Effects of the Nonpeptide Angiotensin II Receptor Antagonist DuP 753 on Blood Pressure and Renal Functions in Spontaneously Hypertensive PH Dogs

Abstract

A colony of genetic hypertensive dogs with systolic blood pressure of 140 to 220 mm Hg and diastolic blood pressure greater than 100 mm Hg in the trained state was used. The objective of this study was to investigate the hemodynamic and renal effects of the novel angiotensin II receptor antagonist DuP 753 given intravenously to these dogs. Renal functions and blood pressure were measured 45 to 75 min after the intravenous administration of DuP 753 at 1, 3, 10, and 30 mg/kg and were compared to control (placebo) treatment. Arterial pressure was slightly but significantly and dose-dependently reduced by DuP 753. Glomerular filtration rate increased significantly in a dose-dependent manner. Similarly, effective renal plasma flow was dose-dependently increased. Filtration fraction was unchanged. Renal vascular resistance was significantly reduced in a dose-dependent manner at 3, 10, and 30 mg/kg of DuP 753. DuP 753 increased fractional sodium excretion at all doses and increased fractional potassium excretion only at the highest doses. The vasopressor effects of angiotensin I and II were dose-dependently inhibited by DuP 753. These data show that DuP 753 has beneficial renal hemodynamic effects and lowers arterial pressure in this canine model of essential hypertension.