Renal actions of the selective angiotensin AT 2 receptor ligands CGP 42112B and PD 123319 in the sodium-depleted rat

Abstract

The purpose of this study was to investigate the renal actions of the new selective angiotensin AT 2 receptor ligands, CGP 42112B and PD 123319, in comparison to those of the AT 1 receptor antagonist losartan, in the sodium-depleted, anesthetized rat. Losartan (1, 3 and 10 mg/kg i.v.) produced a dose-dependent decrease in blood pressure and renal vascular resistance that was statistically significant. Effective renal blood flow tended to increase in response to all doses of losartan while glomerula filtration rate either did not change or decreased, leading to a significant fall in filtration fraction. Losartan did not induce significant changes in urine volume, urinary sodium excretion, urinary potassium excretion or free water formation. The selective AT 2 receptor ligand CGP 42112B at infusion rates of 1–100 μg/kg per min i.v. had no significant effect on blood pressure or any measured parameter of renal function. However, when infused at 1000 μg/kg per min i.v., CGP 42112B did not affect blood pressure, but significantly increased effective renal blood flow, glomerular filtration rate, urinary sodium excretion, urinary potassium excretion and free water formation, while significantly decreasing renal vascular resistance. The selective AT 2 receptor ligand PD 123319 at infusion rates between 1 and 100 μg/kg per min i.v. also had no significant effect on blood pressure or on any measured parameter of renal function. However, at an infusion rate of 1000 μg/kg per min i.v., PD 123319 tended to increase renal vascular resistance, urinary sodium excretion, urinary potassium excretion and free water formation, and to decrease effective renal blood flow, although none of these changes reached a level of statistical significance. Based upon the published affinities of CGP 42112B and PD 123319 for AT 1 and AT 2 receptors, plasma levels of either compound after infusion at rates between 1 and 1000 μg/kg per min would be compatible with an interaction with AT 2 receptors. However, at infusion rates of 1000 μg/kg per min, an interaction with AT 1 receptors could be expected. The data demonstrate that the new AT 2 receptor ligands PD 123319 and CGP 42112B either have little effect on renal function or, at high doses, have actions which might be indirect or explained by an interaction with AT 1 receptors. The results therefore support a role for AT 1 but not AT 2 receptors in the control of renal function in the sodium-depleted, anesthetized rat.