Abstract 11636: Chronic Treatment with Tadalafil Protects against Diastolic Dysfunction and Ischemia/Reperfusion Injury in a Mouse Model of Metabolic Syndrome
Background: Metabolic syndrome (MetS) patients exhibit generalized endothelial and cardiac dysfunction with decreased nitric oxide (NO) production and bioavailability. Since phosphodiesterase-5 (PDE-5) inhibitors restore NO signaling, we tested the hypothesis whether chronic treatment with long acting PDE-5 inhibitor tadalafil (TAD) could reduce cardiac dysfunction and ischemia/reperfusion (I/R) injury in MetS mice.
Methods and Results: Adult male C57BL/6NCrl-Leprdb-lb/Crl (n=12/group) mice, which have phenotypes of MetS, were randomized to receive DMSO (10%, 0.2 ml) or TAD (1 mg/kg) daily i.p. for 28 days. C57BL/6J mice served as healthy controls. After 28 days, cardiac function was assessed by transthoracic echocardiography. In a subset of mice, hearts were isolated and subjected to global ischemia and reperfusion for 30 min in Langendorff mode. Ex vivo ventricular function, heart rate, coronary flow rate were measured during preischemia and reperfusion periods. Myocardial infarct size was measured using computer morphometry of tetrazolium stained sections. As summarized in Table, body weights and fasting blood glucose levels were increased significantly in the MetS groups. Left ventricular systolic dysfunction was not changed among the groups. MetS mice exhibited a reduction in E/A ratio indicating diastolic dysfunction, which was improved upon TAD treatment. Baseline cardiac function, heart rate, coronary flow rate were not significantly different between the groups. However, postischemic cardiac function, heart rate and coronary flow were significantly decreased in MetS group compared to the control group, which were preserved in TAD treated MetS group. Infarct size was significantly reduced in MetS+TAD group demonstrating cardioprotection against I/R injury in MetS mice.
Conclusion: Chronic treatment with TAD could be a novel and safe therapeutic option in preventing diastolic dysfunction and ischemic heart diseases in MetS patients.
- © 2012 by American Heart Association, Inc.