pre- nd fterlod due to direct ctions on hemodynmics However, the reduction in blood pressure does not necessrily correlte with the prevention of crdic hypertrophy since some clsses of ntihypertensive gents, such s clcium ntgonists, do not significntly suppress the development of hypertrophy (Linz et l, 1988; Kromer & Riegger, 1988) In the rt model of pressure overloded crdic hypertrophy by ortic stenosis, AC inhibitors ttenute crdic hypertrophy without ffecting blood pressure ' Author for correspondence (Linz et l, 1989; Linz & Sch6lkens, 1992) Alterntively, erlier studies demonstrte tht the renin-ngiotensin system in the herts my prticipte in the regultion of crdic function nd growth dpttion of the remining vible myocytes (Cmpbel et l, 1986; Hirsch et l, 1991; Ymd et l, 1991; Reiss et l, 1993; Meggs et l, 1993) Angiotensin II stimultes the growth of myocrdium (Aceto et l, 199; Bker et l, 199) nd lso enhnces the relese of nordrenline, which is nother possible meditor of the crdic hypertrophy vi ctivtion of xldrenoceptors (Simpson, 1983) Furthermore, AC inhibitors reduce the degrdtion of brdykinin in the hert (Bumgrten et l, 1993; Nod et l, 1993) This peptide my inhibit the cell growth due to relese of nitric oxide by ctivtion of kinin B2 receptors (Frhy et l, 1992; Linz & Scholkens, 1992) Tken in conjunction, these observtions suggest tht AC inhibitors, independently of fll in blood pressure, cn prevent the progression ofcrdic hypertrophy following coronry ligtion In the present study, the effects of chronic tretment with perindopril, novel long-cting AC inhibitor (Mcfyden et l, 199), nd enlpril t non-hypotensive doses were studied on crdic hypertrophy fter ligtion of the coronry rtery in rts
838 K CHIBA et l Methods Animls Animls in the present study were treted ccording to the guidelines for niml experimenttion prepred by the Jpnese Assocition for Lbortory Animls Science Sprgue-Dwley mle rts (Nihon SLC, Shizuok, Jpn), weighing 25-3 g, were ssigned to shm-opertion or myocrdil infrction group fter n observtion period of three weeks Myocrdil infrction ws produced by ligtion of the left coronry rtery s described by Selye et l (196) with modifiction Briefly, the nimls were nesthetized by inhltion of 2% hlothne, followed by 5% hlothne during rtificil respirtion A left thorcotomy ws performed t the fourth intercostl spce The hert ws gently exteriorized to ligte the left coronry rtery 2 mm from its origin Then, the hert ws replced in its norml position nd the chest ws compressed to remove ir from the pleurl cvity nd stitched with single suture Successful occlusion of the rtery ws confirmed by ppernce of Q wves in the electrocrdiogrm (Leds I, II nd VL), indicting the presence of myocrdil ischemi (Pfeffer et l, 1987; Sweet et l, 1987; 1988; Ry et l, 1989) In the shm-opertion group, the nimls underwent left thorcotomy without ligtion of the coronry rtery One week fter the surgery, the nimls were nesthetized with 2% hlothne to record electrocrdiogrms The nimls with Q wves in leds I, II nd VL were rndomly ssigned to one of five groups: () control tretment, nd chronic tretment with (b) perindopril (2mgkg-' dy-'), (c) perindopril (2mgkg-' dy-'), (d) enlpril (2mgkg'I dy-'), nd (e) enlpril (2mgkg-' dy-') The nimls were llowed free ccess to tp wter (shm-opertion nd control tretment groups) or drinking wter including perindopril or enlpril for three weeks The concentrtion of perindopril ws djusted to be equivlent to dily dose of 2 nd 2mgkg-' nd enlpril, 2 nd 2mgkg-' dy-' The rts were weighed every week to redjust the concentrtions of the compounds in the drinking wter The drug solutions were mde freshly every two dys Systolic rteril pressure nd hert rte were