Vagal Stimulation Facilitates Improving Effects of Ranolazine on Cardiac Function in Rats with Chronic Ischemic Heart Failure

Background: Ranolazine is generally used to treat anginal symptoms for patients with symptomatic chronic stable angina pectoris. By improving ischemiareperfusion, ranolazine is also observed to have protective effects on myocardial ischemic injury in animal models. It is noteworthy to find interventions that can decrease adverse effects of this drug and thereby increase its clinical application.

Methods: In this report, we used a rat model of chronic ischemic heart failure (CHF) to examine if vagal stimulation can strengthen the effects of ranolazine on worsened cardiac function in CHF. Plasma norepinephrine (NE) and brain natriuretic peptide [BNP, termed B-type natriuretic peptide-45 (BNP-45) in rats] are regulated by sympathetic nerve activity. Because NE and BNP are considered as neurohormones indicating heart failure progression, we also determined the levels of plasma NE and BNP-45 besides cardiac function. Moreover, we examined the role of sympathetic pro-inflammatory cytokines in engagement of vagal activation.

Results: Our data show that ranolazine intraperitoneally improved the impaired left ventricular function, and attenuated the exaggerated NE/BNP-45 and cytokines (such as IL-1β, IL-6 and TNF-α) after development of CHF. Particularly, our results show that vagal activation largely amplified the effects of ranolazine on cardiac function in CHF.

Conclusion: Our data indicate that: 1) ranolazine alleviates sympathetic nerve activity thereby leading to improvement of the worsened cardiac function in CHF; and 2) vagal stimulation augments the effect of ranolazine. Accordingly, results of this study have implications for the role played by a combination of vagal stimulation and ranolazine in improving cardiac function in CHF.