Bradykinin type 2 receptor BE1 genotype influences bradykinin-dependent vasodilation during angiotensin-converting enzyme inhibition.
To test the hypothesis that the bradykinin receptor 2 (BDKRB2) BE1+9/-9 polymorphism affects vascular responses to bradykinin, we measured the effect of intra-arterial bradykinin on forearm blood flow and tissue-type plasminogen activator (t-PA) release in 89 normotensive, nonsmoking, white American subjects in whom degradation of bradykinin was blocked by enalaprilat. BE1 genotype frequencies were +9/+9:+9/-9:-9/-9=19:42:28. BE1 genotype was associated with systolic blood pressure (121.4+/-2.8, 113.8+/-1.8, and 110.6+/-1.8 mm Hg in +9/+9, +9/-9, and -9/-9 groups, respectively; P=0.007). In the absence of enalaprilat, bradykinin-stimulated forearm blood flow, forearm vascular resistance, and net t-PA release were similar among genotype groups. Enalaprilat increased basal forearm blood flow (P=0.002) and decreased basal forearm vascular resistance (P=0.01) without affecting blood pressure. Enalaprilat enhanced the effect of bradykinin on forearm blood flow, forearm vascular resistance, and t-PA release (all P<0.001). During enalaprilat, forearm blood flow was significantly lower and forearm vascular resistance was higher in response to bradykinin in the +9/+9 compared with +9/-9 and -9/-9 genotype groups (P=0.04 for both). t-PA release tended to be decreased in response to bradykinin in the +9/+9 group (P=0.08). When analyzed separately by gender, BE1 genotype was associated with bradykinin-stimulated t-PA release in angiotensin-converting enzyme inhibitor-treated men but not women (P=0.02 and P=0.77, respectively), after controlling for body mass index. There was no effect of BE1 genotype on responses to the bradykinin type 2 receptor-independent vasodilator methacholine during enalaprilat. In conclusion, the BDKRB2 BE1 polymorphism influences bradykinin type 2 receptor-mediated vasodilation during angiotensin-converting enzyme inhibition.
Van Guilder
Gary P
GP
Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232-6602, USA.
Pretorius
Mias
M
Luther
James M
JM
Byrd
J Brian
JB
Hill
Kevin
K
Gainer
James V
JV
Brown
Nancy J
NJ
D000328:Adult; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D001794:Blood Pressure / Q000235:genetics; D001920:Bradykinin / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D015773:Enalaprilat / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D005542:Forearm / Q000098:blood supply; D005838:Genotype; D006801:Humans; D007269:Injections, Intra-Arterial; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D011110:Polymorphism, Genetic / Q000502:physiology*; D043782:Receptor, Bradykinin B2 / Q000235:genetics*; D012039:Regional Blood Flow / Q000187:drug effects; D012737:Sex Factors; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D043782:Receptor, Bradykinin B2; D014665:Vasodilator Agents; D016210:Methacholine Chloride; D009599:Nitroprusside; D010959:Tissue Plasminogen Activator; D015773:Enalaprilat; D001920:Bradykinin