title: Antagonism of Nav channels and α1-adrenergic receptors contributes to vascular smooth muscle effects of ranolazine.
abstract: Ranolazine is a recently developed drug used for the treatment of patients with chronic stable angina. It is a selective inhibitor of the persistent cardiac Na(+) current (INa), and is known to reduce the Na(+)-dependent Ca(2+) overload that occurs in cardiomyocytes during ischemia. Vascular effects of ranolazine, such as vasorelaxation,have been reported and may involve multiple pathways. As voltage-gated Na(+) channels (Nav) present in arteries play a role in contraction, we hypothesized that ranolazine could target these channels. We studied the effects of ranolazine in vitro on cultured aortic smooth muscle cells (SMC) and ex vivo on rat aortas in conditions known to specifically activate or promote INa. We observed that in the presence of the Nav channel agonist veratridine, ranolazine inhibited INa and intracellular Ca(2+) calcium increase in SMC, and arterial vasoconstriction. In arterial SMC, ranolazine inhibited the activity of tetrodotoxin-sensitive voltage-gated Nav channels and thus antagonized contraction promoted by low KCl depolarization. Furthermore, the vasorelaxant effects of ranolazine, also observed in human arteries and independent of the endothelium, involved antagonization of the α1-adrenergic receptor. Combined α1-adrenergic antagonization and inhibition of SMCs Nav channels could be involved in the vascular effects of ranolazine.
authors.affiliation: PhyMedExp, INSERM U1046, UMR CNRS 9214, Université de Montpellier, Montpellier F-34295, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Virsolvy
authors.affiliation: Avignon Université, LAPEC EA4278, F-84000, Avignon, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Farah
authors.affiliation: PhyMedExp, INSERM U1046, UMR CNRS 9214, Université de Montpellier, Montpellier F-34295, France.
authors.forename: Nolwenn
authors.initials: N
authors.lastname: Pertuit
authors.affiliation: PhyMedExp, INSERM U1046, UMR CNRS 9214, Université de Montpellier, Montpellier F-34295, France.
authors.forename: Lingyan
authors.initials: L
authors.lastname: Kong
authors.affiliation: PhyMedExp, INSERM U1046, UMR CNRS 9214, Université de Montpellier, Montpellier F-34295, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Lacampagne
authors.affiliation: Avignon Université, LAPEC EA4278, F-84000, Avignon, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Reboul
authors.affiliation: PhyMedExp, INSERM U1046, UMR CNRS 9214, Université de Montpellier, Montpellier F-34295, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Aimond
authors.affiliation: PhyMedExp, INSERM U1046, UMR CNRS 9214, Université de Montpellier, Montpellier F-34295, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Richard
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D001011:Aorta; D006801:Humans; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D000069458:Ranolazine / Q000494:pharmacology*; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D055988:Uterine Artery / Q000187:drug effects / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism*
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D018340:Receptors, Adrenergic, alpha-1; D026941:Sodium Channel Blockers; D061566:Voltage-Gated Sodium Channels; D000069458:Ranolazine