[7-D-ALA]-angiotensin 1-7 blocks renal actions of angiotensin 1-7 in the anesthetized rat.
Exogenous angiotensin (Ang) 1-7 affects renal function, but the receptor(s) involved in this response remain(s) to be determined. In an in vitro preparation of proximal tubules, Ang 1-7 was shown to act on Ang II AT1 receptors (minor component), but also on a non-AT1, non-AT2 Ang receptor (major component) to inhibit reabsorption. In brain, Ang 1-7 also exerts effects mediated by a non-AT1, non-AT2 binding site; these effects are inhibited, however, by the angiotensin analog [7-D-Ala]-Ang 1-7. Therefore we tested the effect of Ang II AT1-receptor antagonist losartan and [7-D-Ala]-Ang 1-7 on the renal response to exogenous Ang 1-7 in standard renal-clearance experiments in the anesthetized rat. We found that Ang 1-7 (100 pmol/kg/min, i.a.) increased glomerular filtration rate (GFR), urinary flow rate (UV), and urinary sodium excretion (UNaV) without affecting mean arterial blood pressure (MAP) or urinary potassium excretion (UKV), confirming previous reports. Losartan (10 mg/kg, i.v.) blocked the pressor effect of exogenous Ang II (100 pmol/kg/min, i.a.), but did not significantly affect the renal response to Ang 1-7. Conversely, pretreatment with [7-D-Ala]-Ang 1-7 (5 nmol/kg/min) did not affect the pressor effect of Ang II, but abolished the renal response to Ang 1-7. Application of [7-D-Ala]-Ang 1-7 in the absence of exogenous Ang 1-7 did not alter MAP or GFR, but increased UNaV (by 52%). Our data indicate that similar to the response in brain, the renal response to exogenous Ang 1-7 may be mediated predominantly by a distinct non-AT1 binding site, which is sensitive to blockade by [7-D-Ala]-Ang 1-7. Furthermore, ambient endogenous Ang 1-7 acting on this distinct binding site may not contribute significantly to control of MAP or GFR, but exerts an antinatriuretic influence in the anesthetized rat.
Vallon
V
V
Department of Pharmacology, University of Tübingen, Germany.
Heyne
N
N
Richter
K
K
Khosla
M C
MC
Fechter
K
K
D000758:Anesthesia; D000803:Angiotensin I; D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects*; D007677:Kidney Function Tests; D007687:Kidney Tubules, Proximal / Q000187:drug effects; D019808:Losartan / Q000494:pharmacology; D008297:Male; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects
C092006:7-Ala-angiotensin (1-7); D000959:Antihypertensive Agents; D010446:Peptide Fragments; D000804:Angiotensin II; D000803:Angiotensin I; C118790:angiotensin I (1-7); D019808:Losartan