RENAL ACTIONS OF ANGIOTENSIN-(1-7) - IN-VIVO AND IN-VITRO STUDIES

In vivo studies were conducted in Na-replete anesthetized male Wistar rats with denervated kidneys. Intrarenal injections of angiotensin-(1- 7) [ANG-(1-7)] at >1 nmol/kg produced a shallow dose-dependent decreas e in renal blood flow that was mediated by the AT(1)-type ANG II recep tor. A constant intrarenal infusion of ANG-(1-7) at 0.1 and 1 nmol . m in(-1). kg(-1) had minimal effects on renal blood flow and blood press ure and resulted in an elevated urinary excretion of Na and water comp ared with the time-control saline-infused group. To determine whether ANG-(1-7) may have a direct action on tubular epithelium to inhibit Na reabsorption, we examined the effect of ANG(1-7) on transport-depende nt O-2 consumption (QO(2)) in fresh suspensions of rat proximal tubule s in vitro. ANG-(1-7) inhibited QO(2) in a concentration-dependent fas hion with a threshold concentration of similar to 100 pM. Stimulating Na-K-adenosinetriphosphatase (Na-K-ATPase) activity with nystatin caus ed a leftward shift of the inhibitory concentration-response curve to ANG-(1-7). The 22% inhibition of QO(2) by 1 pM ANG-(1-7) was abolished by pretreatment with 5 mM ouabain (Na-K-ATPase inhibitor), unaltered by pretreatment with 1 mu M PD-123319 (AT(2) receptor antagonist), par tially attenuated by 1 mu M losartan (AT(1) receptor antagonist), and abolished by 1 mu M [Sar(1),Thr(8)]ANG II (nonselective ANG receptor a ntagonist). Together these findings indicate that ANG-(1-7) has biolog ical activity in the kidney and, at nonvasoconstrictor doses, results in increased Na and water excretion in vivo. One site of action is the proximal tubule, where ANG-(1-7) can inhibit an ouabain-sensitive Na- K-ATPase exit step in cellular Na transport. This novel inhibitory act ion of ANG-(1-7) appears to be mediated by an AT(1) receptor (minor co mponent) and a non-AT(1), non-AT(2) ANG receptor (major component).