Distinct KATP 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 alpha1 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 Ca(2+). 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.[1]References
- Distinct KATP channels mediate the antihypertrophic effects of adenosine receptor activation in neonatal rat ventricular myocytes. Xia, Y., Javadov, S., Gan, T.X., Pang, T., Cook, M.A., Karmazyn, M. J. Pharmacol. Exp. Ther. (2007) [Pubmed]
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