Dipeptide sulfonamides as endothelin ET_A/ET_B receptor antagonists

Abstract

We studied the effect of long-term treatment with the oral endothelin (ET) ET A antagonist 2-benzo[1,3]dioxol-5-yl-3-ben-zyl-4-(4-methoxy-phenyl-)-4-oxobut-2-enoate-sodium (PD 155080; PD) on right ventricular intracellular calcium (Ca 2 i) handling and cardiac and pulmonary artery function in control rats and rats with monocrotaline (MCT)-induced right-heart hypertrophy. Rats were given an intraperitoneal injection of either saline (controls; n 9) or MCT (50 mg/kg; n 12), resulting in pulmonary hypertension-induced myocardial hyper-trophy, or MCT followed by the daily administration of PD (50 mg/kg) for 9 weeks (n 9). After 9 weeks, right ventricular pressure was measured, and the hearts were removed and perfused in vitro. Right ventricular function and Ca 2 i transients were recorded simultaneously on a beat-to-beat basis using aequorin. Surviving animals in the MCT group (58%) developed significant hypertrophy and had 2-fold higher right ventricu-lar pressure and a prolonged duration of isovolumic contraction that correlated with a similar prolongation of the Ca 2 i transient, indicating a reduced rate of Ca 2 sequestration in hypertrophy (P 0.05 versus control). In the PD group, all animals survived, and right ventricular pressure, diastolic relaxation, Ca 2 transport kinetics, and peak systolic and end-diastolic wall stress were all normalized (P 0.05 versus control); and pulmonary artery endothelial function was partly restored (P 0.05 versus MCT and control groups). These results demonstrate for the first time that long-term ET A receptor antagonism normalizes myocardial cytosolic Ca 2 modulation, which may contribute to the antihypertro-phic and cardioprotective effect of ET A receptor therapy in this model. The polypeptide endothelin-1 (ET-1) plays an important role in the cardiovascular system by modulating vasomotion, inotropic state, and growth processes. ET-1 exerts its different biological effects via the activation of specific receptors (ET A and ET B receptors) which are widely expressed on cardiac and vascular cells of both humans and other species (Rubanyi and Polokoff, 1994). Cardiac hypertrophy is an adaptational mechanism to stresses such as neurohumoral stimulation and pressure overload (Homcy, 1998). Recent observations suggest the involvement of ET-1 in left ventricular hypertrophy, but much less is known about its role in right ventricular hypertrophy (Ito, 1997; Kirchengast and Mü nter, 1999). In several rat models of right ventricular hypertrophy, including exposure to normobaric hypoxia, carbon monoxide, MCT (Miyauchi et al., 1993), or volume overload (Brown et al., 1995), prepro-ET-1 mRNA transcription was increased in right atria or ventricles without consistent increase in myocardial ET-1 production. In a recent study, we found no evidence for increased release of ET-1 and big ET-1 in hypertrophic hearts and concluded that the growth process may be fueled by extracardiac ET (Brunner, 1999). Administration of ET A antagonists (Miyauchi et al. over several weeks generally attenuated t...