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. 1994 Oct;38(4):317–321. doi: 10.1111/j.1365-2125.1994.tb04360.x

Inhibition of bradykinin-induced vasodilation in human forearm vasculature by icatibant, a potent B2-receptor antagonist.

J R Cockcroft 1, P J Chowienczyk 1, S E Brett 1, N Bender 1, J M Ritter 1
PMCID: PMC1364774  PMID: 7833220

Abstract

1. The effect of icatibant (D-Arg-[Hyp3, Thi5, D-Tic7, Oic8] bradykinin) a potent B2-kinin receptor antagonist, was studied on bradykinin-induced vasodilation in the human forearm. 2. Eight healthy normotensive men were studied in a rising dose random-placebo controlled study. Placebo and icatibant (20, 50 and 100 micrograms kg-1 i.v.) were administered double-blind. Forearm blood flow was measured by venous occlusion plethysmography during rising dose brachial artery infusions of bradykinin (10-3,000 ng min-1) 60-90 min after placebo or icatibant. 3. Plasma concentrations of icatibant fell exponentially following each of three doses, up to the final measurement. Elimination half-lives calculated from linear regression of the mean data were 25, 27 and 29 min after 20, 50 and 100 micrograms kg-1 doses respectively. 4. Icatibant inhibited the effect of bradykinin (P < 0.001 at each dose of icatibant) in a dose-dependent manner. Bradykinin (100 ng min-1) increased mean blood flow in the infused arm by 238 +/- 31% when infused following placebo, by 112 +/- 21% after icatibant 20 micrograms kg-1, by 71 +/- 14% after icatibant 50 micrograms kg-1 and by 48 +/- 9% after icatibant 100 micrograms kg-1. 5. These results demonstrate that icatibant antagonises B2-receptor mediated vasodilation in human forearm resistance vessels. The findings provide a quantitative basis for future studies of the role of bradykinin in the response to angiotensin converting enzyme inhibitors and in circulatory disease.