mesured weekly during the tretment by mens of til-cuff probe connected to pressure monitor (BP-98, Softron, Jpn) At the end of the tretments, crdic function, crdic weight nd myocrdil infrction size were mesured In the other nimls, plsm nd tissue AC ctivities were determined Crdic function At the end of the tretment, crdic function ws mesured under nesthesi with thiopentone A micro-tip ctheter trnsducer (Model SPR-47, 2F, Miller Instruments Inc, Houston, USA) ws introduced into the left ventricle through the right crotid rtery for the mesurement of systolic nd end-distolic pressure nd mximum positive dp/dt Ventriculr weight nd myocrdil infrction size After the study of crdic function, herts were rpidly removed The herts were seprted into right nd left ventricle including septum, nd the wet weight of the ventricles ws mesured The herts from coronry-ligted rts were fixed in 1% buffered formlin solution for determintion of myocrdil infrction size The left ventricles were trimmed nd sliced trnsversely, prllel to the trioventriculr groove, in five sections of 15-2mm from pex to bse The sliced sections were dehydrted in methyl lcohol, clered with xylene, nd embedded in prffin Then, sections were cut, 5 pm in thickness nd stined with lstic- VnGieson trichrome These seril sections were mounted on slides for photogrphy Infrct size ws mesured by plnimetry nd clculted s the men percentge rtio of infrction to totl left ventriculr circumference (Fletcher et l, 1981) Mesurement of AC ctivity Under nesthesi with thiopentone, blood ws collected from the crotid rtery to obtin plsm Tissues (hert, lung, kidney nd ort) were removed fter exsnguintion, nd homogenized in 3% Triton X solution After centrifugtion of the homogentes t 29,2g for 15min, the superntnt ws used for mesurement of AC ctivity which ws determined by modified fluorometric method ccording to Unger et l (1982), using hippuryl-l-histidine-lleucine s substrte Briefly, the tissue homogente nd plsm smple (5 1I) were incubted in 4 p1 of PBS (ph 8): 3 mm NCl for 2 min t 37C Then, 5 p1 of 167 mm substrte solution ws dded to the rection mixture nd incubted t 37C for 3 min for plsm, 18 min for crdic tissue, 12 min for renl tissue, 1 min for pulmonry tissue nd 6 min for thorcic ort, respectively The rection solution (1 p1) ws removed into 1 N NOH solution nd 25 p1 of 2% ortho-phthldildehyde ws dded Thirty Tble 1 ffects of orl tretment with perindopril or enlpril infrction Systolic blood pressure Shm Control Perindopril 2 mg kg- ' dy-' 2mgkg-' dy-' nlpril 2mg kg-' dy-' 2 mg kg- ' dy- Hert rte Shm Control Perindopril 2mg kg-' dy-' 2 mg kg-' dy-' nlpril 2 mg kg-' dy-' 2 mg kg- ' dy- on systolic blood pressure nd hert rte in rts with myocrdil Tretment with AC inhibitors n Bseline I week 2 weeks 3 weeks 4 weeks 14 963 ± 28 17 974 ± 29 17 976±25 17 988 ± 34 17 973 ± 15 17 123 ± 33 14 456 ± 12 17 4413 ± 121 17 4571 ± 15 17 445 ± 81 17 4439 ± 78 17 423± 7 117 ± 32 819 ± 2 885 ± 22 844 ± 27 858 ± 2 879 ± 34 414 ± 13 4434 ± 12 456 ± 98 4261 ± 79 4339 ± 7 4265 ± 91 192 ± 34 891 ± 2 92 ± 41 746 ± 22 885 ± 35 88 ± 23 4171 ± 69 4161 ± 12 4285 ± 18 4269 ± 72 4293 ± 91 4427 ± 12 Vlues re men ± semen n, number of nimls P<5 vs control tretment group 174 ± 35 99 ± 21 935 ± 36 726 ± 23 886 ± 26 824 ± 17 4413± 134 4171 ± 128 4363 ± 1 4393 ± 74 4359 ± 73 4275 ± 72 138 ± 37 918 ± 22 936 ± 34 752 ± 32 893 ± 33 788 ± 27 4313 ± 12 4331 ± 85 4242 ± 84 4262 ± 75 4388 ± 97 4413 ± 78
