Evidence for Mas-mediated bradykinin potentiation by the angiotensin-(1-7) nonpeptide mimic AVE 0991 in normotensive rats.
We evaluated the effect of the nonpeptide mimic of angiotensin (Ang)-(1-7), AVE 0991, on the hypotensive effect of bradykinin (BK). Increasing doses of intra-arterial or intravenous BK were administered before and 30 minutes after the beginning of AVE 0991 infusion. The effect of AVE 0991 on plasma Ang-converting enzyme activity was tested using Hip-His-Leu as the substrate. The interaction of AVE 0991 with Ang-converting enzyme in vivo was tested by determining its effect on the pressor action of Ang I or Ang II. AVE 0991 produced a significant and similar potentiation of intra-arterial or intravenous bradykinin. AVE 0991 did not inhibit plasma Ang-converting enzyme activity in vitro or the pressor effect of Ang I in vivo. N(W)-nitro-l-arginine methyl ester or D-Ala(7)-Ang-(1-7) administration abolished the BK potentiating effect of AVE 0991. We further examined the BK-potentiating effect of AVE 0991, evaluating its effect on NO production in rabbit endothelial cells. The NO release was measured using the 4-amino-5-methylamino-2'-7'-difluorofluorescein diacetate. A synergistic effect of AVE 0991 and BK on NO release was observed. These results suggest that AVE 0991 potentiates bradykinin through an Ang-converting enzyme-independent, NO-dependent receptor Mas-mediated mechanism. This effect may contribute to the improvement of endothelial function by AVE 0991 in vivo.
Carvalho
Mariana B L
MB
Laboratory of Hypertension, Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
Duarte
Fernanda V
FV
Faria-Silva
Raphael
R
Fauler
Beatrix
B
da Mata Machado
Leonor T
LT
de Paula
Renata D
RD
Campagnole-Santos
Maria J
MJ
Santos
Robson A S
RA
D000803:Angiotensin I / Q000494:pharmacology*; D000804:Angiotensin II / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007022:Hypotension / Q000378:metabolism / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology*
C092006:7-Ala-angiotensin (1-7); C469726:AVE 0991; D004791:Enzyme Inhibitors; D007093:Imidazoles; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D014665:Vasodilator Agents; D000804:Angiotensin II; D009569:Nitric Oxide; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; C118790:angiotensin I (1-7); D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester