Figure 4.

Integrated vision of ranolazine’s putative direct and indirect effects on the cardiovascular system. The therapeutic benefits of ranolazine in the treatment of ischemia and angina pectoris have been documented as primarily based on the inhibition of I_Na,late in heart cells. However, there is mounting evidence that ranolazine also interacts with a broad spectrum of Na_v channels, including cardiac and neuronal isoforms. Reports from the literature point to similar mechanisms in vascular smooth muscle cells and neurons, opening the possibility that these effects may contribute to the overall anti-ischemic effect of ranolazine. Combined α₁-adrenergic receptor antagonization and inhibition of the Na_v channels of vascular smooth muscle cells may account for vascular effects of ranolazine. At the sympathetic perivascular nerve endings, ranolazine may potentially reduce electrical activity and inhibit the release of norepinephrine, in addition to the inhibition of α₁-adrenergic receptors, which may also be relevant for the antianginal effects of the drug. The inhibition of cardiac release of norepinephrine may also have favorable effects by reducing cardiac adrenergic stimulation and improving ATP consumption. These complementary effects have to be confirmed from molecular targets to integrative models.