RENAL-SPECIFIC ACTIONS OF ANGIOTENSIN-II RECEPTOR ANTAGONISM IN THE ANESTHETIZED DOG

The role of angiotensin II (AII) in the regulation of systemic hemodynamic and renal function and sodium excretion, although important in states characterized by the activation of the renin-angiotensin system, remains unclear under basal conditions. The current studies were designed to define the role of AII in the basal regulation of cardiovascular and renal function using a specific AII receptor antagonist, DuP 753, in the normal anesthetized dog. No changes in mean arterial pressure, cardiac output, or systemic vascular resistance were observed during the infusion of DuP 753. In contrast, a significant increase in glomerular filtration rate (19.7 +/- 0.9 to 26.1 +/- 2.0 mL/min) and renal blood flow (151 +/- 20 to 188 +/- 26 mL/min), with a decrease in renal vascular resistance (0.85 +/- 0.10 to 0.66 +/- 0.06 mm Hg/mL/min) was observed. Associated with the renal hemodynamic changes, a diuretic (0.16 +/- 0.05 to 0.57 +/- 0.21 mL/min) and natriuretic (31.2 +/- 7.0 to 100.5 +/- 22.2-mu-Eq/min) response was also demonstrated. Renal hemodynamic changes were also associated with a decrease in tubular sodium reabsorption characterized by an increase in the fractional excretion of sodium (1.10 +/- 0.3 to 2.61 +/- 0.62%), with an associated decrease in whole-kidney proximal tubular reabsorption indicated by an increase in fractional excretion of lithium (31.2 +/- 2.2 to 40.8 +/- 3.9%). In addition, a kaliuretic (17.9 +/- 2.1 to 27.1 +/- 2.4-mu-Eq/min) response was observed despite a concurrent decrease in plasma aldosterone (10.8 +/- 1.5 to 8.1 +/- 1.0 ng/dL). In a second group of dogs, a time control study was performed using a vehicle infusion in a similar protocol to the one used in the first group of studies. No significant changes were noted in the cardiovascular and renal hemodynamic and excretory functions listed above during vehicle infusion in a group of time-control animals. The present study demonstrates that, in the anesthetized dog, specific AII receptor antagonism with DuP 753 results in a greater renal, rather than cardiovascular, effect, such that AII antagonism has selective renal vasodilatory actions and promotes diuresis and natriuresis.