Potentiation of the hypotensive effect of bradykinin by angiotensin-(1-7)-related peptides.
In this study, we evaluated the bradykinin potentiating activity and ACE inhibitory activity of several Ang-(1-7)-related peptides: Ang-(2-7), Ang-(3-7), Ang-(4-7), Ang-(1-6), Ang-(1-5) and the selective antagonist of Ang-(1-7): D-[Ala7]Ang-(1-7) (A-779). In vivo experiments were performed in freely moving Wistar rats. ACE activity was evaluated by a fluorometric assay in rat plasma using Hip-His-Leu as a substrate. Intravenous injections of Ang-(1-7) (2.2 nmol) transformed the effect of a single dose of bradykinin (1 nmol) into the effect produced by a double dose. A similar bradykinin potentiating activity was demonstrated for Ang-(2-7) and Ang-(3-7). On the other hand, Ang-(1-5), Ang-(1-6), Ang-(4-7) and A-779 did not change the hypotensive effect of bradykinin in doses ranging from 8 up to 25 nmols. The hypotensive effect of bradykinin was increased by intravenous infusion (0.3 ng/min) of Ang-(1-7) > Ang-(2-7) > Ang-(3-7). Conversely, Ang-(1-5), Ang-(1-6), Ang-(4-7) or A-779 did not change the hypotensive effect of bradykinin. ACE inhibition with Ang-(1-7) related peptides occurred in the order: Ang-(2-7) > or = Ang-(3-7) > Ang-(1-7) [>>] Ang-(1-5) > Ang-(4-7) > or = Ang-(1-6) > or = A-779. A-779 in concentrations up to 10(-5) M did not change the ACE inhibitory activity of Ang-(1-7). These results suggest that Ang-(1-7), Ang-(2-7) and Ang-(3-7) can modulate bradykinin actions in vivo. More important, our data pointed out that alternative mechanisms besides interaction with ACE are required to explain the bradykinin potentiating activity of Ang-(1-7).
Paula
R D
RD
Departamento de Fisiologia e Biofísica Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Lima
C V
CV
Britto
R R
RR
Campagnole-Santos
M J
MJ
Khosla
M C
MC
Santos
R A
RA
D000803:Angiotensin I / Q000737:chemistry* / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000494:pharmacology*; D004357:Drug Synergism; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology*; D007703:Peptidyl-Dipeptidase A / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D014851:Wakefulness
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D010446:Peptide Fragments; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; C118790:angiotensin I (1-7); D001920:Bradykinin