Role of Cardiac β 2 -Receptors in Cardiac Responses to Exercise in Cardiac Transplant Patients

Abstract

In healthy human hearts, beta 2-receptor-mediated chronotropic and inotropic responses contribute to the cardiac responses to beta-agonists. A (patho)physiological relevance for beta 2-receptor-mediated responses has so far not been demonstrated, in part because beta 1-receptor-mediated responses to cardiac neuronally released norepinephrine can mask beta 2-receptor-mediated responses. In the present study, we evaluated the blood pressure and heart rate responses to bicycle exercise in cardiac transplant patients (n = 7) compared with patients with essential hypertension (n = 8) on placebo and two doses of the beta 1-selective beta-blocker atenolol (25 and 50 mg/d) and the nonselective beta-blocker nadolol (20 and 40 mg/d), each dose for 1 week using a double-blind, randomized, crossover design. Exercise was performed 3 hours after dosing, using a stepwise increase in load until exhaustion. Exercise performance was less in the transplant patients and significantly further (25%) decreased by nadolol. Exercise caused equivalent increases in plasma norepinephrine in the two groups, but more marked increases in plasma epinephrine in the transplant patients despite less exercise. In the essential hypertension patients, systolic blood pressure increased by 80 mm Hg on placebo and 60 mm Hg on either blocker. The increase in heart rate (by about 75 beats per minute) was inhibited by 10% and 20% by the lower and higher doses, respectively, similar for the two blockers. In contrast, in the transplant patients, systolic blood pressure increased by 60 mm Hg on placebo, but this increase was totally blocked by either blocker. The heart rate increase (by 50 beats per minute on placebo) was blunted (dose related) by either blocker but 50% more by nadolol versus atenolol. The present study shows that cardiac beta 2-receptors contribute to a clear extent to the heart rate responses to endogenous circulating catecholamines in the absence of cardiac neuronally released norepinephrine. Nonselective beta-blockade probably is less well tolerated in cardiac transplant patients compared with beta 1-selective blockade.