Effect of various angiotensin receptor antagonists on cardiovascular responses to angiotensin II in pithed rats.
The effects of four nonpeptide angiotensin receptor antagonists, i.e., losartan (AT1) PD123177 (AT2), and 4'-[(2-n-butyl-6-cyclohexylaminocarbonylamino-benzimidazole-1-yl)- methyl]biphenyl-carboxylic acid (BIBS 39; AT1 and AT2), and 2-n-butyl-1-[4-(6-carboxy-2,5-di-chlorbenzoylamino)-benzyl]-6-N- (methylaminocarbonyl)-n-pentylamino-benzimidazole (BIBS 222; AT1 and AT2) on cardiovascular responses to angiotensin II (AII) were investigated in propranolol-pretreated pithed rats. AII (0.01-10 nmol/kg intravenously, i.v.) induced a dose-dependent increase in diastolic blood pressure (DBP), the rate of increase in left ventricular pressure (LVdP/dtmax), cardiac output (CO), and total peripheral resistance (TPR) without changing LV end-diastolic pressure (LVEDP) or heart rate (HR). Losartan 3 and 10 mg/kg i.v. caused dose-dependent parallel rightward shifts of the dose-response curves (DBP and LVdP/dtmax) without altering the maximal responses to AII. PD123177 (100 mg/kg i.v.) did not influence the dose-response curves for AII significantly. BIBS 39 (1, 3, and 10 mg/kg i.v.) and BIBS 222 (1, 3, and 10 mg/kg, i.v.) shifted the dose-response curves (DBP and LVdP/dtmax) for AII to the right. Although these two compounds (BIBS 39 1, 3, and 10 mg/kg and BIBS 222 1 and 3 mg/kg) did not alter the maximal increase in DBP to angiotensin AII, they decreased the maximal increase in LVdP/dtmax by approximately 35%. BIBS 39 (3 and 10 mg/kg) significantly reduced the increase in CO caused by AII and therefore mean arterial pressure (MAP), whereas the AII-induced increase in TPR remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)
Zhang
J
J
Department of Pharmacotherapy, University of Amsterdam, The Netherlands.
Pfaffendorf
M
M
van Zwieten
P A
PA
D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D002320:Cardiovascular Physiological Phenomena; D002319:Cardiovascular System / Q000187:drug effects* / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan; D008297:Male; D008782:Methylurea Compounds / Q000494:pharmacology; D011433:Propranolol; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011945:Receptors, Angiotensin / Q000187:drug effects / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007093:Imidazoles; D008782:Methylurea Compounds; D011725:Pyridines; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; C066253:PD 123177; C077352:BIBS 39; C077353:BIBS 222; D011433:Propranolol; D019808:Losartan