ABSTRACT
OBJECTIVES: The aim was to investigate the nephroprotective effect of combination of aliskiren (ASK), a direct renin inhibitor and pentoxifylline (PTX), inhibitor of tumor necrotic factor-alpha (TNF-alpha), in rat remnant kidney model of chronic kidney disease (CKD). MATERIALS AND METHODS: Nephrectomized (NPX) rats were treated with ASK (10 mg/kg, p.o.), PTX (100 mg/kg, p.o.), and combination of PTX + ASK once daily for 28 days. We have performed analysis of various renal injury parameters after 4 weeks of treatment. RESULTS: Treatment with PTX, ASK and combination showed significant improvement in urea, creatinine and total protein in plasma when compared with vehicle treated group in NPX rats. ASK and combination of PTX + ASK elicited significant reduction in blood pressure but PTX alone did not produce blood pressure reduction. ASK treatment showed significant elevation in TNF-alpha, whereas PTX and ASK + PTX showed significant reduction in TNF-alpha in plasma. Histopathologically, the extent of the kidney injury was similar in NPX + vehicle and NPX + ASK-treated rats. PTX and ASK + PTX-treated group showed lesser extent of kidney injury. There was good correlation of mRNA expression levels of kidney injury molecule-1 and bradykinin B1 receptor data with histopathological findings in kidney samples and elevated TNF-alpha levels in plasma. CONCLUSIONS: We conclude that combination of PTX + ASK may be better therapeutic intervention for nephroprotection in CKD patients.
Subject(s)
Amides/pharmacology , Fumarates/pharmacology , Kidney Failure, Chronic/drug therapy , Kidney/drug effects , Nephrectomy , Pentoxifylline/pharmacology , Animals , Arterial Pressure/drug effects , Cell Adhesion Molecules/genetics , Cell Adhesion Molecules/metabolism , Creatinine/blood , Disease Models, Animal , Drug Therapy, Combination , Kidney/metabolism , Kidney/pathology , Kidney/physiopathology , Kidney Failure, Chronic/genetics , Kidney Failure, Chronic/metabolism , Kidney Failure, Chronic/pathology , Kidney Failure, Chronic/physiopathology , Male , RNA, Messenger/metabolism , Rats, Sprague-Dawley , Receptor, Bradykinin B1/genetics , Receptor, Bradykinin B1/metabolism , Renin/antagonists & inhibitors , Renin/metabolism , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/blood , Urea/bloodABSTRACT
OBJECTIVES: The cytokine erythropoietin is the primary stimulator of erythropoiesis and recombinant human erythropoietin (rHuEPO), which is widely used in the treatment of anemia associated with advanced chronic kidney disease (CKD). Adverse cardiovascular outcomes have been observed during clinical trials of anemia correction with rHuEPO in CKD patients. We investigated the effects of short-term, high-dose treatment with rHuEPO on platelet reactivity and effects of aspirin on platelet reactivity in healthy rats. MATERIALS AND METHODS: Animals received three daily dose of rHuEPO (25 µg/kg s.c.). Platelets were isolated after 48 h of last dose of rHuEPO to study the arachidonic acid-induced platelet aggregation. Aspirin (75 mg/kg p.o.) was given to animals just before 1 h of isolation of platelets. RESULTS: In rats, treatment with rHuEPO increased platelet reactivity and platelet count. The increased platelet reactivity was paralleled by decreased time-to-occlusion (TTO) in arterial thrombosis model, and decreased bleeding time after tail transection in rats. Treatment with rHuEPO followed by single dose of aspirin showed significant reduction in TTO and bleeding time as compared with aspirin-treated group. CONCLUSIONS: These findings suggest that rHuEPO increases platelet reactivity and aspirin normalizes the hyper-reactive platelet and may reduce the cardiovascular events associated with rHuEPO in CKD patients.
Subject(s)
Aspirin/pharmacology , Blood Platelets/drug effects , Erythropoietin/pharmacology , Platelet Aggregation Inhibitors/pharmacology , Animals , Bleeding Time , Epoetin Alfa , Humans , Male , Platelet Aggregation/drug effects , Platelet Count , Rats, Wistar , Recombinant Proteins/pharmacologyABSTRACT
Although the cardioprotective role of carbon monoxide (CO) has been studied against myocardial ischemia-reperfusion (I/R) injury, the role of coronary endothelium and underlying mechanism in carbon monoxide-induced cardioprotection is not well understood in isolated heart. The present study was designed to determine the role of coronary endothelium in CORM-2-mediated cardioprotection during I/R injury in isolated rat heart. Preconditioning with 30microM/l and 50microM/l of CORM-2 for 10min markedly reduced lactate dehydrogenase (LDH) and creatinin kinase (CK) levels in coronary effluent after global ischemia. There was also a significant improvement in coronary flow rate, heart rate, cardiodynamic parameters and marked attenuation in infarct size. However, protective effect was abolished when hearts were pretreated with 100microM CORM-2. We observed that pretreatment with L-NAME (100microM/l), a nitric oxide synthase (NOS) inhibitor did not affect protection by CORM-2 (50microM/l). On the other hand pretreatment with Triton X-100 (0.05% for 20s) to denude endothelium before CORM-2 treatment followed by I/R injury showed similar cardioprotection. Moreover, pretreatment with K(ATP) channel inhibitor, glibenclamide almost completely reversed the cardioprotective effect of CORM-2 in endothelium-denuded hearts. These results indicate that cardioprotection by CORM-2 is highly concentration-dependent, independent of coronary endothelium and cardioprotective effect might be attributed to the activation of K(ATP) channel present on vascular smooth muscle cell (VSMC).
