title: Renal actions of angiotensin-(1-7): in vivo and in vitro studies.
abstract: 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 decrease in renal blood flow that was mediated by the AT1-type ANG II receptor. A constant intrarenal infusion of ANG-(1-7) at 0.1 and 1 nmol.min-1.kg-1 had minimal effects on renal blood flow and blood pressure and resulted in an elevated urinary excretion of Na and water compared 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-dependent O2 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 approximately 100 pM. Stimulating Na-K-adenosinetriphosphatase (Na-K-ATPase) activity with nystatin caused a leftward shift of the inhibitory concentration-response curve to ANG-(1-7). The 22% inhibition of Qo2 by 1 pM ANG-(1-7) was abolished by pretreatment with 5 mM ouabain (Na-K-ATPase inhibitor), unaltered by pretreatment with 1 microM PD-123319 (AT2 receptor antagonist), partially attenuated by 1 microM losartan (AT1 receptor antagonist), and abolished by 1 microM [Sar1, Thr8]ANG II (nonselective ANG receptor antagonist). Together these findings indicate that ANG-(1-7) has biological 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 action of ANG-(1-7) appears to be mediated by an AT1 receptor (minor component) and a non-AT1, non-AT2 ANG receptor (major component).
authors.affiliation: Department of Physiology and Pharmacology, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina 27157, USA.
authors.forename: R K
authors.initials: RK
authors.lastname: Handa
authors.forename: C M
authors.initials: CM
authors.lastname: Ferrario
authors.forename: J W
authors.initials: JW
authors.lastname: Strandhoy
mesh_terms: D000803:Angiotensin I; D000804:Angiotensin II / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects; D007668:Kidney / Q000187:drug effects*; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D008297:Male; D009761:Nystatin / Q000494:pharmacology; D009994:Osmolar Concentration; D010042:Ouabain / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation / Q000187:drug effects; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
chemical_list: D057911:Angiotensin Receptor Antagonists; D010446:Peptide Fragments; D000804:Angiotensin II; D009761:Nystatin; D010042:Ouabain; D000803:Angiotensin I; D000254:Sodium-Potassium-Exchanging ATPase; C118790:angiotensin I (1-7)