Mechanism of cardiac involvement in the WBN/Kob rat

The cardiac characteristics of the WBN/Kob rat resemble those of rats with catecholamine-induced myocarditis. To determine the etiology of these WBN cardiac characteristics, we assessed the number and affinity of beta-adrenergic receptors, and investigated adenylate cyclase activity, the cardiac myocyte cyclic adenosine monophosphate (cAMP) concentration and the activity of guanosine triphosphate (GTP)-binding protein in 3-month-old WBN/Kob rats. Age-matched Wistar rats served as controls. The mean number of beta-adrenergic receptors was similar in WBN/Kob and Wistar rats (28.0+/-9.1 v 28.3+/-8.9 fmol/mg protein), and there was no significant difference in beta-adrenergic receptor affinity between groups (1.09+/-0.54 v 1.26+/-0.60 nM). The mean cAMP concentration in cardiac myocytes was significantly higher in WBN/Kob rats than in Wistar rats 1975.6+/-247.8 v 344.9+/-83.6 pmol/g wet tissue), (P=0.0112) as was adenylate cyclase activity (33.61+/-8.32 v 24.3+/-12.78 pmol/mg/min), (P=0.0174). The activity of GTP-binding protein was significantly higher in WBN/Kob rats than in Wistar rats. After a beta-agonist binds to a beta-adrenergic receptor, activated adenylate cyclase produces cAMP in myocytes, which in turn opens the Ca2+ channel, leading to an influx of Ca2+ into myocytes. Our results suggest that the increase in adenylate cyclase activity in WBN/Kob rats have led to an increase in the cAMP concentration in myocytes. This process may have resulted in excessive beta-adrenergic activity due to high activity of GTP binding protein in WBN/Kob rats, which may explain the hypersensitivity of WBN/Kob rats to isoproterenol and the development of catecholamine-induced myocarditis.