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CARDIOVASCULAR

Methyl--cyclodextrin Prevents Angiotensin II-Induced Tachyphylactic Contractile Responses in Rat Aorta

Department of Physiology (R.C.W., R.L.), Medical College of Georgia, Augusta, Georgia; and Department of Pharmacology and Toxicology (A.E.L., K.M.T., J.M.T., S.W.W.), Michigan State University, East Lansing, Michigan

Tachyphylaxis or desensitization is frequently observed following angiotensin II type I (AT₁) receptor activation by angiotensin II. One of the possible mechanisms contributing to receptor desensitization involves receptor internalization. In addition to clathrin-coated pits/vesicles, caveolae, small invaginations in the plasma membrane rich in cholesterol, may also be involved in receptor internalization. After activation, AT₁ receptor partially redistributes to lipid-enriched domains. We hypothesize that AT₁ receptor internalization via caveolae contributes to the tachyphylactic response observed to angiotensin II. Endothelium-denuded rat aortic rings were exposed to increasing concentrations of angiotensin II or phenylephrine, generating two cumulative concentration-effect curves (CCEC) with a 90-min interval separating each curve (CCEC-I and CCEC-II). CCEC-II was performed in the presence of either vehicle or methyl--cyclodextrin (CD), a drug that depletes cholesterol from the membrane and disassembles caveolae. CCEC-II to angiotensin II, but not to phenylephrine, was blunted in aortic rings treated with vehicle. In the presence of CD, CCEC-II did not differ significantly from CCEC-I for both agonists. CCEC-I to angiotensin II was abolished when in the presence of the AT₁ receptor antagonist. The presence of AT₁ receptors at the aortic smooth muscle cells' membrane treated with angiotensin II was observed by immunofluorescence only in the presence of CD. In addition, caveolin-1 coimmunoprecipitated with AT₁ receptor after agonist stimulation, and this interaction was inhibited by CD. Our data suggest that caveolae are involved in the tachyphylactic contractile response induced by angiotensin II in rat aorta, and this effect is related to receptor internalization.

Address correspondence to: Dr. A. Elizabeth Linder, Michigan State University, Department of Pharmacology and Toxicology, B-445 Life Sciences Building, East Lansing, MI 48824-1317. E-mail: linderau{at}msu.edu

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