PT  - JOURNAL ARTICLE
AU  - A. Elizabeth Linder
AU  - Keshari M. Thakali
AU  - Janice M. Thompson
AU  - Stephanie W. Watts
AU  - R. Clinton Webb
AU  - Romulo Leite
TI  - Methyl-β-cyclodextrin Prevents Angiotensin II-Induced Tachyphylactic Contractile Responses in Rat Aorta
AID  - 10.1124/jpet.107.123463
DP  - 2007 Oct 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 78--84
VI  - 323
IP  - 1
4099  - http://jpet.aspetjournals.org/content/323/1/78.short
4100  - http://jpet.aspetjournals.org/content/323/1/78.full
SO  - J Pharmacol Exp Ther2007 Oct 01; 323
AB  - 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-β-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. The American Society for Pharmacology and Experimental Therapeutics