Translocation of AT1- and AT2-receptors by higher concentrations of angiotensin II in the smooth muscle cells of rat internal anal sphincter.
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) (AT(1)-R) and subtype II receptor(s) (AT(2)-R) activation, respectively. These studies determined the role and mechanism of AT(2)-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 AT(1)-Rs reside in the plasma membrane, whereas AT(2)-Rs are present in the cytosol. Higher concentrations of Ang II caused movement of AT(1)-R and AT(2)-R in opposite directions to the cytosol and the membrane, respectively. Losartan (AT(1)-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; AT(2)-R antagonist) selectively inhibited these movements. These results are based on biotinylation assays, confocal images, and Western blot analyses of the densities of AT(1)-Rs and AT(2)-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 AT(1)-R and externalization of AT(2)-R may be responsible for the activation of the AT(2)-R, which leads to the relaxation of the IAS with higher concentrations of Ang II.
de Godoy
Márcio A F
MA
Jefferson Medical College of Thomas Jefferson University, Department of Medicine, Philadelphia, PA 19107, USA.
Rattan
Satish
S
D001003:Anal Canal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000804:Angiotensin II / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001710:Biotin / Q000378:metabolism; D015153:Blotting, Western; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D019808:Losartan / Q000494:pharmacology; D008297:Male; D018613:Microscopy, Confocal; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014178:Translocation, Genetic / Q000187:drug effects
D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II; C073402:PD 123319; D001710:Biotin; D019808:Losartan