Our laboratory has demonstrated that healthy, normotensive adults homozygous for glycine (Gly) of the Arg16/Gly β2-adrenergic receptor polymorphism produce 1) greater forearm β2-receptor mediated vasodilation and 2) a higher heart rate (HR) response to isometric handgrip than arginine (Arg) homozygotes. To test the hypothesis that the higher HR response in Gly16 subjects serves to maintain the pressor response (increased cardiac output, CO) in the setting of augmented peripheral vasodilation to endogenous catecholamines, we measured continuous HR (ECG), arterial pressure (AP, Finapres), and CO (transthoracic echocardiography) during isometric, 40% submaximal handgrip to fatigue in healthy subjects homozygous for Gly (n = 25; mean age ± SE: 30 ± 1, 9 women) and Arg (n = 14, age 29 ± 1, 8 women). Resting data were similar between groups. Handgrip produced similar increases in AP, venous norepinephrine and epinephrine concentrations; however, HR increased greater in the Gly group (62 ± 5% increase from baseline vs. 44 ± 4%, p<0.05) which correlated with a higher CO (Gly: 7.8 ± 0.4 L/m vs. Arg: 6.6 ± 0.3, p<0.05) and a tendency toward a lower systemic vascular resistance. We conclude that Gly16 homozygotes generate a higher CO to maintain the pressor response to handgrip, in part consistent with augmented peripheral vasodilation. Supported by HL-63328, GCRC RR-00585, NCRR K23-17520.