Erythropoietin Has an Additive Cytoprotective and Beneficial Effect to Sildenafil in a Model of Diastolic Heart Failure in Rats

Abstract

Development of new forms of interventions for diastolic heart failure (HFpEF) remains a challenging task. The aim: Assessing the effect of combining erythropoietin and sildenafil on the left ventricle "LV" functions and morphometry in N G-nitro-Larginine methyl ester (L-NAME)-induced HFpEF model in rats. Method: Forty-eight female albino rats were randomly assigned to one of six treatment groups: "C" (Control), "L" (L-NAME-treated), "L+M" (L-NAME+milrinone-treated), "L+S" (L-NAME+sildenafil-treated), "L+E" (L-NAME+erythropoietin-treated), and "L+S+E" (L-NAME+sildenafil+erythropoietin-treated). Assessment was done by morphometric examination, LV ejection fraction (LVEF) and fraction of shortening (LVFS)], ECG changes, and mean time to peak tension (TPT) and to complete relaxation (TCR) of isometric contraction of LV muscle strip stimulated by single (TPT-S & TCR-S) and by repeated pulses (TPT-R & TCR-R), respectively. Results: L-NAME resulted in cardiac dysfunction with significant reduction in the mean "LVEF" and "LVFS", and prolonged both the mean "TPT-R" and "TCR-R". Milrinone and sildenafil treatment significantly corrected these parameters. In addition, erythropoietin significantly ameliorated "LVEF" and "LVFS" and shortened "TPT-S". Similarly, "sildenafil+erythropoietin" treatment significantly corrected the measured parameters; however, they were insignificantly different from that of sildenafil only treatment. Morphometrically, sildenafil treatment resulted in significant but partial improvement in L-NAME-induced myocardial injury. Meanwhile, erythropoietin treatment showed more improvement. Moreover, combination treatment showed the best histologic picture in all of the treated groups. Conclusion: Sildenafil was able to improve cardiac functions mainly by accelerating diastolic relaxation. Addition of erythropoietin to sildenafil improved its cytoprotective effect.