Effect of angiotensin receptor blockade in the rabbit aorta: influence of the endothelium.
Contractile responsiveness of the rabbit aorta (endothelium intact and denuded) to angiotensin I, II, and III was compared. The effects of converting-enzyme inhibition with enalapril, the selective AT1-receptor antagonist (losartan), and the AT2-receptor antagonist (PD 123319) on these contractile profiles were examined. In all preparations, it was found that the angiotensins produced concentration-dependent increases in tension. Differences in sensitivity were encountered; in endothelium-intact preparations, the mean EC50 values (nM with 95% confidence interval in parentheses) for angiotensin I, II, and III were 9 (95% CI 7-11), 40 (20-60), and 30 (10-40), respectively, and for denuded preparations they were 20 (11-29), 0.8 (0.7-0.9), and 30 (20-40), respectively. Enalapril decreased the maximal tension developed to angiotensin I and II, which was greater in endothelium-intact preparations. Losartan was a competitive antagonist against angiotensin I and angiotensin II in both intact and denuded preparations, with pA2 values as follows: against angiotensin I, 9.0 and 9.3 for intact and denuded, respectively; against angiotensin II, 8.3 and 8.9 for intact and denuded, respectively. Losartan antagonized angiotensin III, but the slopes of the Schild analysis were significantly less than unity. In endothelium-intact preparations, PD 123319 failed to significantly antagonize responsiveness to angiotensin I. Against angiotensin II, PD 123319 was a competitive antagonist with a pA2 of 8.3. The antagonism for PD 123319 against angiotensin III was insurmountable. In endothelium-denuded preparations, PD 123319 failed to antagonize angiotensin I and angiotensin III. Although PD 123319 appeared to inhibit the responsivenss of the rabbit aorta by angiotensin II, the slope of the Schild plot was significantly less than unity. These experiments provide evidence that angiotensin I possesses different actions from angiotensin II and III and that a functional endothelium modulates the underlying vascular response to angiotensin. In addition, the endothelium modulates the antagonism by losartan and PD 123319, supporting the notion that the endothelium possesses distinct angiotensin receptors.
le Tran
Y
Y
Department of Pharmacology, University of Toronto, ON, Canada.
Forster
C
C
D000803:Angiotensin I / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000805:Angiotensin III / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000378:metabolism; D001713:Biphenyl Compounds / Q000494:pharmacology; D004656:Enalapril / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan; D008297:Male; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D011945:Receptors, Angiotensin / Q000187:drug effects*; D013777:Tetrazoles / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D011725:Pyridines; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; D000805:Angiotensin III; C073402:PD 123319; D004656:Enalapril; D000803:Angiotensin I; D019808:Losartan