Ranolazine May Exert its Beneficial Effects by Increasing Myocardial Adenosine Levels.
Am J Physiol Heart Circ Physiol. 2019 Dec 13;:
Authors: Le DE, Davis CM, Wei K, Zhao Y, Cao Z, Nugent M, Scott KL, Liu L, Nagarajan S, Alkayed NJ, Kaul S
We hypothesized that ranolazine-induced adenosine release is responsible for its beneficial effects in ischemic heart disease. Sixteen open-chest anesthetized dogs with non-critical coronary stenosis were studied at rest, during dobutamine stress, and during dobutamine stress with ranolazine. Six additional dogs without stenosis were studied only at rest. Regional myocardial function and perfusion were assessed. Coronary venous blood was measured. Murine endothelial cells and cardiomyocytes were incubated with ranolazine and adenosine metabolic enzyme inhibitors, and adenosine levels were measured. Cardiomyocytes were also exposed to dobutamine and dobutamine with ranolazine. Modeling was employed to determine whether ranolazine can bind to an enzyme that alters adenosine stores. Ranolazine was associated with increased adenosine levels in the absence (21.7±3.0 vs. 9.4±2.1 ng∙mL-1, p<0.05) and presence of ischemia (43.1±13.2 vs. 23.4±5.3 ng∙mL-1, p<0.05). Left ventricular end-systolic wall stress decreased (49.85±4.68 vs. 57.42±3.73 dynes∙[cm2]-1, p<0.05) and endocardial/epicardial myocardial blood flow ratio tended to normalize (0.89±.08 vs. 0.76±0.10, p=NS). Adenosine levels increased in cardiac endothelial cells and cardiomyocytes when incubated with ranolazine that was reversed when cytosolic-5’nucleotidase (cN-II) was inhibited. Point mutation of cN-II aborted an increase in its specific activity by ranolazine. Likewise, adenosine levels did not increase when cardiomyocytes were incubated with dobutamine. Modeling demonstrated plausible binding of ranolazine to cN-II with a docking energy of -11.7 kcal∙mol-1. We conclude that the anti-adrenergic and cardioprotective effects of ranolazine-induced increase in tissue adenosine levels likely mediated by increasing cN-II activity may contribute to its beneficial effects in ischemic heart disease.
PMID: 31834840 [PubMed – as supplied by publisher]