Effect of the Endothelin Receptor Antagonist Cpu0213, and Its Modulation by Rifampin, on Cardiac and Vascular Tissue Following Chronic Isoproterenol Treatment

Abstract

1. The aim of the present study was to investigate the effects of the endothelin (ET) receptor antagonist CPU0213 on cardiac and vascular tissues after impairment by chronic isoproterenol treatment. Because rifampin reduces plasma concentrations of CPU0213, the modulation of the effects of CPU0213 by rifampin was also investigated. 2. Thirty rats were randomly divided into five groups as follows: (i) control; (ii) isoproterenol treated (1 mg/kg, s.c., for 10 days); (iii) isoproterenol treated with a single injection of CPU0213 (30 mg/kg, s.c., on Day 11); (iv) isoproterenol treated with a single injection of rifampin (50 mg/kg, p.o., on Day 11); and (v) isoproterenol treated with rifampin gvien 3 h before CPU0213 on Day 11. Serum concentrations of CPU0213, haemodynamic and biochemical parameters, mRNA and protein expression levels of the ET(A) receptor (ET(A)R), calstabin 2 (FKBP12.6) and sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2a), and vasoactivity of the thoracic aorta were determined. 3. Haemodynamic parameters, serum creatine phosphokinase, lactate dehydrogenase and malondialdehyde levels, mRNA and protein expression of FKBP12.6, SERCA2a and vascular responses were altered following isoproterenol treatment for 10 days. These effects were significantly reversed by CPU0213. Rifampin caused a reduction in serum concentrations of CPU0213 to 36% of control values. However, this reduction in the serum concentrations of CPU0213 did not affect its effects on the heart, but did eliminate its beneficial action on vascular responses. Rifampin alone had no effect these paramters. 4. The data suggest that isoproterenol acts on the myocardium to cause cardiac insufficiency by upregulating ET(A)R and downregulating FKBP12.6 and SERCA2a. These effects were ameliorated by CPU0213, but were resistant to rifampin-induced decreases in plasma CPU0213 concentrations. In vascular tissue, the pathological effects of isoproterenol were ameliorated by CPU0213; however, lowering plasma CPU0213 concentrations with rifampin did partly eliminate the amelioration in vascular activity in respones to CPU0213.

Stress-induced cardiac insufficiency relating to abnormal leptin and FKBP12.6 is ameliorated by CPU0213, an endothelin receptor antagonist, which is not affected by the CYP3A suppressing effect of erythromycin

“…However, the benefits of CPU0213 plus erythromycin to the myocardium were not significantly different from CPU0213 alone 13 . In this study we designed a low dose of CPU0213, 20 mg/kg (s.c.) against 30 mg/kg (s.c.) in the study by Luo et al 14 , in which rifampicin caused a decline from 2.795 to 0.939 μg/ml, and a reduction in plasma concentration did not affect the effects on abnormality of FKBP12.6, SERCA2a and ET A , but a mild modulation of effects on the improved vascular activity. Effects of CPU0213 in the two studies, however, did not respond positively to a fluctuation of plasma levels by the CYP3A inhibitor erythromycin.…”

“…The effects of CPU0213 were investigated while exposed to the enzyme‐inducing drug rifampicin. It was found that it caused a reduction in plasma levels but had no effect on the heart; however; the relationship of the effects of the endothelin receptor antagonist CPU0213 in response to plasma levels has not been fully clarified 14 . It is uncertain whether erythromycin, as the inhibitor of CYP3A, by raising blood concentrations of CPU0213, augments its benefits on stress‐induced cardiac injury by improving further abnormal leptin and the calcium modulating protein FKBP12.6 15 …”

Stress-induced cardiac insufficiency relating to abnormal leptin and FKBP12.6 is ameliorated by CPU0213, an endothelin receptor antagonist, which is not affected by the CYP3A suppressing effect of erythromycin

“…However, the benefits of CPU0213 plus erythromycin to the myocardium were not significantly different from CPU0213 alone. [13] In this study we designed a low dose of CPU0213, 20 mg/kg (s.c.) against 30 mg/kg (s.c.) in the study by Luo et al [14] , in which rifampicin caused a decline from 2.795 to 0.939 mg/ml, and a reduction in plasma concentration did not affect the effects on abnormality of FKBP12.6, SERCA2a and ET A , but a mild modulation of effects on the improved vascular activity. Effects of CPU0213 in the two studies, however, did not respond positively to a fluctuation of plasma levels by the CYP3A inhibitor erythromycin.…”

“…It was found that it caused a reduction in plasma levels but had no effect on the heart; however; the relationship of the effects of the endothelin receptor antagonist CPU0213 in response to plasma levels has not been fully clarified. [14] It is uncertain whether erythromycin, as the inhibitor of CYP3A, by raising blood concentrations of CPU0213, augments its benefits on stress-induced cardiac injury by improving further abnormal leptin and the calcium modulating protein FKBP12.6. [15] We hypothesized that isoprenaline developed cardiac hypertrophy and insufficiency by upregulating the endothelin A receptor (ET A ) and leptin to downregulate FKBP12.6, therefore compromising cardiac function, and the endothelin receptor antagonist may counteract these abnormalities in the myocardium.…”

Role of endothelin receptor A and NADPH oxidase in vascular abnormalities

“…Chronic medication of isoproterenol mimicking a stress status related to an increase in sympathetic outflow, causes an impairment of vascular activity which is effectively reversed by endothelin receptor antagonist CPU0213 45. The abnormal vascular activity is characterized by an increase in expression of ETA, NOX, and MMP9 in the vasculature which are attenuated by either CPU0213 a blockade on ET receptors and an antioxidant activity by aminoguanidine.…”