I-F CURRENT MEDIATES BETA-ADRENERGIC ENHANCEMENT OF HEART-RATE BUT NOT CONTRACTILITY IN-VIVO

Background: The hyperpolarization-activated ''I-f'' current in the sinoatrial (SA) node participates in the spontaneous diastolic depolarization responsible for pacemaking function. Both sympathetic and parasympathetic control of heart rate is thought to involve modulation of I-f. This study tested whether beta-adrenoceptor activation of heart rate, but not contractile state, could be reduced by blockade of I-f channels in the intact, anesthetized pig. Methods: Both isoproterenol (ISO, 0.1 mu g/kg/min i.v. for 5 min) and norepinephrine (NE, 0.3 mu g/kg/min i.v. for 5 min) were used sequentially to activate beta-adrenoceptors in five metomidathydrochloride-anesthetized pigs. Left ventricular pressure and dP/dt, aortic blood pressure and cardiac output were measured. I-f channels were then blocked selectively with 0.3 mg/kg i.v. zatebradine (ULFS49) and the test doses of ISO and NE were repeated. Following a further high dose (10 mg/kg, i.v.) of zatebradine, the test doses of ISO and NE were repeated once again. Results: Before I-f blockade, ISO and NE elicited reproducible increases in both heart rate and left ventricular dP/dt. Whereas NE caused an increase in both systolic (56%) and diastolic (53%) aortic pressure and a modest heart rate increase (22%), ISO caused a decrease in diastolic aortic pressure (-22%) and a marked increase in heart rate (81%). Low dose zatebradine reduced basal heart rate from 98 +/- 6 to 66 +/- 3 bpm, p < 0.05; cardiac output fell by 20%, stroke volume increased by 18% and total peripheral resistance was unchanged. ISO after low-dose zatebradine still elicited marked increases in heart rate (66 +/- 3 to 105 +/- 5 bpm, p < 0.05) and left ventricular dP/dt (774 +/- 94 to 3364 +/- 206 mmHg/s, p < 0.05) and reduced aortic diastolic pressure (37 +/- 2 to 33 +/- 1 mmHg, p < 0.05). NE after low-dose zatebradine increased heart rate (73 +/- 4 to 89 +/- 5 bpm, p < 0.05), left ventricular dP/dt (810 +/- 95 to 3372 +/- 196 mmHg/s, p < 0.05) and both systolic and diastolic aortic pressures. High dose zatebradine caused no further reduction in heart rate (77 +/- 4 vs 82 +/- 6 bpm, NS) but left ventricular dP/dt decreased (798 +/- 92 to 418 +/- 50 mmHg/s, p < 0.05) as did both systolic and diastolic aortic pressures. Subsequent administration of ISO had no effect on heart rate but increased left ventricular dP/dt from 418 +/- 50 to 3468 +/- 256 mmHg/s (p < 0.05) and systolic aortic pressure increased from 58 +/- 7 to 90 +/- 3 mmHg (p < 0.05). NE administered after high dose zatebradine also increased left ventricular dP/dt (580 +/- 54 to 2608 +/- 182 mmHg/s, p < 0.05) while heart rate fell (86 +/- 4 to 74 +/- 6 bpm, p < 0.05). Both systolic and diastolic aortic pressures increased substantially during the NE infusion after high dose zatebradine. Conclusion: Zatebradine dose-dependently inhibits beta-adrenoceptor-mediated heart rate increases while leaving beta-adrenoceptor-mediated increases in myocardial contractile state intact. This observation can be explained by a selective blockade of the hyperpolarization-activated current I-f by low concentrations of the drug.