Endothelium-dependent desensitization to angiotensin II in rabbit aorta: the mechanisms involved

The aim of this study was to characterize the role of the endothelium in an giotensin II-desensitization and its mechanisms of action. Rabbit aortic ri ngs were exposed to increasing doses of angiotensin II (Ang II, 10(-9) to 2 .5 x 10(-6)) to generate two cumulative dose-response curves (CDRC I and II ). A 50-min interval separated CDRC I and II. Desensitization was observed at all doses in unrubbed aortic tissue and at lower doses in rubbed aortic tissue. Tachyphylaxis was greater in arteries with endothelium. Treatment o f intact rings with L-N-G-nitroarginine methyl ester (L-NAME, 10(-4) M) did not prevent this phenomenon. However, indomethacin (10(-5) M) and miconazo l (10(-6) M) attenuated Ang II-desensitization. Treatment of unrubbed rings with nifedipine (10(-6) M) and cromakalim (10(-6) M) inhibited the effect of indomethacin. To confirm the involvement of K+ channels, unrubbed and ru bbed aortic rings were treated with the K-Ca(2+) blockers apamin (10(-7) M) , tetraethylammonium (TEA, 10(-3) M), and iberiotoxin (10(-8) M), and the K -ATP blocker glibenclamide (10(-5) M). In both arteries apamin, TEA, and gl ibenclamide abolished the tachyphylaxis without changes in the maximal resp onse. Iberiotoxin diminished Ang II-desensitization in rubbed but not unrub bed arteries. Results from this study suggest that Ang II-desensitization i nvolves endothelium-dependent and -independent mechanisms. Endothelium-depe ndent desensitization could be mediated by a cyclooxygenase-cytochrome P-45 0 product, which could act by increasing K-Ca(2+) channel activity.