Stephen Turner

β2‐Adrenergic receptor polymorphism and nitric oxide‐dependent forearm blood flow responses to isoproterenol in humans

Polymorphisms in the gene encoding the β2‐adrenoceptor have been associated with interindividual differences in blood pressure and the diagnosis of hypertension. A common polymorphism resulting in a change from arginine to glycine at amino acid 16 (Arg16 → Gly) enhances agonist‐promoted downregulation of receptor expression in vitro. It is unknown whether genotype‐dependent differences in nitric oxide generation contribute to differences in vasodilator responses to β2‐agonists in vivo. To address this question, venous occlusion plethysmography was used to measure forearm blood flow responses to graded brachial artery infusions of the β‐agonist isoproterenol in 41 healthy normotensive Caucasian adults (mean age (±s.d.) = 29 ± 6 years), who were either Arg16 (n= 18) or Gly16 (n= 23) homozygotes. Compared to Arg16 homozygotes, Gly16 homozygotes demonstrated significantly greater blood flow responses to isoproterenol (P= 0.02). After inhibition of nitric oxide synthase by Nγ‐monomethyl‐l‐arginine, blood flow responses did not differ significantly between genotype groups (P= 0.27). Consequently, effects of the Arg16 → Gly polymorphism on forearm blood flow responses to isoproterenol appear to be dependent on differences in endothelial generation of nitric oxide. In contrast to previous reports based on systemic infusions of β2‐agonists, our findings indicate that regional blood flow responses to locally infused isoproterenol are significantly greater in Gly16 than in Arg16 homozygotes.

Gene Variant of the Bradykinin B2 Receptor Influences Pulmonary Arterial Pressures in Heart Failure Patients.

Background Pulmonary arterial pressure (PAP) varies considerably in heart failure (HF) despite similar degrees of left ventricular (LV) dysfunction. Bradykinin alters vascular tone and common variations in the kinin B2 receptor (BDKRB2) gene exists. We hypothesized that genetic variation in this receptor would influence PAP in HF. Methods 131 HF patients (>1yr history systolic HF), without COPD, not currently smoking, BMI < 40, without atrial fibrillation completed the study which included a blood draw for genotyping and neurohormones (ACE, A-II, Bradykinin, ANP, BNP, and catecholamines), an echocardiogram for cardiac function and systolic PAP (PAPsys). Results Mean LVEF was 29% ∓ 12%, NYHA class 2 ∓ 1, age 56 ∓ 12 yr, BMI 28 ∓ 5 kg/m2. Forty-six patients (35%) were homozygous for the +9 allele, 58 (44%) were heterozygous (+9/-9) and 27 (21%) were homozygous for the -9 allele of the BDKRB2. PAPsys averaged 42 ∓ 13, 38 ∓ 12, and 35 ∓ 11 mmHg for +9/+9, +9/-9 and -9/-9, respectively (p = 0.03). There was a trend towards gene effect for plasma ACE with the highest values in +9/+9 and lowest in -9/-9 patients (9.5 ∓ 10.7, 7.1 ∓ 8.7, and 5.4 ∓ 6.4 U/L, respectively, p = 0.06). There were no differences in plasma bradykinin or A-II, LVEF, or NYHA across genotypes. Conclusion These data suggest the +9/+9 polymorphism of the BDKRB2 receptor influences pulmonary vascular tone in stable HF.