DISTRIBUTION AND FUNCTION OF CARDIAC ANGIOTENSIN AT(1)-RECEPTOR AND AT(2)-RECEPTOR SUBTYPES IN HYPERTROPHIED RAT HEARTS

To determine distribution and function of cardiac angiotensin (ANG) II receptor AT(1) and AT(2) subtypes in left ventricular (LV) hypertroph y (LVH), ANG II (10(-8) M) was infused into isolated rat hearts with h ypertrophy from aortic banding and into sham-operated controls. ANG II was infused alone or in the presence of ATL inhibitor [losartan (10(- 5) M) or CL-329167 (10(-7) M)] or AT(2) inhibitor [CG-42112A (10(-8) M )]. ANG II alone caused less increase in coronary vascular resistance (CVR) in LVH compared with. control hearts (19 vs. 39%; P < 0.01), alt hough baseline CVR was higher in LVH hearts. This was prevented by AT( 1) but not AT(2) antagonists. ANG II also increased LV end-diastolic p ressure in LVH hearts, signifying decreased diastolic relaxation that was prevented by AT(1) but not AT(2) inhibition. Characterization of A NG II binding sites in LV membrane preparations revealed similar disso ciation constants between groups (1.6 +/- 0.95 vs. 2.2 +/- 2.0 nM; not significant) but lower maximum binding capacity in the LVH group (21. 1 +/- 5.9 vs. 33.5 +/- 3.0 fmol/mg protein; P < 0.05). Competition ass ays demonstrated that control left ventricles contain predominantly th e AT(1) subtype (68.8 +/- 20%), whereas LVH ventricles contain primari ly the putative AT(2) subtype (59.8% +/- 10.8%; P < 0.05). This sugges ts that receptor subtype redistribution occurs in LVH with AT(1) subty pe downregulation. Nonetheless, the AT(1) subtype mediates the effects of ANG II on coronary tone and diastolic dysfunction in pressure-over load hypertrophy.