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Selected References

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  1. Barrow S. E., Cockcroft J., Dollery C. T., Hickling N. E., Ritter J. M. Identification of 13,14-dihydro-15-oxo-prostaglandin F2 alpha in the circulation during infusions of bradykinin and prostaglandin E2 in man. Br J Pharmacol. 1987 May;91(1):245–250. doi: 10.1111/j.1476-5381.1987.tb09005.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barrow S. E., Dollery C. T., Heavey D. J., Hickling N. E., Ritter J. M., Vial J. Effect of vasoactive peptides on prostacyclin synthesis in man. Br J Pharmacol. 1986 Jan;87(1):243–247. doi: 10.1111/j.1476-5381.1986.tb10177.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Benjamin N., Cockcroft J. R., Collier J. G., Dollery C. T., Ritter J. M., Webb D. J. Local inhibition of converting enzyme and vascular responses to angiotensin and bradykinin in the human forearm. J Physiol. 1989 May;412:543–555. doi: 10.1113/jphysiol.1989.sp017630. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bhoola K. D., Figueroa C. D., Worthy K. Bioregulation of kinins: kallikreins, kininogens, and kininases. Pharmacol Rev. 1992 Mar;44(1):1–80. [PubMed] [Google Scholar]
  5. Cherry P. D., Furchgott R. F., Zawadzki J. V., Jothianandan D. Role of endothelial cells in relaxation of isolated arteries by bradykinin. Proc Natl Acad Sci U S A. 1982 Mar;79(6):2106–2110. doi: 10.1073/pnas.79.6.2106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cockcroft J. R., Chowienczyk P. J., Brett S. E., Ritter J. M. Effect of NG-monomethyl-L-arginine on kinin-induced vasodilation in the human forearm. Br J Clin Pharmacol. 1994 Oct;38(4):307–310. doi: 10.1111/j.1365-2125.1994.tb04358.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cockcroft J. R., Sciberras D. G., Goldberg M. R., Ritter J. M. Comparison of angiotensin-converting enzyme inhibition with angiotensin II receptor antagonism in the human forearm. J Cardiovasc Pharmacol. 1993 Oct;22(4):579–584. doi: 10.1097/00005344-199310000-00011. [DOI] [PubMed] [Google Scholar]
  8. Collier J. G., Nachev C., Robinson B. F. Effect of catecholamines and other vasoactive substances on superficial hand veins in man. Clin Sci. 1972 Sep;43(3):455–467. doi: 10.1042/cs0430455. [DOI] [PubMed] [Google Scholar]
  9. Dorer F. E., Kahn J. R., Lentz K. E., Levine M., Skeggs L. T. Hydrolysis of bradykinin by angiotensin-converting enzyme. Circ Res. 1974 Jun;34(6):824–827. doi: 10.1161/01.res.34.6.824. [DOI] [PubMed] [Google Scholar]
  10. Erdös E. G. The angiotensin I converting enzyme. Fed Proc. 1977 Apr;36(5):1760–1765. [PubMed] [Google Scholar]
  11. FOX R. H., GOLDSMITH R., KIDD D. J., LEWIS G. P. Bradykinin as a vasodilator in man. J Physiol. 1961 Aug;157:589–602. doi: 10.1113/jphysiol.1961.sp006745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Girolami J. P., Praddaude F., Ader J. L., Tran Van T., Eche J. P., Suc J. M. Bilateral urinary kallikrein excretion in the Goldblatt hypertensive rat. Eur Heart J. 1983 Nov;4 (Suppl G):67–72. doi: 10.1093/eurheartj/4.suppl_g.67. [DOI] [PubMed] [Google Scholar]
  13. Heavey D. J., Barrow S. E., Hickling N. E., Ritter J. M. Aspirin causes short-lived inhibition of bradykinin-stimulated prostacyclin production in man. Nature. 1985 Nov 14;318(6042):186–188. doi: 10.1038/318186a0. [DOI] [PubMed] [Google Scholar]
  14. Hock F. J., Wirth K., Albus U., Linz W., Gerhards H. J., Wiemer G., Henke S., Breipohl G., König W., Knolle J. Hoe 140 a new potent and long acting bradykinin-antagonist: in vitro studies. Br J Pharmacol. 1991 Mar;102(3):769–773. doi: 10.1111/j.1476-5381.1991.tb12248.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Ignarro L. J., Buga G. M., Wood K. S., Byrns R. E., Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A. 1987 Dec;84(24):9265–9269. doi: 10.1073/pnas.84.24.9265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Keiser H. R., Geller R. G., Margolius H. S., Pisano J. J. Urinary kallikrein in hypertensive animal models. Fed Proc. 1976 Feb;35(2):199–202. [PubMed] [Google Scholar]
  17. Marks E. S., Bing R. F., Thurston H., Swales J. D. Vasodepressor property of the converting enzyme inhibitor captopril (SQ 14 225): the role of factors other than renin-angiotensin blockade in the rat. Clin Sci (Lond) 1980 Jan;58(1):1–6. doi: 10.1042/cs0580001. [DOI] [PubMed] [Google Scholar]
  18. McGiff J. C., Carroll M. A., Escalante B. Arachidonate metabolites and kinins in blood pressure regulation. Hypertension. 1991 Nov;18(5 Suppl):III150–III157. doi: 10.1161/01.hyp.18.5_suppl.iii150. [DOI] [PubMed] [Google Scholar]
  19. Miyamori I., Brown M. J., Dollery C. T. Single-dose captopril administration in DOCA/salt rats: reduction of hypotensive effect by indomethacin. Clin Exp Hypertens. 1980;2(6):935–945. doi: 10.3109/10641968009037152. [DOI] [PubMed] [Google Scholar]
  20. Ogawa K., Ito T., Ban M., Mochizuki M., Satake T. Effects of orally administered glandular kallikrein on urinary kallikrein and prostaglandin excretion, plasma immunoreactive prostanoids and platelet aggregation in essential hypertension. Klin Wochenschr. 1985 Apr 1;63(7):332–336. doi: 10.1007/BF01731977. [DOI] [PubMed] [Google Scholar]
  21. Palmer R. M., Ferrige A. G., Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987 Jun 11;327(6122):524–526. doi: 10.1038/327524a0. [DOI] [PubMed] [Google Scholar]
  22. Regoli D., Barabé J. Pharmacology of bradykinin and related kinins. Pharmacol Rev. 1980 Mar;32(1):1–46. [PubMed] [Google Scholar]
  23. Regoli D., Rhaleb N. E., Dion S., Drapeau G. New selective bradykinin receptor antagonists and bradykinin B2 receptor characterization. Trends Pharmacol Sci. 1990 Apr;11(4):156–161. doi: 10.1016/0165-6147(90)90067-I. [DOI] [PubMed] [Google Scholar]
  24. Ritter J. M., Cockcroft J. R., Doktor H. S., Beacham J., Barrow S. E. Differential effect of aspirin on thromboxane and prostaglandin biosynthesis in man. Br J Clin Pharmacol. 1989 Nov;28(5):573–579. doi: 10.1111/j.1365-2125.1989.tb03544.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Seino M., Abe K., Nushiro N., Omata K., Yoshinaga K. Role of endogenous bradykinins in the acute depressor effect of angiotensin converting enzyme inhibitor captopril--assessed by a competitive antagonist of bradykinin. Clin Exp Hypertens A. 1989;11(1):35–43. doi: 10.3109/10641968909035289. [DOI] [PubMed] [Google Scholar]
  26. Thurston H., Swales J. D. Converting enzyme inhibitor and saralasin infusion in rats. Evidence for an additional vasodepressor property of converting enzyme inhibitor. Circ Res. 1978 May;42(5):588–592. doi: 10.1161/01.res.42.5.588. [DOI] [PubMed] [Google Scholar]
  27. Vavrek R. J., Stewart J. M. Competitive antagonists of bradykinin. Peptides. 1985 Mar-Apr;6(2):161–164. doi: 10.1016/0196-9781(85)90033-6. [DOI] [PubMed] [Google Scholar]
  28. WHITNEY R. J. The measurement of volume changes in human limbs. J Physiol. 1953 Jul;121(1):1–27. doi: 10.1113/jphysiol.1953.sp004926. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Wiemer G., Schölkens B. A., Becker R. H., Busse R. Ramiprilat enhances endothelial autacoid formation by inhibiting breakdown of endothelium-derived bradykinin. Hypertension. 1991 Oct;18(4):558–563. doi: 10.1161/01.hyp.18.4.558. [DOI] [PubMed] [Google Scholar]

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