1. We investigated the effects of omega-conotoxin GVIA (omega-CgTX), a blocker of N-type voltage-operated calcium channels, on the chronotropic response to stimulation of the intracardiac sympathetic and parasympathetic nerves in the isolated, blood-perfused right atrium of the dog. 2. omega-CgTX (0.3-3 nmol) itself did not affect the sinus rate significantly, but it inhibited the negative followed by positive chronotropic response to simultaneous stimulation of sympathetic and parasympathetic nerves in a dose-dependent manner. 3. omega-CgTX at higher doses (1-3 nmol) inhibited the positive response to sympathetic stimulation more strongly than the negative response to parasympathetic stimulation. omega-CgTX (3 nmol) abolished the positive chronotropic response to sympathetic nerve stimulation in the atrium treated with atropine, but did not abolish the negative response to selective parasympathetic stimulation. Neither the chronotropic response to noradrenaline nor the response to acetylcholine was affected by omega-CgTX. 4. These results indicate that omega-CgTX inhibits not only the response to sympathetic stimulation but also the response to parasympathetic stimulation in the dog heart and it inhibits the positive chronotropic response to sympathetic stimulation more strongly than the negative chronotropic response to parasympathetic stimulation.
We investigated whether the intracardiac parasympathetic ganglia for sinoatrial (SA) nodal pacemaker cells control the right atrial contractility selectively and totally in the autonomically decentralized heart of the open-chest anesthetized dog. Stimulation of the intracardiac parasympathetic nerves to the SA nodal area (SAP Stim) decreased the right atrial pressure (a wave pressure) and its first pressure derivative (dP/dt) as well as the atrial rate but did not change the atrioventricular (AV) conduction time. Stimulation of right and left cervical vagosympathetic complexes (CV Stim) decreased the a wave pressure, dP/dt, and atrial rate and prolonged the AV conduction time. When SAP and CV Stim decreased the atrial rate similarly, the decreases in a wave pressure and dP/dt in response to SAP Stim were less than those to CV Stim in unpaced and paced hearts. When treatment with hexamethonium bromide or tetrodotoxin into the SAP Stim locus abolished the decreases in atrial rate evoked by SAP and CV Stim, each treatment abolished the decrease in a wave pressure response to SAP Stim but only slightly attenuated the pressure response to CV Stim. These results demonstrate that right atrial pressure is modified by efferent parasympathetic neurons, which are located in a region that differs from that of efferent parasympathetic neurons controlling heart rate.
1. Inhibition of I(f) or ICa by zatebradine has been reported in mammalian SA nodal cells. We thus investigated whether zatebradine differentially attenuates the positive chronotropic and inotropic responses to norepinephrine, isoproterenol, NKH 477 (an adenylyl cyclase activator), 3-isobutyl-1-methylxanthine (IBMX) and Bay k 8644 (a calcium channel agonist) in the isolated, blood-perfused dog atrium. 2. When zatebradine (0.03-1 mumol) decreased sinus rate from 104 +/- 4.5 to 73 +/- 4.9 beats/min dose-dependently, it selectively attenuated the positive chronotropic but not inotropic responses to norepinephrine in a dose-related manner. Zatebradine decreased the norepinephrine-induced tachycardia (by approximately 80% from the control) more effectively than the spontaneous sinus rate (by approximately 30% from the control). 3. Zatebradine similarly attenuated the positive chronotropic but not inotropic responses to isoproterenol, NKH 477 and IBMX. Fifty per cent inhibition doses of zatebradine (0.10-0.18 mumol) for the chronotropic responses to each substance were not significantly different. 4. On the other hand, zatebradine attenuated neither positive chronotropic nor inotropic responses to Bay k 8644. 5. We therefore suggest that zatebradine selectively attenuates the positive chronotropic but not inotropic responses to cyclic AMP-related substances due to inhibition of I(f) but not ICa in the dog heart.
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