I(f) current mediates beta-adrenergic enhancement of heart rate but not contractility in vivo.

Abstract

The hyper-polarization-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. Both isoproterenol (ISO, 0.1 micrograms/kg/min i.v. for 5 min) and norepinephrine (NE, 0.3 micrograms/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. 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. 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.