Beta-adrenergic signalling and threshold adrenaline concentration for induction of fibrillation in the perfused heart pretreated with antihypertensive drugs.
Recent investigations have shown that antihypertensive drug treatment leads to enhanced myocardial beta-adrenoceptor sensitivity. This study was therefore conducted to establish whether or not such hypersensitivity might trigger myocardial arrhythmia subsequent to adrenaline exposure. Adult male Wistar rats (n = 6 per group) were treated with either placebo (vehicle), metoprolol (2.40 mg.kg-1.day-1), timolol (0.075 mg.kg-1.day-1), verapamil (5.50 mg.kg-1.day-1) or enalapril (0.50 mg.kg-1.day-1) for 20 consecutive days. Hearts were excised and perfused ad modum Langendorff in the presence of an adrenaline gradient (0-300 nM) for 20 min with either 3.0 mM or 5.9 mM of potassium in the perfusion buffer. Adrenaline threshold concentration (ATC, nanomolar) at myocardial fibrillation was recorded, as well as tissue cAMP contents, beta-adrenoceptor number, G-protein levels and signalling effector enzyme activities. The main findings were: (1) ATC and cAMP levels were affected in hearts perfused with low-concentration potassium buffer only. In terms of ATC, the beneficial effect of each drug regimen appeared to be in the rank order of: placebo = enalapril > verapamil > timolol > metoprolol. There was an inverse correlation between ATC and myocardial cAMP contents at the start of fibrillation; (2) Subsequent to fibrillation, beta-adrenoceptor number, hormone-elicited adenylate cyclase activities and Gs alpha:Gi2 alpha-ratio were no different from preperfusion values; (3) Significant inverse correlations between beta 1-adrenoceptor numbers and ATC were observed. We conclude that alterations in beta-adrenoceptor number, G proteins and cAMP induced by antihypertensive drugs are predictive of the myocardial sensitivity to adrenaline in terms of time to continuous and irrevocable fibrillation.
Gordeladze
J O
JO
Institute of Medical Biochemistry, University of Oslo, Norway.
Sellevold
O F
OF
Jynge
P
P
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000503:physiopathology; D000242:Cyclic AMP / Q000378:metabolism; D004656:Enalapril / Q000494:pharmacology; D004837:Epinephrine / Q000008:administration & dosage*; D019204:GTP-Binding Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008790:Metoprolol / Q000494:pharmacology; D010477:Perfusion; D011188:Potassium / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000502:physiology*; D015398:Signal Transduction; D013999:Timolol / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D000959:Antihypertensive Agents; D011943:Receptors, Adrenergic, beta; D004656:Enalapril; D013999:Timolol; D014700:Verapamil; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D008790:Metoprolol; D011188:Potassium; D004837:Epinephrine