Polymorphisms in the gene encoding the beta(2)-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 beta(2)-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 beta-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 N(gamma)-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 beta(2)-agonists, our findings indicate that regional blood flow responses to locally infused isoproterenol are significantly greater in Gly16 than in Arg16 homozygotes.