Therapeutic effects of CPU 86017 on acute and chronic congestive cardiac failure mediated by reducing ET‐1?NOS and oxidative stress in rats

Abstract

CPU 86017, a derivative of berberine, was administered to rats in which acute and chronic heart failure was induced by left coronary artery ligation for 3 h and 8 weeks, respectively. The rats were divided into the following groups: sham operation, coronary artery ligation (CAL), CALþ CPU 86017 (80, 40 and 20 mg/kg, ig) and CALþ captopril (60 mg/kg, ig). In the acute model, the systolic parameters of LVSP and LVþdp/dtmax as well as the diastolic parameters of LVEDP and LV-dp/dtmin improved significantly on pretreatment of CPU 86017 (80 mg/kg). Reductions in elevated serum CPK, LDH, MDA, GOT, GPT, infarcted area and blood viscosity were also significant (P o 0.01). In the chronic model, CPU 86017 (80 mg/kg) preserved the systolic parameters of LVSP and LVþdp/dtmax and the diastolic function of the LVEDP and LV-dp/dtmin. CPU 86017 completely suppressed elevated plasma ANP and ET-1, serum and tissue iNOS, NO and MDA, whereas the decreased SOD was improved. CPU 86017 and captopril improved cardiac failure performance and regressed cardiac remodeling in CHF by reducing tissue weight index: lung weight/body weight (BW), right ventricular weight/BW, and left ventricular weight/BW. CPU 86017 exerted beneficial actions in cardiac performance in models of both acute and chronic heart failure, mainly by suppressing ET-1, iNOS, and oxidative stress in infarcted tissue.

Ethanol extracts of Rehmannia complex (Di Huang) containing no Corni fructus improve early diabetic nephropathy by combining suppression on the ET-ROS axis with modulate hypoglycemic effect in rats

“…ET-1 is involved in pulmonary hypertension (Zhang et al, 2005a(Zhang et al, , 2005b and cardiac failure (Wang et al, 2004) and upregulation of the ET pathway has been found in various renal disorders (Ohshiro et al, 2006;Richter, 2006;Dhaun et al, 2007). An over-activation of the ET A receptor subtype is consistent with findings in diabetic patients or animal models (Sugimoto et al, 2002).…”

Up-regulated inflammatory factors endothelin, NFκB, TNFα and iNOS involved in exaggerated cardiac arrhythmias in l-thyroxine-induced cardiomyopathy are suppressed by darusentan in rats

“…Cardiac hypertrophy can be produced by thyroid hormone (Shohet et al, 2004) and is associated with downregulation of activity of MMP2.9 (matrix metalloproteinases 2.9) and proα2(I) collagen mRNA levels which are normalized by a dual endothelin receptor antagonist CPU0213 . Ventricular hypertrophy in association with cardiac failure is associated with up-regulation of the ET signaling pathway and is suppressed by CPU86017, a calcium antagonist and K + channel blocker of plant origin (Wang et al, 2004b). Cardiac hypertrophy is a major risk factor for arrhythmias and is associated with an altered function of ion channels (Dai, 2000;Lloyd-Jones et al, 2002).…”

Abrupt changes in FKBP12.6 and SERCA2a expression contribute to sudden occurrence of ventricular fibrillation on reperfusion and are prevented by CPU86017

“…Increased calcium in the diastole mediates triggered activity to initiate DAD, and eventually malignant tachyventricular arrhythmias [24] . Compound JTV-519, a derivative of diltiazem, possesses a blockade on calcium and potassium channels [33] and has been discovered to correct deficiencies of RyR2 and FKBP12.6 effectively [34] .…”

“…(A) mRNA of ECE was upregulated in CM and showed further upregulation on reperfusion and was suppressed by CPU86017, respectively (ANOVA P<0. 0001 augmented I Ca.L channel is attributed to PKA (presumably including PKC) phosphorylation relating to an activated ET system [42] and arrhythmogenesis [24] . In the CM there may be a link (which may be an upregulation of PKA or PKC) between augmented I Kr , I Ks , and I Ca.L currents and abnormal expression of FKBP12.6, RyR2, SERCA2a, and PLB.…”