The Cardiac β -Adrenoceptor-G-protein(s)-adenylyl Cyclase System in Monocrotaline-treated Rats

In rats, injection of the alkaloid monocrotaline (MCT) causes right ventricular hypertrophy and cardiac failure. In order to study whether, in MCT-treated rats, changes in the cardiac β -adrenoceptor-G-protein(s)-adenylyl cyclase system might be comparable to those found in human primary pulmonary hypertension, we assessed in right and left ventricles from MCT-treated rats the components of the β -adrenoceptor system: the receptor number and subtype distribution (by (-)-[¹²⁵I]iodocyanopindolol binding), the G-proteins (by quantitative Western blotting), and the activity of adenylyl cyclase. A single injection of 60 mg/kg i.p. MCT caused in rats right ventricular hypertrophy (RVH); part of the rats developed cardiac failure (RVF). In these rats the cardiac β -adrenoceptor-G-protein(s)-adenylyl cyclase system was markedly changed β -adrenoceptors were desensitized due to a decrease in receptor number, an uncoupling of the receptor from the G_s-adenylyl cyclase system, a decrease in G_sand a decrease in the activity of the catalytic unit of adenylyl cyclase. In general, these changes were more pronounced in right ventricles v left ventricles, and in rats with RVF v rats with RVH. On the other hand, cardiac muscarinic receptors and G_iappeared not to be altered. We conclude that in MCT-treated rats changes in the cardiac β -adrenoceptor-G-protein(s)-adenylyl cyclase system occur that resemble those observed in human primary pulmonary hypertension. Thus, MCT-treated rat appears to be a suitable animal model to study in more detail the pathophysiology of the development of right heart failure, and to identify new therapeutic possibilities.