title: Inhibition of phenylephrine induced hypertrophy in rat neonatal cardiomyocytes by the mitochondrial KATP channel opener diazoxide.
abstract: The effect of the putative mitochondrial K(ATP) channel opener diazoxide (100 microM) was studied in terms of its ability to modulate the hypertrophic effect of 24 h treatment with the alpha(1) adrenoceptor agonist phenylephrine (PE; 10 microM) in cultured neonatal rat ventricular myocytes. PE on its own significantly increased cell size by 40%, (3)H leucine incorporation by 37% and produced more than a threefold elevation in both atrial natriuretic peptide and myosin light chain-2 expression. These effects were nearly completely prevented by diazoxide although the inhibitory effect of this agent was generally mitigated by the mitochondrial K(ATP) channel antagonists 5-hydroxydecanoic acid (100 microM) and glibenclamide (50 microM). Although PE produced an early threefold elevation in MAP kinase activation this was generally unaffected by diazoxide. PE also produced a greater than threefold increase in Na-H exchanger isoform 1 (NHE-1) expression which, was prevented by diazoxide treatment. Our study therefore, demonstrates a potential antihypertrophic influence of mitochondrial K(ATP) channel activation which, is related to diminished NHE-1 expression. Mitochondrial K(ATP) channel activation could represent an effective approach to minimize the myocardial hypertrophic process.
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, Medical Sciences Building, London, Ont., Canada N6A 5C1.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xia
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Rajapurohitam
authors.forename: Michael A
authors.initials: MA
authors.lastname: Cook
authors.forename: Morris
authors.initials: M
authors.lastname: Karmazyn
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists; D000818:Animals; D000831:Animals, Newborn; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D006332:Cardiomegaly / Q000517:prevention & control; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D003652:Decanoic Acids / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology*; D005905:Glyburide / Q000494:pharmacology; D006880:Hydroxy Acids / Q000494:pharmacology; D006984:Hypertrophy / Q000139:chemically induced / Q000517:prevention & control; D008928:Mitochondria / Q000378:metabolism; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D010656:Phenylephrine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000819:agonists* / Q000502:physiology; D051381:Rats
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D000889:Anti-Arrhythmia Agents; D003652:Decanoic Acids; D006880:Hydroxy Acids; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D010656:Phenylephrine; C052853:5-hydroxydecanoic acid; D003981:Diazoxide; D005905:Glyburide