ArticleBasic research in cardiology
I(f) current mediates beta-adrenergic enhancement of heart rate but not contractility in vivo.
Article in Basic research in cardiology. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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5 citing papers in PubMed, 24 citations in OpenAlex.
- Novel cardiac cell subpopulations: Pnmt-derived cardiomyocytes.Open biology · 2020Review
- Glucagon Increases Beating Rate but Not Contractility in Rat Right Atrium. Comparison with Isoproterenol.PloS one · 2015Article
- Ivabradine prevents heart rate acceleration in patients with chronic obstructive pulmonary disease and coronary heart disease after salbutamol inhalation.Pharmaceuticals (Basel, Switzerland) · 2012Article
- I(f) channel inhibitor ivabradine lowers heart rate in mice with enhanced sympathoadrenergic activities.British journal of pharmacology · 2004Article
- Enhancement of murine cardiac chronotropy by the molecular transfer of the human beta2 adrenergic receptor cDNA.The Journal of clinical investigation · 1998Article
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2 authors at 1 institution in 1 country.
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Abstract
backgroundThe 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.
methodsBoth 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.
resultsBefore 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.
conclusionZatebradine 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.
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