Renal actions of angiotensin-(1-7): in vivo and in vitro
studies.
Handa, Rajash K., Carlos M. Ferrario, and Jack W. Strandhoy.
Department of Physiology & Pharmacology and Hypertension Center,
Bowman Gray School of Medicine of Wake Forest University, Winston
-Salem, North Carolina 27157, Department of Veterinary and Comparative
Anatomy, Pharmacology and Physiology, College of Veterinary Medicine,
Washington State University, Pullman, Washington State 99164
APStracts 2:0139F, 1995.
In vivo studies were conducted in sodium replete, anesthetized male
Wistar rats with denervated kidneys. Intrarenal injections of Ang-(1
-7) at doses > 1 nmol/kg produced a dose-dependent decrease in
renal blood flow that was mediated by the AT1 type Ang II receptor.
The dose-response curve to Ang-(1-7) was shallow and at least four
orders of magnitude to the right of that generated for Ang II. A
constant intrarenal infusion of Ang-(1-7) at 0.1 and 1 nmol/min/kg
had minimal effects on renal blood flow and blood pressure, and
resulted in an elevated urinary excretion of sodium and water
compared to the time control, saline-infused group. To determine
whether Ang-(1-7) may have a direct action on tubular epithelium to
inhibit sodium reabsorption, we examined the effect of Ang-(1-7) on
transport-dependent oxygen consumption (QO2) in fresh suspensions of
rat proximal tubules, in vitro. Ang-(1-7) inhibited QO2 in a
concentration-dependent fashion with a threshold concentration of 100
pM. Nystatin (Na ionophore) bypasses the rate-limiting step of apical
sodium entry and results in increased basal QO2 due to enhanced Na,K
-ATPase activity. Under nystatin-stimulated conditions, the inhibitory
concentration-response curve to Ang-(1-7) was shifted to the left. A
22% inhibition of QO2 by 1 pM Ang-(1-7) was abolished by pre
-treatment with the Na,K-ATPase inhibitor, ouabain. To define the
receptor subtype that mediated this inhibitory action of Ang-(1-7),
proximal tubules were pre-incubated with either a selective AT2 (PD
123319 at 1 [mu]M) or an AT1 receptor antagonist (losartan at 1
[mu]M). The decrease in nystatin-stimulated QO2 by 1 pM Ang-(1-7) was
unaltered by PD 123319 and only partially attenuated by losartan.
Pre-incubation with a non-selective angiotensin receptor antagonist
(Sar1,Thr8-Ang II at 1 [mu]M) abolished the inhibitory action of Ang
-(1-7). Together, these findings indicate that Ang-(1-7) has
biological activity in the kidney, and at non-vasoconstrictor doses
results in increased sodium and water excretion, in vivo. One site of
action is the proximal tubule where Ang-(1-7) can inhibit a ouabain
-sensitive Na,K-ATPase exit step in cellular sodium transport. This
novel inhibitory action of Ang-(1-7) appears to be mediated by both
an AT1 receptor (minor component) and a non-AT1, non-AT2 angiotensin
receptor (major component).
Received 4 November 1994; accepted in final form 17 July 1995.
APS Manuscript Number F394-4.
Article publication pending Am. J. Physiol. (Renal Fluid Electrolyte
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 14 August 1995.