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.
Tsuruta
S
S
First Department of Internal Medicine, Nara Medical University, Kashihara City, Japan.
Sutani
T
T
Masuda
J
J
Sakaguchi
Y
Y
Tsuchihashi
M
M
Hashimoto
T
T
Nakamura
Y
Y
Dohi
K
K
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D006352:Heart Ventricles / Q000201:enzymology; D008297:Male; D009205:Myocarditis / Q000378:metabolism / Q000503:physiopathology*; D009929:Organ Size / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000378:metabolism / Q000502:physiology*; D016276:Ventricular Function
D011943:Receptors, Adrenergic, beta; D000242:Cyclic AMP; D000262:Adenylyl Cyclases