Comparison of the acute hypotensive effects of renin inhibition, converting enzyme inhibition, and angiotensin II antagonism in rats.
The purpose of this study was to compare the acute hypotensive efficacy of different types of inhibitor of the renin-angiotensin system. A renin inhibitor (RI), CGP 44,099 A, a converting enzyme inhibitor (CEI), enalaprilat, a peptidic angiotensin II (Ang II) antagonist, [Sar1, Ile8]Ang II (P-Ang IIA), and a nonpeptidic Ang II antagonist devoid of agonistic properties, 2-butyl-4-chloro-1- ([2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl)-5- (hydroxymethyl)imidazol (NP-Ang IIA), were administered intravenously to sodium-depleted rats (SDRs), renal hypertensive rats (two-kidney, one-clip) (RHRs), and spontaneously hypertensive rats (SHRs). The four compounds were all effective in lowering blood pressure (BP) in SDRs and RHRs. The maximum hypotensive response observed within 30 min of administration was similar for all four compounds (approximately 30 mm Hg in SDRs and 60 mm Hg in RHRs). In SHRs, the P-Ang IIA induced a pressor response whereas the RI, CEI, and NP-Ang IIA lowered BP to a similar extent (approximately 15 mm Hg). Pretreatment with the CEI completely prevented the hypotensive response to RI in SHRs, and vice versa. These observations indicate that the principal mechanism by which converting enzyme inhibitors lower BP after acute administration in these rat models is by inhibition of the formation of Ang II. The pressor response to the P-Ang IIA in SHRs is probably a consequence of its partial agonistic properties. Renin inhibitors and nonpeptidic Ang II antagonists, devoid of agonistic properties, promise to be effective antihypertensive agents similar to the CEIs.
Wood
J M
JM
Department of Cardiovascular Research, Ciba-Geigy Ltd., Basel, Switzerland.
Mah
S C
SC
Schnell
C
C
D015059:1-Sarcosine-8-Isoleucine Angiotensin II / Q000494:pharmacology; D000704:Analysis of Variance; D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D015773:Enalaprilat / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy*; D006977:Hypertension, Renal / Q000188:drug therapy*; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan; D009842:Oligopeptides / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D013997:Time Factors; D000092502:Renin Inhibitors
D015059:1-Sarcosine-8-Isoleucine Angiotensin II; D000804:Angiotensin II; D000806:Angiotensin-Converting Enzyme Inhibitors; D001713:Biphenyl Compounds; D015773:Enalaprilat; D007093:Imidazoles; D019808:Losartan; D009842:Oligopeptides; D000092502:Renin Inhibitors; C064186:CGP 44099