Adult, Angiotensin-Converting Enzyme Inhibitors, Blood Pressure, Bradykinin, Drug Synergism, Enalaprilat, Endothelium, Vascular, Female, Forearm, Genotype, Humans, Injections, Intra-Arterial, Male, Methacholine Chloride, Nitroprusside, Polymorphism, Genetic, Receptor, Bradykinin B2, Regional Blood Flow, Sex Factors, Tissue Plasminogen Activator, Vascular Resistance, Vasodilation, Vasodilator Agents
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.
DOI of Published Version
American Heart Association
In Copyright - Non-Commercial Use Permitted
Van Guilder, Gary; Pretorius, Mias; Luther, James M; Byrd, J Brian; Hill, Kevin; Gainer, James V; and Brown, Nancy J, "Bradykinin Type 2 Receptor BE1 Genotype Influences Bradykinin-dependent Vasodilation During Angiotensin-converting Enzyme Inhibition" (2008). Health and Nutritional Sciences Faculty Publications. 53.