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Abstract The present study was designed to explore the effect of erythropoietin on the cardiac intrinsic function both under basal condition as well as following ischemia-reperfusion in rats with experimentally induced uremic cardiomyopathy. Rats in the present study were classified into I. 6 week groups: Rats in this group were further divided into: a) 6 week sham-operated control group (n= 20) b) 6 week uremic cardiomyopathy group (UCM) (n= 25), subjected to 5/6 nephrectomy for experimental induction of uremic cardiomyopathy and were studied after 6 weeks. c) 6 week uremic cardiomyopathy erythropoietintreated group (UCM-Epo) (n=19), subjected to 5/6 nephrectomy, followed postoperatively by immediate intraperitonial (i.p.) injection of erythropoietin, and were studied after 6 weeks. II. 12 week groups: Rats in this group were further divided into: a) 12 week sham-operated control group (n= 26) b) 12 week uremic cardiomyopathy group (UCM) Summary and conclusion (299) (n= 28), subjected to 5/6 nephrectomy and were studied after 12 weeks. c) 12 week uremic cardiomyopathy erythropoietin-treated group (UCM-Epo) (n=17), subjected to 5/6 nephrectomy, and received i.p. injection of erythropoietin 6 weeks after the operation that continued for 6 weeks. Rats of this group were studied after 12 weeks. At the end of the study period, rats were subjected to measurement of body weight and arterial blood pressure, ECG recording, as well as heart isolation on Langendorff preparation for assessment of the basal cardiac activities and cardiac responses to 30 minutes of reperfusion following 30 minutes of total global ischemia. Plasma was assessed for creatinine and urea for confirmation of renal failure as well as oxidants/antioxidants markers, the total antioxidant capacity and malondialdehyde. Hematocrite value and haemoglobin concentration were determined. Cardiac muscle was also, assessed for its content of the oxidative stress marker malondialdehyde as well as the antioxidant glutathione peroxidase enzyme activity. Renal failure was confirmed by the significant elevation in the plasma levels of creatinine and urea, that was significantly Summary and conclusion (300) decreased upon Epo treatment, denoting better kidney functions with Epo administration. The results obtained revealed the final BMI showed significant decrease in the 12 weeks UCM-Epo group compared to the sham-operated group. Hematocrite value was significantly decreased in 6 weeks UCM group and significantly increased in 6 and 12 weeks UCM groups upon Epo treatment. Plasma MDA increased significantly in 6 weeks UCM group and decreased upon Epo treatment. Plasma TAC decreased significantly in 12 weeks UCM group and increased by Epo administration. Cardiac tissue GPx was increased in both 6 and 12 weeks Epo treated groups. ECG recordings showed significant bradycardia in the 6 weeks UCM group and significant increase in the QRS voltage together with decrease in PR interval and QRS duration in both 6 weeks UCM and UCM- Epo groups. Q-To was increased in 6 weeks UCM and decreased upon Epo treatment. The SBP was significantly elevated in UCM groups, whether 6 week or 12 weeks, treated or not treated. Also, the 12 weeks UCM showed significantly higher DBP and MAP. Epo treatment resulted in a significant decrease in SBP in the 6 week group and in all arterial blood pressure values (SBP, DBP, MAP) in the 12 weeks group probably due to its antioxidant action as well as Summary and conclusion (301) correction of volume overload through maintaining better kidney functions. Hearts isolated from both 6 and 12 weeks uremic cardiomyopathy rats exhibited significantly reduced baseline PT/LV denoting deterioration of inotropic activity. Epo treated 6 weeks group showed significant reduction of their HRT denoting better diastolic function. In 12 weeks UCM-Epo group, MFR was significantly reduced compared to 12 weeks UCM and sham-operated groups but MFR/LV was insignificantly different. Following 30 minutes of ischemiareperfusion, hearts subjected to Epo treatment, showed significantly higher PT and PT/LV in the 6 weeks group, and significant increase in PT/LV at 30 min of reperfusion in the 12 weeks treated group, both findings highlight the favourable effects of Epo on cardiac inotropy following ischemia/reperfusion (I/R) injury. The HRT was prolonged at 5 min of reperfusion in the 6 weeks UCM group and at all recorded periods of reperfusion in 12 weeks UCM group compared to baseline values but was insignificantly changed at 15 and 30 min of reperfusion from baseline in the 6 and 12 weeks UCM-Epo groups, denoting preserved diastolic function upon Epo administration in these Summary and conclusion (302) rats after I/R. The CT was also, insignificant from baseline value in the 12 weeks UCM-Epo rats. In 6 weeks and 12 weeks UCM groups, the MFR and MFR/LV were significantly decreased at all recorded periods of reperfusion from baseline values. Upon Epo treatment in both groups, MFR and MFR/LV were insignificantly different from baseline values after 5 min of reperfusion, this effect reflects better perfusion with Epo treatment. On the other hand, the MFR/LV was significantly reduced in the 12 weeks UCM group at 15 and 30 min of reperfusion compared to their respective 6 weeks UCM group, which denotes detrimental effect in longer term renal failure, through its effect on coronary vasculature. Also, MFR was significantly reduced in 12 weeks UCM-Epo group at 15 and 30 min compared to 12 weeks UCM and sham-operated groups. 6 and 12 weeks UCM groups demonstrated cardiac hypertrophy shown by increased absolute weights of atria, ventricles and whole heart as well as their cardiac indices (AT/BW, LV/BW, WH/BW). Epo treatment significantly decreased absolute cardiac weights and cardiac indices only in the 12 weeks group compared to the UCM group, and their respective 6 weeks UCM-Epo group as well, probably through its effect on arterial blood pressure and kidney functions. Also, Summary and conclusion (303) positive correlations were found between LV weight and creatinine level and SBP as well from the aforementioned data, it could be concluded that Epo treatment ameliorated hypertension and cardiac hypertrophy encountered in uremic cardiomyopathic state possibly through its antioxidant effect. Also, Epo improved the systolic and diastolic dysfunctions that uremic cardiomyopathic rat hearts suffered in response to ischemia-reperfusion injury. Moreover, early Epo treatment is more beneficial to hearts with uremic cardiomyopathy subjected to ischemia-reperfusion injury and has a preventive effect against the development of hypertension, rather than amelioration upon late treatment. Therefore, early Epo administration in uremic patients is recommended. |