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