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This Article Full Text Full Text (PDF) All Versions of this Article: 293/5/H2826    most recent 00101.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Collis, L. P. Articles by Artman, M. Search for Related Content PubMed PubMed Citation Articles by Collis, L. P. Articles by Artman, M.

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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