title: Alterations in dihydropyridine receptors in dystrophin-deficient cardiac muscle.
abstract: The deficiency of dystrophin, a critical membrane stabilizing protein, in the mdx mouse causes an elevation in intracellular calcium in myocytes. One mechanism that could elicit increases in intracellular calcium is enhanced influx via the L-type calcium channels. This study investigated the effects of the dihydropyridines BAY K 8644 and nifedipine and alterations in dihydropyridine receptors in dystrophin-deficient mdx hearts. A lower force of contraction and a reduced potency of extracellular calcium (P < 0.05) were evident in mdx left atria. The dihydropyridine agonist BAY K 8644 and antagonist nifedipine had 2.7- and 1.9-fold lower potencies in contracting left atria (P < 0.05). This corresponded with a 2.0-fold reduction in dihydropyridine receptor affinity evident from radioligand binding studies of mdx ventricular homogenates (P < 0.05). Increased ventricular dihydropyridine receptor protein was evident from both radioligand binding studies and Western blot analysis and was accompanied by increased mRNA levels (P < 0.05). Patch-clamp studies in isolated ventricular myocytes showed no change in L-type calcium current density but revealed delayed channel inactivation (P < 0.05). This study indicates that a deficiency of dystrophin leads to changes in dihydropyridine receptors and L-type calcium channel properties that may contribute to enhanced calcium influx. Increased influx is a potential mechanism for the calcium overload observed in dystrophin-deficient cardiac muscle.
authors.affiliation: Centre for Biomedical Research, Faculty of Sciences, University of Southern Queensland, Toowoomba, 4350 Queensland, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Woolf
authors.forename: Sai
authors.initials: S
authors.lastname: Lu
authors.forename: Renee
authors.initials: R
authors.lastname: Cornford-Nairn
authors.forename: Michael
authors.initials: M
authors.lastname: Watson
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Xiao
authors.forename: Sean M
authors.initials: SM
authors.lastname: Holroyd
authors.forename: Lindsay
authors.initials: L
authors.lastname: Brown
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Hoey
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000502:physiology*; D020013:Calcium Signaling / Q000187:drug effects; D016189:Dystrophin / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D004594:Electrophysiology; D006321:Heart / Q000502:physiology*; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D009200:Myocardial Contraction / Q000502:physiology; D009543:Nifedipine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011869:Radioligand Assay; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D016189:Dystrophin; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D009543:Nifedipine; D002118:Calcium