Distinct K-Atp Channels Mediate The Antihypertrophic Effects Of Adenosine Receptor Activation In Neonatal Rat Ventricular Myocytes

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 alpha(1) adrenoceptor agonist phenylephrine (PE). The A(1)R agonist N-6-cyclopentyladenosine (CPA), the A(2A)R agonist CGS21680 [2-p-(2-carboxyethyl)phenethylamino-5 '-N-ethylcarboxamidoadenosine], and the A(3)R agonist N-6-(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 A(1)R activation, whereas mitoK(ATP) activation mediates the antihypertrophic effects of both A(2A)R and A(3)R agonists.