Vol. 283, Issue 3, 1389-1395, 1997

Abnormality in Plasma Catecholamines and Myocardial Adrenoceptors in Cardiomyopathic BIO 53.58 Syrian Hamsters and Improvement by Metoprolol Treatment

Shizuo Yamada, Takashi Ohkura, Tooru Yamadera, Osamu Ito, Ryohei Kimura, Yoshihisa Nozawa, Shuji Hayashi and Hidekazu Miyake

Department of Biopharmacy, School of Pharmaceutical Sciences, University of Shizuoka (S.Y., T.O., T.Y., O.I., R.K.), Shizuoka, and Research Laboratories of Pharmacology (Y.N., H.M.) and Drug Safety (S.H.), Taiho Pharmaceutical Company, Ltd., Tokushima, Japan

The catecholaminergic neuronal activity and the densities of alpha-1 and beta adrenoceptors and angiotensin II receptors were simultaneously determined in BIO 53.58, a model of idiopathic dilated cardiomyopathy, and F1B control hamsters. Further, we examined the effect of repeated p.o. administration of metoprolol on these biochemical parameters. Compared with F1B control hamsters, there was a significant decrease in B_max of specific binding of both ()-[¹²⁵I]iodocyanopindolol and [³H]prazosin with a marked elevation of plasma catecholamine (mainly norepinephrine and epinephrine) concentrations, in BIO 53.58 hamsters at 11 and 18 weeks of age (severe cardiomyopathic stage), but not at 5 weeks of age. On the other hand, the B_max value of myocardial [¹²⁵I]angiotensin II binding in BIO 53.58 hamsters was almost identical to that in F1B hamsters. These results suggest a development of down-regulation of myocardial beta and alpha-1 adrenoceptors because of an increased catecholaminergic neuronal activity with aging in BIO 53.58 hamsters. Repeated p.o. administration of a relatively low dose (1 mg/kg/day) of metoprolol for 7 weeks in 11-week-old BIO 53.58 hamsters caused a significant increase of myocardial ()-[¹²⁵I]iodocyanopindolol binding sites with a marked reduction in plasma catecholamine levels; this indicated a significant recovery to the F1B levels. The improvement of these biochemical parameters by metoprolol treatment was also accompanied by a significant decrease in the fibrosis in the heart in BIO 53.58 hamsters. These data suggest that catecholaminergic neurons and adrenoceptors play a part in the development of heart failure in idiopathic dilated cardiomyopathy. Consequently, the present study may provide a further pharmacological basis for the use of beta-1 adrenoceptor antagonists in patients with idiopathic dilated cardiomyopathy.