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CARDIOVASCULAR

Distinct K_ATP Channels Mediate the Antihypertrophic Effects of Adenosine Receptor Activation in Neonatal Rat Ventricular Myocytes

Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada

Recent evidence suggests that both adenosine receptor (AR) and K_ATP channel activation exert antihypertrophic effects in cardiac myocytes. We studied the relative contributions of mitochondrial K_ATP (mitoK_ATP) and sarcolemmal K_ATP (sarcK_ATP) to the antihypertrophic effects of ARs in primary cultures of neonatal rat ventricular myocytes exposed for 24 h with the 1 adrenoceptor agonist phenylephrine (PE). The A₁R agonist N⁶-cyclopentyladenosine (CPA), the A_2AR agonist CGS21680 [2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine], and the A₃R agonist N⁶-(3-iodobenzyl)adenosine-5'-methyluronamide (IB-MECA) all prevented PE-induced hypertrophy. Glibenclamide, a nonselective K_ATP channel blocker reversed the antihypertrophic effect of all three AR agonists as determined by cell size and atrial natriuretic peptide expression and early c-fos up-regulation. In contrast, the mitoK_ATP blocker 5-hydroxydecanoic acid selectively attenuated the effect of CGS21680 and IB-MECA, whereas HMR1098 [1-[[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthiourea, sodium salt], a specific blocker of sarcK_ATP, only abolished the antihypertrophic effect of CPA. Moreover, both CGS21680 and IB-MECA but not CPA decreased the mitochondrial membrane potential when PE was present, similarly to that seen with diazoxide, and both agents inhibited PE-stimulated elevation in mitochondrial Ca²⁺. All AR agonists diminished PE-induced phosphoserine/threonine kinase and protein kinase B up-regulation, which was unaffected by any K_ATP blocker. Our data suggest that AR-mediated antihypertrophic effects are mediated by distinct K_ATP channels, with sarcK_ATP mediating the antihypertrophic effects of A₁R activation, whereas mitoK_ATP activation mediates the antihypertrophic effects of both A_2AR and A₃R agonists.

Address correspondence to: Dr. Morris Karmazyn, Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Medical Sciences Building, University of Western Ontario, London, ON, Canada N6A 5C1. E-mail: Morris.Karmazyn{at}Schulich.uwo.ca

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