CARDIAC HYPRTROPHY AND AC INHIBITORS 839 minutes lter, 1 ml of 8 N HCl ws dded nd centrifuged t 9 g for 1 min Then, fluorospectrometry of the smple ws performed (excittion: 355 nm, emission: 46 nm) with >i ' I - wci b 6 4 2 c 2 1r ChI I I 15 1 8 : 5 I- -J ;-- IU, - >o : d Sh 1 - - - - - - Control@ T 2 2 Perindopril F - @ Shm Control 2 2 Perindopril (mg kg-') - @ v v X 2 2 nlpril 2 2 nlpril 2 2 2 2 Perindopril nlpril (mg kg-') Figure 1 Crdic function in shm-operted nd coronry-ligted rts treted with perindopril (2 or 2 mg kg-' dy-'), enlpril (2 or 2 mg kg-' dy-'), or wter (control) () LVP, left ventriculr pressure; (b) LVDP, left ventriculr end-distolic pressure; (c) LV dp/dt,,, the mximum rte of rise in LVP; (d) LV dp/dt,,,rp, LV dp/dt,,,, divided by instntneous LVP P< 5 versus shmoperted rts; #P<5 versus control-tretment rts Results re expressed s mens ± semen of 18-23 nimls fluoroscnner (Titertek, Fluoroskn II, type 371, Flow Lbortories Jpn Co Ltd, Tokyo, Jpn) Drugs Perindopril tert-butylmin ws obtined from Institut De Recherches Interntionles Servier (Courbevoie Cedex, Frnce) nlpril mlte ws synthesized t Diichi Phrmceuticl Co, Ltd (Tokyo, Jpn) Hippuryl-L-histidine-Lleucine nd ngiotensin I were obtined from Sigm Chemicl Co (St Louis, MO, USA); ortho-phthldildehyde from Peptide Institute, Inc (Osk, Jpn); hlothne from Tked Chemicl Industries, Ltd (Osk, Jpn) Sttisticl nlysis Results re expressed s men ± semen; n refers to the number of nimls Sttisticl comprison ws performed by mens of Kruskl-Wllis test, followed by Mnn-Whitney test A P vlue of less thn 5 were considered to indicte sttisticlly significnt differences between groups Results Chnges in systemic blood pressure nd hert rte fter coronry ligtion (Tble 1) There ws no significnt difference between the groups in systolic blood pressure nd hert rte t the beginning of the experiments In the coronry-ligted rts, systolic blood pressure decresed one week fter the ligtion from 987 ± 12 mmhg to 861 ± 12 mmhg (in totl, n = 85) The orl dministrtion of perindopril (2 mg kg-' dy-') nd enlpril (2 mg kg-' dy-') reduced systolic blood pressure, which lsted until the end of the experiments Neither perindopril nor enlpril ffected hert rte ) U) O o C_ cn (n 15 r ) (I 1 F ^ D ) ) - I o O M: C_ 4- cn 5 I uo y = -512x + 9221 r= 58676 )4 8 12 RVW/BW (mg/g) b 15 y = -64335x + 9112 r= 178 1 5 c~p 4 8 12 16 RVW/BW (mg/g) Figure 2 Correltion between crdic hypertrophy nd systemic blood pressure () Controls nd perindopril-treted group (2 nd 2mg kg-' dy-'); (b) controls nd enlpril-treted groups (2 nd 2 mg kg- dy- ') RVW/BW, rtio of right ventriculr weight to body weight r = correltion coefficient 16
84 K CHIBA et l Tble 2 ffects of orl tretment with perindopril or enlpril on crdic hypertrophy nd infrct size in rts with myocrdil infrction Weights BW (g) RVW (mg) LVW (mg) WVW (mg) Crdic hypertrophic RVW/BW (mg/g) LVW/BW (mg/g) WVW/BW (mg/g) Infrction size (%) indices Coronry ligtion Perindopril Shm Control 2mgkg-' dy-' 2 mg kg -' dy- ' (n= 14) (n= 17) (n= 17) (n= 17) 434 ± 5$ 249 ± 7 846± 18 195 ± 24 57 ± 1: 195 ± 3 252 ± 4: 398 ± 6 31 ± 19 81 ± 16 112 ± 19 393 ± 6 24 ± 9 786 ± 19$ 126±25$ 76 ± 6 61 ± 2: 22 ± 44 2 ± 4 278 ± 7 261 ± 5 56±3 49±3 381 ± 7 229 ± 7 678 io1 96 i±15 6 ± 2: 178 ± 2 238 ± 3: 45±3: nlpril 2mgkg-' dy-' (n= 17) (n= 17) 4 ± 6 277 ± 2 757± 1: 134 ± 24$ 69 ± 5 19 ± 2: 259 ± 6: 44±2$ 2mgkg-' dy-' 38 ± 7$ 228 ± 7$ 77 ± 111 935 ± 14$ 6 ± 2: 187 ± 4: 247 ± 4: 43±3: Vlues re men ± semen BW, body weight; RVW, right ventriculr weight; LVW, left ventriculr weight; WVW, whole ventriculr weight; infrction size, percent of the ventricle; n, number of nimls P<5 vs shm; tp<5 vs control I~f (,7 4L-C > cn )I LUc CD Hert VA A - G L [r - 2 - O ' t t v 2 2 o,_ to o % - NL C M 2 2 Cc 6 6 _7_ > 4 = M ) 2 C o Plsm o _ C Uj M 4) 9- > 3 o _ Lung Kidney t (Un2 () cn 1!o > C 2 2 2 2 LA- 2 2 2 2 - = r 4- > A 1% Anrtq QJ ch Co s C ~ ~ Uo S o Figure 3 Angiotensin converting enzyme (AC) ctivity in shm-operted nd coronry-ligted rts treted with perindopril (2 or 2 mg kg-' dy- 1), enlpril (2 or 2 mg kg- dy- ), or wter (control) P < 5 versus shm-operted rts; #P< 5 versus control rts Results re expressed s mens ± semen of five nimls
