[[beta].sub.2]-Adrenergic receptor agonists stimulate L-type calcium current independent of PKA in newborn rabbit ventricular myocytes

Selective stimulation of [[beta].sub.2]-adrenergic receptors (ARs) in newborn rabbit ventricular myocardium invokes a positive inotropic effect that is lost during postnatal maturation. The underlying mechanisms for this age-related stimulatory response remain unresolved. We examined the effects of [[beta].sub.2]-AR stimulation on L-type [Ca.sup.2+] current ([I.sub.Ca,L]) during postnatal development. [I.sub.Ca,L] was measured (37[degrees]C; either [Ca.sup.2+] or [Ba.sup.2+] as the charge carrier) using the whole-cell patch-clamp technique in newborn (1 to 5 days old) and adult rabbit ventricular myocytes. [Ca.sup.2+] transients were measured concomitantly by dialyzing the cell with indo-1. Activation of [[beta].sub.2]-ARs (with either 100 nM zinterol or 1 [micro]M isoproterenol in the presence of the [[beta].sub.1]-AR antagonist, CGP20712A) stimulated [I.sub.Ca,L] twofold in newborns but not in adults. The [[beta].sub.2]-AR-mediated increase in [Ca.sup.2+] transient amplitude in newborns was due exclusively to the augmentation of [I.sub.Ca, L]. Zinterol increased the rate of inactivation of [I.sub.Ca.L] and increased the [Ca.sup.2+] flux integral. The [[beta].sub.2]-AR inverse agonist, ICI- 118551 (500 nM), but not the [[beta].sub.1]-AR antagonist, CGP20712A (500 nM), blocked the response to zinterol. Unexpectedly, the PKA blockers, H-89 (10 [micro]M), PKI 6-22 amide (10 [micro]M), and Rp-cAMP (100 [micro]M), all failed to prevent the response to zinterol but completely blocked responses to selective [[beta].sub.1]-AR stimulation of [I.sub.Ca,L] in newborns. Our results demonstrate that in addition to the conventional [[beta].sub.1]-AR/cAMP/PKA pathway, newborn rabbit myocardium exhibits a novel [[beta].sub.2]-AR-mediated, PKA-insensitive pathway that stimulates [I.sub.Ca,L]. This striking developmental difference plays a major role in the age-related differences in inotropic responses to [[beta].sub.2]-AR agonists. development; protein kinase A; adenosine 3',5'-cyclic monophosphate