Antagonism of Nav channels and alpha1-adrenergic receptors contributes to vascular smooth muscle effects of ranolazine.

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Virsolvy A, Farah C, Pertuit N, Kong L, Lacampagne A, Reboul C, Aimond F, Richard S

Antagonism of Nav channels and alpha1-adrenergic receptors contributes to vascular smooth muscle effects of ranolazine.

Sci Rep. 2015 Dec 10;5:17969. doi: 10.1038/srep17969.

PubMed ID

26655634 [ View in PubMed

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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 alpha1-adrenergic receptor. Combined alpha1-adrenergic antagonization and inhibition of SMCs Nav channels could be involved in the vascular effects of ranolazine.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Ranolazine	Alpha-1 adrenergic receptors (Protein Group)	Protein group	Humans	No	Antagonist	Details