Ranolazine

To mechanistically test effects of late sodium channel inhibition among patients with reduced CFR, we conducted a double-blind, placebo-controlled, crossover trial with Ranolazine and placebo exposure order randomly assigned. Angina measured by the SAQ and SAQ-7 were the co-primary outcomes. Other outcomes of interest included stress MPRI, LV diastolic filling, and quality of life (QoL). Absence of obstructive CAD and CRT measures were core-lab ascertained (WISE Angiography and Coronary Reactivity Cores). At baseline and follow-up visits, subjects completed demographic/health history questionnaires, the SAQ and SAQ-7.
Study periods were 2 weeks in duration, followed by 2-week washout, and crossover to 2 weeks of alternate therapy. Ranolazine (Gilead Sciences, Foster City, CA, USA) was administered as 500 mg orally twice daily for 1-week and increased to 1000 mg twice daily for 1 week as tolerated (subjects taking verapamil or diltiazem maintained Ranolazine or placebo 500 mg twice daily). Treatment compliance was measured by pill count. Data were collected at baseline (SAQ and SAQ-7) and at the end of each treatment period (SAQ, SAQ-7, and CMRI). Other anti-anginal medications were unchanged during the study.

ATX-II and tetrodotoxin were purchased from Alomone Labs and Tocris Bioscience, respectively. Dithiothreitol (DTT) and coenzyme Q10 (CoQ10) were purchased from Sigma Chemical. The CaMKII inhibitor KN-93 and its inactive analog KN-92 were purchased from EMD Millipore. Ranolazine and the selective I_NaL blocker GS-967 [23 (link)] were provided by Gilead Sciences. The sources of fluorescent dyes and antibodies are indicated in the relevant sections below.

Ranolazine (Gilead Sciences, Foster City, CA), dissolved in distilled water, was prepared fresh as a stock of 5 mM before each experiment.