Beta 2-adrenergic receptor actions in neonatal and adult rat ventricular myocytes

Abstract

The physiological function of beta 2-adrenergic receptors in the neonatal and adult heart is incompletely understood, and possible age-dependent differences in beta 2-receptor actions have not been considered. We used isoproterenol (mixed beta 1- and beta 2-receptor agonist) and zinterol (beta 2-selective agonist) to compare beta-receptor subtype actions in neonatal and adult rat ventricular myocytes. When delivered as a bolus at a final concentration of 10(-7) mol/L, both isoproterenol and zinterol increased the amplitude and hastened the kinetics of the calcium and cell-shortening transients in neonatal myocytes. Under identical experimental conditions, isoproterenol increased the amplitude and accelerated the kinetics of the calcium transient and the twitch in adult myocytes, whereas zinterol did not. In the presence of CGP 20712A (beta 1-receptor blocker), a 100-fold higher concentration of zinterol increased the amplitude but prolonged the duration of the twitch in adult myocytes. To probe the mechanism for this age-dependent difference in beta 2-receptor responsiveness, we compared beta-receptor expression and stimulation of cAMP accumulation in neonatal and adult myocytes. beta-Receptor density was 44,339 +/- 5178 sites per cell in neonatal myocytes and 186,346 +/- 13,356 sites per cell in adult myocytes; the relative proportion of beta 2-receptors was comparable in each (16.7 +/- 2.3% and 16.9 +/- 0.9%, respectively). Isoproterenol induced a large increase in cAMP accumulation in neonatal and adult myocytes (20.0 +/- 1.0- and 20.6 +/- 2.6-fold over basal). In contrast, zinterol evoked a substantial increase in cAMP accumulation in neonatal myocytes but only a minor increase in adult myocytes. These studies provide evidence that at low agonist concentrations, beta 2-receptor activation contributes to the positive inotropic response by increasing cAMP and increasing the amplitude and hastening the kinetics of the twitch in neonatal, but not adult, myocytes. Moreover, these results suggest that age-dependent differences in beta 2-receptor coupling to more distal elements in the signaling cascade can influence myocyte beta 2-receptor responsiveness.