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₂-Adrenergic receptor agonists stimulate L-type calcium current independent of PKA in newborn rabbit ventricular myocytes

¹Department of Pediatrics, Program in Pediatric Cardiology, New York University School of Medicine, New York, New York; and ²Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa

Submitted 24 January 2007 ; accepted in final form 20 August 2007

Selective stimulation of 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 ₂-AR stimulation on L-type Ca²⁺ current (I_Ca,L) during postnatal development. I_Ca,L was measured (37°C; either Ca²⁺ or Ba²⁺ as the charge carrier) using the whole-cell patch-clamp technique in newborn (1 to 5 days old) and adult rabbit ventricular myocytes. Ca²⁺ transients were measured concomitantly by dialyzing the cell with indo-1. Activation of ₂-ARs (with either 100 nM zinterol or 1 µM isoproterenol in the presence of the ₁-AR antagonist, CGP20712A) stimulated I_Ca,L twofold in newborns but not in adults. The ₂-AR-mediated increase in Ca²⁺ transient amplitude in newborns was due exclusively to the augmentation of I_Ca,L. Zinterol increased the rate of inactivation of I_Ca,L and increased the Ca²⁺ flux integral. The ₂-AR inverse agonist, ICI-118551 (500 nM), but not the ₁-AR antagonist, CGP20712A (500 nM), blocked the response to zinterol. Unexpectedly, the PKA blockers, H-89 (10 µM), PKI 6-22 amide (10 µM), and Rp-cAMP (100 µM), all failed to prevent the response to zinterol but completely blocked responses to selective ₁-AR stimulation of I_Ca,L in newborns. Our results demonstrate that in addition to the conventional ₁-AR/cAMP/PKA pathway, newborn rabbit myocardium exhibits a novel ₂-AR-mediated, PKA-insensitive pathway that stimulates I_Ca,L. This striking developmental difference plays a major role in the age-related differences in inotropic responses to ₂-AR agonists.

development; protein kinase A; adenosine 3',5'-cyclic monophosphate

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