CPU0213, A NON‐SELECTIVE ET_A/ET_B RECEPTOR ANTAGONIST, IMPROVES PULMONARY ARTERIOLAR REMODELING OF MONOCROTALINE‐INDUCED PULMONARY HYPERTENSION IN RATS

Abstract

1. The aim of the present study was to explore the effects of CPU0213, a dual endothelin ET(A)/ET(B) receptor antagonist, and nifedipine, a calcium antagonist, in relieving pulmonary hypertension (PH). Both endothelin receptor and calcium antagonists have been reported to be effective in alleviating the remodelling of pulmonary arteries induced by monocrotaline (MCT) in rats. 2. After an initial single dose of 60 mg/kg, s.c., MCT, CPU0213 was administered to rats at doses of 25, 50 or 100 mg/kg, p.o., for 28 days. In addition, nifedipine was administered to another group of rats at a dose of 10 mg/kg, p.o., for 28 days. The haemodynamics of the right ventricle, pulmonary vascular activity, remodelling of the pulmonary arterioles (< 150 microm) and biochemical changes were evaluated. 3. Right ventricular systolic pressure (RVSP), central venous pressure (CVP), the maximum rate of uprising pressure (dP/dT(max)) and the weight index of the right ventricle were significantly elevated in MCT-treated rats. In addition, increases in pulmonary endothelin-1, malonyldialdehyde (MDA) and hydroxyproline content and a reduction in superoxide dismutase activity was found after MCT treatment. The thickness and area of the pulmonary arterial wall were significantly increased in MCT-treated rats compared with control rats. At all three doses tested, CPU0213 ameliorated these changes in a dose-dependent manner and the effects were associated with a greater reduction in the remodelling of pulmonary arterioles. However, nifedipine was only partially effective in amelerioating biochemical and haemodynamic changes induced by MCT, significantly reducing RVSP, CVP, +dp/dt(max), tissue MDA, inducible nitric oxide synthase and hydroxyproline content, increasing -dp/dt(min) and having no effect on the other parameters investigated. In addition, nifedipine had no effect on remodelling of the arterial wall. 4. In conclusion, CPU0213 is more effective than nifedipine in suppressing the remodelling of pulmonary arterioles in PH induced by MCT treatment of rats. Furthermore, CPU0213 may have promise in treating PH secondary to connective tissue disease.

Inhalation of the BKCa-Opener NS1619 Attenuates Right Ventricular Pressure and Improves Oxygenation in the Rat Monocrotaline Model of Pulmonary Hypertension

“…This effect could be caused by a decreased afterload, which has been reported previously and indicate a reduced right ventricular work in consequence of PH treatment [21]–[23]. Accordingly, we observed an increase of the relaxation velocity (dP/dt min ), which frequently accompanies a treatment-induced dP/dt max reduction [21]–[23].…”

Isoproterenol disperses distribution of NADPH oxidase, MMP-9, and pPKCε in the heart, which are mitigated by endothelin receptor antagonist CPU0213

“…An endothelin receptor antagonist CPU0213 has been developed possessing a potent blockade on the ET A receptor but a relative low blocking effect on ET B receptor [20] and is effective in suppressing both pulmonary artery hypertension [21] and ventricular fibrillation [18] . The ET-ROS (endothelin-reactive oxygen species) pathway influences transcription and expression of genes through the MAPK (mitogen-activated protein kinase) pathway in heart failure and arrhythmia [22,23] .…”

The PPARγ ligand rosiglitazone attenuates hypoxia-induced endothelin signaling in vitro and in vivo

“…A final cleavage step, performed by endothelin-converting enzyme (ECE), converts big ET-1 to the 21-amino acid product ET-1 (23,56). ET-1, one of the strongest endogenous vasoconstrictors and mitogens (56), is expressed in and released by endothelial cells (ECs), epithelial cells, and mesenchymal cells in the normal lung (7,9). Once released, ET-1 binds to two G protein-coupled endothelin receptors A and B (ETAR and ETBR) (2,4).…”