Acta Pharmacologica Sinica (2009) 30: 1099-1106; doi: 10.1038/aps.2009.104; published online 13 July 2009

Aim: Spatial dispersion of bioactive substances in the myocardium could serve as pathological basis for arrhythmogenesis and cardiac impairment by β-adrenoceptor stimulation.  We hypothesized that dispersed NADPH oxidase, protein kinase Cε (PKCε), early response gene (ERG), and matrix metalloproteinase 9 (MMP-9) across the heart by isoproterenol (ISO) medication might be mediated by the endothelin (ET) ?ROS pathway. We aimed to verify if ISO induced spatially heterogeneous distribution of pPKCε, NAPDH oxidase, MMP-9 and ERG could be mitigated by either an ET receptor antagonist CPU0213 or iNOS inhibitor aminoguanidine.

Methods: Rats were treated with ISO (1 mg/kg sc) for 10 days, and drug interventions (mg/kg) either CPU0213 (30 sc) or aminoguanidine (100 ip) were administered on days 8−10.  Expression of NADPH oxidase, MMP-9, ERG, and PKCε in the left and right ventricle ( LV, RV) and septum (S) were measured separately.   

Results: Ventricular hypertrophy was found in the LV, S, and RV, in association with dispersed QTc and oxidative stress in ISO-treated rats.  mRNA and protein expression of MMP-9, PKCε, NADPH oxidase and ERG in the LV, S, and RV were obviously dispersed, with augmented expression mainly in the LV and S.  Dispersed parameters were re-harmonized by either CPU0213, or aminoguanidine.   

Conclusion: We found at the first time that ISO-induced dispersed distribution of pPKCε, NADPH oxidase, MMP-9, and ERG in the LV , S, and RV of the heart, which were suppressed by either CPU0213 or aminoguanidine. It indicates that the ET-ROS pathway plays a role in the dispersed distribution of bioactive substances following sustained β-receptor stimulation.

Keywords: endothelin receptor antagonists; isoproterenol; PKCε; NADPH oxidase; MMP-9; aminoguanidine