Kimiaki Saegusa

Pharmacologic analysis of ketamine-induced cardiac actions in isolated, blood-perfused canine atria.

Summary: Effects of ketamine were investigated on atrial rate and contractile force in the isolated, blood-perfused canine atrium. When a relatively small dose (3 μg) of ketamine was injected into the sinus node artery, positive chronotropic and inotropic responses were consistently observed. With doses of 10–300 μg i.a., biphasic (i.e., negative followed by positive) chronotropic and inotropic responses were induced. An extremely large dose of ketamine frequently produced biphasic chronotropic and only negative inotropic responses. The negative effects of ketamine were not affected by atropine pretreatment. After treatment with propranolol or imipramine, the positive effects were significantly suppressed. The effects were not influenced by tetrodotoxin. These results suggest that ketamine has (a) indirect cardioexcitatory properties mediated by a release of catecholamines which is due to a tyramine-like action, and (b) direct cardioinhibitory properties by which high doses depress the contractility rather than the pacemaker activity.

Pharmacological analyses of hydralazine-induced cardiac action in intact dogs and isolated, blood-perfused canine atria.

Summary: The effects of hydralazine (HYD) on heart rate and blood pressure in the intact dog and on atrial rate and contractile force in the isolated atrium were investigated. HYD (0.1–1 mg) injected into the sinus node artery produced double peaked positive inotropic and negative chronotropic effects in a dose-related manner. The initial positive inotropic and negative chronotropic responses were not affected by propranolol and atropine, respectively. The second positive inotropic response was inhibited by propranolol or reserpine, but it was not suppressed by imipramine or tetrodotoxin. When HYD (0.1–1 mg/kg) was administered intravenously to the donor dog, an initial increase followed by a decrease in blood pressure and an increase in heart rate were observed. In the isolated atrium, an increase in contractile force was induced. The increases of blood pressure and heart rate in the donor dog and the positive inotropic effect in the isolated atrium after HYD treatment were suppressed by reserpine. These results suggest that HYD has direct positive inotropic and negative chronotropic effects and indirect cardiac stimulating effects caused by a release of catecholamines from sympathetic nerve terminals, and that HYD-induced catecholamine release is not mediated by a tyramine-like action or via nerve excitation.

The mode of action of 4-aminopyridine on the chronotropic and inotropic responses in the isolated, blood-perfused dog heart

The effects of 4-aminopyridine (4-AP, 0.3 to 300 micrograms) on atrial rate and atrial muscle contractile force were investigated in the isolated, blood-perfused dog atrial preparation. Low doses (less than 30 micrograms) of 4-AP injected into the sinus node artery caused a dose-dependent positive inotropic response and a negligible positive chronotropic response. A higher dose (300 micrograms) of 4-AP induced a transient positive chronotropic response followed by a negative response and positive and negative inotropic responses. The negative cardiac responses to 4-AP were completely inhibited by an adequate dose of atropine and were potentiated by physostigmine. TTX or C6 suppressed partly, but significantly the negative responses induced by 4-AP. On the other hand, the negative responses to electrical stimulation (ES) were inhibited by atropine, C6 and TTX and those to ACh were blocked by atropine but not by C6 or TTX. The positive responses to 4-AP were not affected by propranolol but were potentiated by atropine. The positive inotropic response to 4-AP was significantly suppressed by a calcium channel blocker, diltiazem. From these results, it is concluded that the cardiac responses to 4-AP are composed of direct positive responses and negative responses which are related to activation of parasympathetic ganglionic neurotransmission.

Effects of ketanserin on the pacemaker activity and contractility in the isolated, blood-perfused dog atrium

Summary: Effects of ketanserin on the pacemaker activity and atrial contractility and on 5-hydroxytryptamine (5-HT)-induced cardiac responses were investigated in the isolated, blood-perfused dog atrium. Ketanserin (1–300 μg) injected into the sinus node artery evoked a transient positive followed by a negative chronotropic effect, and a dose above 30 μg of ketanserin produced a dose-dependent negative inotropic effect with a little positive one. Ketanserin-induced negative chronotropic and inotropic effects were not affected by atropine in a dose which blocked ACh-induced responses. Propranolol inhibited positive inotropic responses to ketanserin and norepinephrine and significantly augmented the negative chronotropic and inotropic responses to ketanserin. Imipramine did not affect the transient positive followed by negative chronotropic and the negative inotropic responses to ketanserin but it induced the positive cardiac responses following the negative ones. Tetrodotoxin, phentolamine, and diphenhydramine did not modify the effects of ketanserin. From these results, it is concluded that ketanserin might induce the direct negative chronotropic and inotropic effects and the indirect effects by catecholamine release. Ketanserin-induced catecholamine release might not be due to tyramine-like or nicotine-like action. Ketanserin significantly inhibited a low dose (3 μg) of 5-HT-induced negative chronotropic and inotropic effects, suggesting the possibility of 5-HT2 receptors in the isolated dog atrium.

