Selective inhibition by zatebradine and discrete parasympathetic stimulation of the positive chronotropic response to sympathetic stimulation in anesthetized dogs.
To investigate how to reduce the positive chronotropic response to sympathetic nerve activation selectively without affecting other cardiac actions, we studied the effects of zatebradine, an inhibitor of the hyperpolarization-activated current (I(f)), verapamil and parasympathetic nerve stimulation on the positive chronotropic, dromotropic and inotropic responses to sympathetic nerve stimulation in the autonomically decentralized heart of the open-chest anesthetized dog. Parasympathetic input was activated by stimulation of the cervical vagus (CV) or parasympathetic nerves to the sinoatrial (SA) nodal region (SAP). Zatebradine (0.1-3 mumol/kg i.v.) decreased the heart rate but not other cardiac responses to sympathetic nerve stimulation, i.e., a wave component of the right atrial pressure (RAP), the first derivative of the RAP (dRAP/dt), atrioventricular (AV) conduction time (AVCT), right ventricular pressure (RVP) and its first derivative (dRVP/dt). Zatebradine (1 mumol/kg) inhibited basal heart rate by 28% but inhibited the chronotropic response to sympathetic stimulation by 85%. Verapamil (0.06-0.6 mumol/kg i.v.) attenuated the increases in heart rate, RVP and dRVP/dt elicited by sympathetic stimulation but potentiated shortening of the AVCT from the prolonged basal AVCT. The SAP stimulation attenuated the heart rate and dRAP/dt responses to sympathetic stimulation without affecting other cardiac responses, whereas CV stimulation decreased the positive chronotropic and atrial and ventricular inotropic responses. Cervical vagus stimulation did not change the positive dromotropic response. These results demonstrate that in contrast to CV nerve activation or verapamil, zatebradine and SAP stimulation cause bradycardia but preserve the myocardial contractile force and AVCT in response to sympathetic nerve activation or sympathomimetic drugs in the heart in situ.
Department of Pharmacology, Shinshu University School of Medicine, Matsumoto, Japan.
Y
Y
Furukawa
H
H
Nakano
T
T
Oguchi
M
M
Kasama
Y
Y
Hoyano
S
S
Chiba
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D002317:Cardiovascular Agents / Q000494:pharmacology*; D004285:Dogs; D004558:Electric Stimulation; D006339:Heart Rate / Q000187:drug effects*; D010275:Parasympathetic Nervous System / Q000502:physiology*; D012849:Sinoatrial Node / Q000294:innervation; D013564:Sympathetic Nervous System / Q000502:physiology*; D014700:Verapamil / Q000494:pharmacology
D001552:Benzazepines; D002317:Cardiovascular Agents; D014700:Verapamil; C043636:zatebradine