Low sodium diet inhibits the local counter-regulator effect of angiotensin-(1-7) on angiotensin II.
OBJECTIVE
The heptapeptide angiotensin-(1-7) [Ang-(1-7)] has been identified as a versatile, endogenous inhibitor of the renin-angiotensin system (RAS). As the therapeutic response to exogenous RAS inhibitors, such as AT1 receptor antagonists, is altered by changes in salt intake, we investigated the effect of a low, normal and high sodium diet on the antagonism of Ang II by Ang-(1-7). The role of angiotensin receptor subtypes and the endothelium was assessed.


METHODS
Male Wistar rats received a normal sodium (0.3% NaCl), high sodium (2.0% NaCl) or low sodium (0.05% NaCl) diet for 10 days. Vascular responses were assessed ex vivo in thoracic aortic rings in the presence of the nitric oxide (NO) inhibitor N-monomethyl-l-arginine (l-NMMA) to avoid aspecific vasodilator effects of Ang-(1-7).


RESULTS
After a normal or high salt diet, Ang-(1-7) significantly decreased maximal Ang II-induced vascular constrictions by 40-50%. After a low salt diet this non-competitive antagonism disappeared. The AT2 receptor antagonist PD 123319 and the Ang-(1-7) receptor antagonist A779 attenuated the effect of Ang-(1-7) found in rats fed with a normal or high sodium diet. Further, removal of endothelium and pretreatment with the prostaglandin synthesis inhibitor indomethacin (10 mol/l) abolished the non-competitive antagonism by Ang-(1-7).


CONCLUSIONS
Ang-(1-7) elicits a specific, endothelium-dependent and non-competitive antagonism of Ang II, which involves AT2 and Ang-(1-7) receptors but is independent of NO production. This non-competitive antagonism of Ang-(1-7) is abolished by a low sodium intake in normotensive rats, suggesting that it serves as a negative feedback towards Ang II in response to an altered sodium intake.
Roks
Anton J M
AJ
Department of Clinical Pharmacology, Groningen University Institute for Drug Exploration (GUIDE), University of Groningen, Groningen, The Netherlands. a.j.m.roks@med.rug.nl
Nijholt
Jeroen
J
van Buiten
Azuwerus
A
van Gilst
Wiek H
WH
de Zeeuw
Dick
D
Henning
Robert H
RH
D000803:Angiotensin I / Q000378:metabolism / Q000494:pharmacology*; D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D057912:Angiotensin II Type 2 Receptor Blockers; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects*; D004039:Diet, Sodium-Restricted; D004730:Endothelium, Vascular / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044139:Receptor, Angiotensin, Type 2 / Q000502:physiology; D011945:Receptors, Angiotensin / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects*
D057912:Angiotensin II Type 2 Receptor Blockers; D057911:Angiotensin Receptor Antagonists; D010446:Peptide Fragments; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D000803:Angiotensin I; C118790:angiotensin I (1-7)