Beta-adrenergic signalling and threshhold adrenaline concentration for induction of fibrillation in the perfused heart pretreated with antihypertensive drugs

Citation
Jo. Gordeladze et al., Beta-adrenergic signalling and threshhold adrenaline concentration for induction of fibrillation in the perfused heart pretreated with antihypertensive drugs, RES EXP MED, 199(3), 1999, pp. 129-140
Citations number
36
Categorie Soggetti
Medical Research General Topics
Journal title
RESEARCH IN EXPERIMENTAL MEDICINE
ISSN journal
03009130 → ACNP
Volume
199
Issue
3
Year of publication
1999
Pages
129 - 140
Database
ISI
SICI code
0300-9130(199912)199:3<129:BSATAC>2.0.ZU;2-Z
Abstract
Recent investigations have shown that antihypertensive drug treatment leads to enhanced myocardial P-adrenoceptor sensitivity. This study was therefor e 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), metoprolo l (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 consecu tive days. Hearts were excised and perfused ad modum Langendorff in the pre sence of an adrenaline gradient (0-300 nM) for 20 min: with either 3.0 mM o r 5.9 mM of potassium in the perfusion buffer. Adrenaline threshold concent ration (ATC, nanomolar) at myocardial fibrillation was recorded, as well as tissue cAMP contents, beta-adrenoceptor number, G-protein levels and signa lling effector enzyme activities. The main findings were: (1) ATC and cAMP levels were affected in hearts perfused with low-concentration potassium bu ffer only. In terms of ATC, the beneficial effect of each drug regimen appe ared to be in the rank order of: placebo=enalapril>verapamil>timolol>metopr olol. There was an inverse correlation between ATC and myocardial cAMP cont ents at the start of fibrillation; (2) Subsequent to fibrillation, beta-adr enoceptor number, hormone-elicited adenylate cyclase activities and G(s)alp ha:G(i2)alpha-ratio were no different from preperfusion values; (3) Signifi cant inverse correlations between beta(1)-adrenoceptor numbers and ATC were observed. We conclude that alterations in beta-adrenoceptor number, G prot eins and cAMP induced by antihypertensive drugs are predictive of the myoca rdial sensitivity to adrenaline in terms of time to continuous and irrevoca ble fibrillation.