CARDIAC HYPRTROPHY AND AC INHIBITORS 841 Crdic function t the end of tretment (Figure 1) In the controls, left ventriculr pressure (LVP), the mximum rte of rise of LVP (LV dpidtm) nd LV dp/dt, divided by instntneous LVP (LV dp/dt,,/,jp; n index of crdic contrctility) were reduced, nd left ventriculr end-distolic pressure (LVDP) ws incresed compred to the shmoperted group Perindopril (2 mg kg-' dy-') nd enlpril (2 mg kg' dy-') decresed LVP nd LV dp/dtr,,, respectively There ws no significnt difference in LVDP nd LV dp/dt,,i/p between the controls, perindopril- nd enlpriltreted groups Crdic weight nd myocrdil infrction size (Tble 2) The rtio of right ventriculr weight to body weight (RVW/ BW) ws higher in the controls thn in the shm-operted group This increse in RVW/BW ws significntly ttenuted in the nimls treted with perindopril (2 mg kg-' dy- ' or 2 mg kg'-l dy- ') or enlpril (2 mg kg- dy-'), but not in the nimls treted with 2 mg kg-' dy-' enlpril There ws no significnt correltion between RVW/BW nd systemic blood pressure t the end of tretments with perindopril (r = 6) or enlpril (r = 1) (Figure 2) Although myocrdil infrction size vried in nrrow rnge (43-562% of left ventricle) in ll of the coronry-ligted rts, the size in nimls treted with perindopril (2 mg kg-' dy-') nd enlpril (2 nd 2mgkg-' dy-') ws significntly smller thn in controls AC ctivity (Figure 3) Crdic AC ctivity ws four fold higher in the control tretment group with coronry ligtion (control) thn in the shm-operted group In contrst, there ws no significnt difference between control nd shm-operted groups in AC ctivities in plsm nd kidney, lung nd ort The increse in crdic AC ctivity ws significntly inhibited by chronic tretment with perindopril (2 nd 2mgkg-' dy-'), but not by tretment with enlpril (2 nd 2mg kg-' dy-') AC ctivities in the kidney nd lung were lowered in the groups treted with perindopril or enlpril t both doses, respectively Aortic AC ctivity ws suppressed in the perindopril-treted (2 nd 2 mg kg-' dy-') nd 2 mg kg-' dy-' enlpril-treted groups, but not in the 2mgkg-' dy-' enlpril-treted group Discussion To clrify the beneficil effects of chronic tretment with AC inhibitors on crdic hypertrophy nd dysfunction fter coronry ligtion, the present study focused on the chnges in hemodynmics nd tissue AC ctivities In the cute phse of myocrdil infrction, the ctivtion of renin in plsm cn lter systemic hemodynmics, which my ffect the chronic progression of crdic hypertrophy nd dysfunction (Dzu et l, 1981) To void n interction with the cute effects of AC inhibitors on hemodynmics, the inhibitors were given to the rts from one week fter ligtion of coronry rteries, when the ctivities of circulting reninngiotensin system return to bseline The selection of two orl doses of ech perindopril or enlpril ws bsed on the effects of the compounds on systemic blood pressure in preliminry studies (dt not shown); lower doses which did not lter blood pressure nd higher doses which decresed systolic blood pressure by 1-15 mmhg At the end of the experiments, four weeks fter coronry ligtion, significnt crdic hypertrophies were induced in the right ventricles The progression of right ventriculr hypertrophy is n dptive response to the incresed pre- nd fterlod due to impired function of left ventricle with myocrdil infrction The hypertrophy in the right ventricle ws ssocited with the elevtion of LVDP nd increse in crdic AC ctivity in the controls with coronry ligtion