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 NG-nitro-L-arginine 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.
Highlights
Development of new forms of interventions for diastolic heart failure (HFpEF) remains a challenging task
Development of diastolic HF in rats induced by 8-week administration of L-NAME was associated with significant reductions in the mean left ventricular (LV) ejection fraction (LVEF) and left ventricular fraction of shortening (LVFS) and decreased lusitropy and prolonged contraction time evidenced by increased to complete relaxation (TCR)-R and to peak tension (TPT)-R compared to that recorded in the control non-treated animals
In failing or chronically loaded hearts, the chronic inhibition significantly improved the myocardial dysfunction and LV end diastolic pressure and stiffness with inhibition of myocardial remodeling (Takimoto et al 2005; Nagayama et al 2009; Ferreira-Melo et al 2011 and Westermann et al 2012). This finding could be explained by increased PDE5A-dependent cGMP-esterase activity in failed hearts, thereby amplifying the cGMP-dependent signaling resulting in much larger changes in protein kinase G (PKG)-1 activation after PDE5A inhibition
Summary
Development of new forms of interventions for diastolic heart failure (HFpEF) remains a challenging task. A new hypothesis for HFpEF development proposes that certain comorbid conditions as obesity can induce a systemic proinflammatory state with coronary microvascular endothelial inflammation This reduces nitric oxide bioavailability, cyclic guanosine monophosphate content and protein kinase G (PKG) activity in adjacent cardiomyocytes. Previous experimental studies of PDE5 inhibitors as sildenafil in failing murine and human hearts showed significant beneficial effects on dilation, hypertrophy, remodeling, and dysfunction associated with increased protein kinase G activity, shortening, and relaxation of sarcomere and enhancement of transients and decay of Ca2+ in the isolated myocytes (Nagayama et al 2009; Guazzi et al 2011 and Gong et al 2013). EPO has been shown to render organ protection in various experimental models of acute ischemia and improves cardiac function in experimental models of chronic myocardial dysfunction and improved microvascularisation of the myocardium through Akt–endothelial nitric oxide synthase (eNOS) activation (Urao et al 2006; Hefer et al 2012 and Westenbrink et al, 2007)
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