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 angiotensin II-desensitization and its mechanisms of action.Rabbit aortic rings were exposed to increasing doses of angiotensin II (Ang II, 10 -9 to 2.5 × 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 of 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 miconazol (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 rubbed 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 glibenclamide abolished the tachyphylaxis without changes in the maximal response.Iberiotoxin diminished Ang II-desensitization in rubbed but not unrubbed arteries.Results from this study suggest that Ang II-desensitization involves endothelium-dependent and -independent mechanisms.Endothelium-dependent desensitization could be mediated by a cyclooxygenase-cytochrome P 450 product, which could act by increasing K Ca 2+ channel activity.