Differential vagal inhibition of the positive chronotropic and inotropic responses to cardiotonics in the isolated dog atrium.

The effects of vagal nerve stimulation on the chronotropic and inotropic responses to norepinephrine (NE), dobutamine, forskolin, 3-isobutyl-1-methylxanthine (IBMX) and Bay k 8644 were investigated in the isolated, blood-perfused right atrium of the dog. Electrical stimulation of intramural vagal nerves evoked decreases in the sinus rate and atrial contractile force, which were maintained at almost constant levels during stimulation. Vagal stimulation consistently attenuated both the positive chronotropic and inotropic responses to NE, dobutamine, forskolin and IBMX. The vagal inhibition of the chronotropic response to each substance was greater than that of the inotropic one except that to Bay k 8644. Vagal stimulation did not depress the positive chronotropic and inotropic responses to Bay k 8644. These results, therefore, suggest that, under parasympathetic tonic conditions, NE, dobutamine, forskolin and IBMX induce a positive chronotropic effect much less than a positive inotropic effect in the isolated dog atrium. Our results also suggest that the vagal inhibition of the chronotropic response to a beta-adrenoceptor agonist is induced at intracellular sites in the cyclic AMP cascade proximal to the Ca channel activation and also at a site proximal to the catalytic unit of adenylate cyclase.

Potentiating effects of 4-aminopyridine on responses to intramural vagal stimulation in the isolated dog atrium

The effects of 4-aminopyridine (4-AP) on the chronotropic and inotropic responses to intramural parasympathetic nerve stimulation and to injection of acetylcholine (ACh) into the sinus node artery were investigated after treatment with propranolol in the isolated, blood-perfused dog atrium. 4-AP (3-100 micrograms) induced positive chronotropic and inotropic effects and 300 micrograms of 4-AP induced biphasic, negative and positive effects. The negative responses to 4-AP were completely blocked by 10 micrograms of atropine. 4-AP (more than 30 micrograms) potentiated significantly the negative chronotropic and inotropic responses to intramural parasympathetic nerve stimulation at a frequency of 3-30 Hz. The potentiation of the responses to stimulation was greater at a low than at a high frequency of stimulation. Potentiation of the chronotropic effect was greater than that of the inotropic one. 4-AP in the doses used did not change the negative chronotropic and inotropic responses to injection of ACh into the sinus node artery. These results suggest that the potentiation by 4-AP of the cardiac responses to parasympathetic nerve stimulation was due to an increase in release of ACh from nerve terminals but not to an increase in responsiveness at the effector site.

Tyraminelike Action of Succinylcholine in the Isolated, Blood-Perfused Canine Atrium

The mechanisms of succinylcholine-induced cardiac effects have not been fully elucidated. Accordingly, we studied the effects of succinylcholine on atrial rate and contractile force in the isolated canine atrium perfused with donor blood. The sinus node artery was perfused with heparinized blood from the common carotid artery of the donor dog at a constant pressure of 100 mm Hg. When succinylcholine in a dose range of 30–1000 μg was injected directly into the sinus node artery of the isolated atrium, increases in atrial rate and contractile force were observed in a dose-related manner. The atrial rate and contractile force were increased to 10.5% ± 1.8% (mean ± SEM) and 56.8% ± 8.5% above the control values after the administration of 1000 μg of succinylcholine, respectively. After treatment with propranolol, the positive chronotropic and inotropic effects of succinylcholine and norepinephrine were significantly suppressed. Hexamethonium or tetrodotoxin pretreatment inhibited the cardiac effects of nicotine but did not modify the succinylcholine-induced cardiac effects. The succinylcholine-induced effects were significantly inhibited by treatment with imipramine, which also suppressed the tyramine-induced effects. We conclude that succinylcholine has cardioexcitatory properties mediated by release of catecholamine due to a tyraminelike action.