Bradykinin potentiation by angiotensin-(1-7) and ACE inhibitors correlates with ACE C- and N-domain blockade
ACE inhibitors block B(2) receptor desensitization, thereby potentiating bradykinin beyond blocking its hydrolysis. Angiotensin (Ang)-(1-7) also acts as an ACE inhibitor and, in addition, may stimulate bradykinin release via angiotensin II type 2 receptors. In this study we compared the bradykinin-potentiating effects of Ang-(1-7), quinaprilat, and captopril. Porcine coronary arteries, obtained from 32 pigs, were mounted in organ baths, preconstricted with prostaglandin F(2alpha), and exposed to quinaprilat, captopril, Ang-(1-7), and/or bradykinin. Bradykinin induced complete relaxation (pEC(50)=8.11+/-0.07, mean+/-SEM), whereas quinaprilat, captopril, and Ang-(1-7) alone were without effect. Quinaprilat shifted the bradykinin curve to the left in a biphasic manner: a 5-fold shift at concentrations that specifically block the C-domain (0.1 to 1 nmol/L) and a 10-fold shift at concentrations that block both domains. Captopril and Ang-(1-7) monophasically shifted the bradykinin curve to the left, by a factor of 10 and 5, respectively. A 5-fold shift was also observed when Ang-(1-7) was combined with 0.1 nmol/L quinaprilat. Repeated exposure of porcine coronary arteries to 0.1 micromol/L bradykinin induced B(2) receptor desensitization. The addition of 10 micromol/L quinaprilat or Ang-(1-7) to the bath, at a time when bradykinin alone was no longer able to induce relaxation, fully restored the relaxant effects of bradykinin. Angiotensin II type 1 or 2 receptor blockade did not affect any of the observed effects of Ang-(1-7). In conclusion, Ang-(1-7), like quinaprilat and captopril, potentiates bradykinin by acting as an ACE inhibitor. Bradykinin potentiation is maximal when both the ACE C- and N-terminal domains are inhibited. The inhibitory effects of Ang-(1-7) are limited to the ACE C-domain, raising the possibility that Ang-(1-7) synergistically increases the blood pressure-lowering effects of N-domain-specific ACE inhibitors.
|Keywords||*Tetrahydroisoquinolines, Adolescent, Adult, Angiotensin I/*pharmacology, Angiotensin-Converting Enzyme Inhibitors/*pharmacology, Animals, Bradykinin/*pharmacology, Captopril/pharmacology, Coronary Vessels/*drug effects/physiology, Drug Synergism, Female, Humans, In Vitro, Isoquinolines/pharmacology, Male, Peptide Fragments/*pharmacology, Peptidyl-Dipeptidase A/chemistry/*metabolism, Protein Structure, Tertiary, Receptor, Bradykinin B2, Receptors, Bradykinin/drug effects/metabolism, Swine, Vasodilation/drug effects|
Tom, B., de Vries, R., Saxena, P.R., & Danser, A.H.J.. (2001). Bradykinin potentiation by angiotensin-(1-7) and ACE inhibitors correlates with ACE C- and N-domain blockade. Hypertension. Retrieved from http://hdl.handle.net/1765/9693