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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Translocation of AT₁- and AT₂-Receptors by Higher Concentrations of Angiotensin II in the Smooth Muscle Cells of Rat Internal Anal Sphincter

Department of Medicine, Division of Gastroenterology and Hepatology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania

Previous studies have reported bimodal effects by angiotensin II (Ang II) in the rat internal anal sphincter (IAS), a concentration-dependent contraction (at lower concentrations) and relaxation (at higher concentrations). The experiments suggest the above-mentioned responses are the result of Ang II subtype I receptor(s) (AT₁-R) and subtype II receptor(s) (AT₂-R) activation, respectively. These studies determined the role and mechanism of AT₂-R-induced relaxation of the smooth muscle cells (SMCs) from the IAS in response to Ang II. Laser confocal microscopy showed that in the basal state, the AT₁-Rs reside in the plasma membrane, whereas AT₂-Rs are present in the cytosol. Higher concentrations of Ang II caused movement of AT₁-R and AT₂-R in opposite directions to the cytosol and the membrane, respectively. Losartan (AT₁-R antagonist) but not S-(+)-1-([4-(dimethylamino)-3-methylphenyl]methyl)-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo(4,5-c)pyridine-6-carboxylic acid (PD123319; AT₂-R antagonist) selectively inhibited these movements. These results are based on biotinylation assays, confocal images, and Western blot analyses of the densities of AT₁-Rs and AT₂-Rs in the plasma membrane versus cytosolic fractions of the IAS SMCs. Ang II in higher concentrations did not change the total contents of Ang II receptors. These data combined with the functional data using measurements of IAS SMC lengths suggest that internalization of AT₁-R and externalization of AT₂-R may be responsible for the activation of the AT₂-R, which leads to the relaxation of the IAS with higher concentrations of Ang II.

Address correspondence to: Dr. Satish Rattan, Jefferson Medical College, Thomas Jefferson University, 1025 Walnut St., Room 901 College, Philadelphia, PA 19107. E-mail: satish.rattan{at}jefferson.edu