title: Differential effects of angiotensin converting enzyme inhibitors on the vasodepressor and prostacyclin responses to bradykinin.
abstract: Angiotensin converting enzyme (ACE) inhibitors block degradation of bradykinin and bradykinin stimulates prostacyclin production. ACE inhibitors are reported to increase prostaglandins. Therefore, we set out to determine 1) the contribution of prostacyclin to the bradykinin-mediated vasodepressor effects of ACE inhibitors, 2) whether ACE inhibitors alter the effect of bradykinin on prostacyclin, and 3) whether the effects of ACE inhibitors on bradykinin and prostaglandins are class effects or dependent on ACE inhibitor structure. To address these questions, we compared the effects of captopril, quinapril and placebo on blood pressure, urinary excretion of 2,3-dinor-6-keto-PGF1 alpha, and the vasodepressor response to i.v. bradykinin in 21 salt-replete normal-to-high renin hypertensive patients. Captopril and quinapril doses were titrated to lower pressure similarly. Captopril, but not quinapril, increased excretion of prostacyclin metabolite (217 +/- 50 vs. 135 +/- 21 pg/mg Cr base line, P < .05). Both ACE inhibitors dramatically, equally potentiated the vasodepressor response to bradykinin; the bradykinin dose required to decrease mean arterial pressure 15 mm Hg or increase pulse 20 bpm was 50-fold lower in ACEI-treated than in placebo-treated subjects (10 +/- 0 and 12.1 +/- 2.1 ng/kg/min in captopril and quinapril groups vs. 567 +/- 109 ng/kg/min in the placebo group; P < .005). ACE inhibition significantly attenuated the prostacyclin response to bradykinin at any given level of hypotensive response. Indomethacin abolished the prostacyclin response to bradykinin but did not alter the vasodepressor response. These data demonstrate that ACE inhibitors potentiate bradykinin-mediated vasodepression through a prostaglandin-independent mechanism. They suggest that although ACE inhibitors increase prostaglandins by increasing bradykinin, ACE inhibitors may attenuate prostaglandin production through a second bradykinin-independent mechanism.
authors.affiliation: Vanderbilt University Medical Center, Division of Clinical Pharmacology, Nashville, Tennessee, USA.
authors.forename: N J
authors.initials: NJ
authors.lastname: Brown
authors.forename: D
authors.initials: D
authors.lastname: Ryder
authors.forename: J V
authors.initials: JV
authors.lastname: Gainer
authors.forename: J D
authors.initials: JD
authors.lastname: Morrow
authors.forename: J
authors.initials: J
authors.lastname: Nadeau
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000031:analogs & derivatives / Q000652:urine; D000293:Adolescent; D000328:Adult; D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D001920:Bradykinin / Q000494:pharmacology*; D011464:Epoprostenol / Q000378:metabolism*; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D011674:Pulse / Q000187:drug effects; D016037:Single-Blind Method
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D015121:6-Ketoprostaglandin F1 alpha; C028290:2,3-dinor-6-ketoprostaglandin F1alpha; D011464:Epoprostenol; D001920:Bradykinin; D007213:Indomethacin