compred to shm-operted nimls However, AC ctivities were not enhnced in plsm, lung, kidney nd ort, indicting selective ctivtion of crdic AC in rts with myocrdil infrction The present results re consistent with previous findings (Hirsch et l, 1991) Chronic tretment with perindopril t both doses of 2 nd 2 mg kg-' dy-' ttenuted right ventriculr hypertrophy nd lowered AC ctivities in hert, lung, ort nd kidney, but not in plsm Perindopril t 2 mg kg-' dy-' did not lter systemic blood pressure nd hert rte during the experiments The increse in LVDP in controls my contribute to stimulte the progression of the crdic hypertrophy However, perindopril nd enlpril did not significntly reduce LVDP t the end of experiments In contrst to perindopril, enlpril t nonhypotensive dose (2 mg kg-' dy-') did not inhibit right ventriculr hypertrophy A dose of 2 mg kg-' dy-' of enlpril ws required (which lowered blood pressure) to ttenute the hypertrophy in right ventricles However, it is unlikely tht enlpril inhibits crdic hypertrophy due to its effects on hemodynmics since there is no correltion between systolic blood pressure nd right ventriculr hypertrophy t the end of tretment with enlpril Hence, the present findings demonstrte tht the beneficil effects of AC inhibitors re independent of significnt fll in blood pressure on the crdic hypertrophy Thus, the direct influence on hemodynmics is seprte from the nti-hypertrophic effects of AC inhibitors in the rt hert filure model of coronry ligtion The present results re in greement with previous studies showing tht rmipril prevents left ventriculr hypertrophy without blood pressure reduction in the ortic stenosis model in rts (Linz et l, 1989; Linz & Sch6lkens, 1992) Alterntively, the present findings suggest tht selective ugmenttion of AC ctivities in crdic tissues explins, t lest in prt, the progression of crdic hypertrophy fter coronry ligtion Stimultion of conversion of ngiotensin I to ngiotensin II my led to cell growth of myocytes The discrepncy between the two AC inhibitors, perindopril nd enlpril, in the selectivity of ctions on crdic hypertrophy nd hemodynmics my be due to the different potency of AC inhibition in herts nd vessels (Hirsch et l, 1992) The ttenution by perindopril of the progression of crdic hypertrophy nd the increse in crdic AC ctivity is consistent with erlier observtions (Pfeffer et l, 1985; 1988; Hirsch et l, 1991; Fornes et l, 1992) Perindopril (2 mg kg' dy-') nd enlpril (2 nd 2 mg kg-' dy-') lowered the weight of left ventricles including septum (LVW or LVW/BW) The inhibitors my suppress the cell growth in the non-infrcted region of the left ventricle; however, the interprettion of the present results requires cution since most of the infrcted myocrdium hd degenerted The reduction of infrct size by perindopril nd enlpril might ttenute the impired crdic function In ddition, the results of the present study do not rule out other possibilities concerning the mechnism of ction of AC inhibitors The enhnced concentrtion of brdykinin produced by AC inhibitors in the herts my prticipte in the regultion of crdic hypertrophy since the nti-hypertrophy effect of rmipril is inhibited by Hoe 14, kinin B2 receptor ntgonist (Linz & Scholkens, 1992) Furthermore, ngiotensin II stimultes the relese of nordrenline from drenergic nerve endings, which my ccelerte crdic hypertrophy due to the ctivtion of,-drenoceptors (Newling et l, 1989) In conclusion, the present study demonstrtes seprtion of hypotensive effects from nti-hypertrophic ctions of AC inhibitors fter myocrdil infrction in rts
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(Received October 8, 1993 Revised Jnury 24, 1994 Accepted Mrch 25, 1994)