Antihypertensive activity of the novel, nonpeptide angiotensin II receptor antagonists BIBS 39 and BIBS 222 in conscious renal hypertensive rats.
BIBS 39 and BIBS 222 are novel, nonpeptide angiotensin II receptor antagonists with a benzimidazole structure. These compounds, in contrast to the angiotensin II receptor subtype 1 (AT1) selective drug DuP 753, also display affinity for the angiotensin II receptor subtype 2. Their antihypertensive activity was established in conscious renal hypertensive rats. BIBS 39, BIBS 222 and DuP 753, when administered intravenously, caused a substantial dose-dependent antihypertensive effect with very similar ED30 values of approximately 2 mg/kg. The antihypertensive effect was accompanied by mild and transient reflex tachycardia. Captopril, when administered directly after the maximally effective dose of the three angiotensin II receptor antagonists, caused no further fall in blood pressure. This finding indicates that these angiotensin II receptor antagonists had caused a functionally effective suppression of the activity of the renin-angiotensin-aldosterone system. BIBS 222 had a longer duration of antihypertensive action than its congener BIBS 39. The hemodynamic pattern of DuP 753 was somewhat more complex; after a rapid fall and recovery blood pressure was maintained for a long time at a level somewhat below the control value. BIBS 39 and BIBS 222 appear to be effective antihypertensives in the model of the renal hypertensive rat. Their activity is likely to be associated with AT1 receptor blockade.
Zhang
J
J
Department of Pharmacotherapy, University of Amsterdam, Academic Medical Centre, The Netherlands.
Van Meel
J C
JC
Van Zwieten
P A
PA
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006977:Hypertension, Renal / Q000188:drug therapy*; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan; D008297:Male; D008782:Methylurea Compounds / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013777:Tetrazoles / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007093:Imidazoles; D008782:Methylurea Compounds; D013777:Tetrazoles; C077352:BIBS 39; C077353:BIBS 222; D019808:Losartan