Yasuhiro Ogiwara

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.

Different antagonism of the positive chronotropic and inotropic responses of the isolated, blood-perfused dog atrium to Bay k 8644 by nicardipine and verapamil

The effects of Bay k 8644, a dihydropyridine calcium agonist, on sinoatrial (SA) node pacemaker activity and atrial contractility and its interaction with the calcium antagonists, nicardipine and verapamil, were investigated in the isolated, blood-perfused dog atrium. Bay k 8644 (0.03-30 micrograms) increased sinus rate and atrial contractility dose dependently. Norepinephrine (NE) and CaCl2 dose dependently increased the sinus rate and contractility but the positive chronotropic effect of CaCl2 was much less than that of the other drugs. The positive chronotropic effect of Bay K 8644 (0.3-1 microgram) was dose dependently depressed by nicardipine at doses of 1-10 micrograms but the inotropic effect was depressed only by a large dose of 10 micrograms. After sinus arrest induced by nicardipine (10-30 micrograms), SA node pacemaker activity was readily restored by Bay k 8644 or NE. Verapamil (1-3 micrograms) also depressed the positive chronotropic effect of Bay k 8644 more effectively than the inotropic effect although it did not attenuate the chronotropic effect of NE. The inotropic interaction could not be evaluated at higher doses of antagonists because of sinus arrest. Propranolol (3 micrograms) suppressed both positive chronotropic and inotropic effects of NE but did not depress the Bay k 8644-induced responses. These results show that the antagonism between Bay k 8644 and calcium antagonists is predominant on SA node pacemaker activity in cardiac tissues.

K+ channel blocking and anti-muscarinic effects of a novel piperazine derivative, INO 2628, on the isolated dog atrium

The effects of a novel piperazine derivative, INO 2628, on the negative inotropic and chronotropic responses to intracardiac parasympathetic nerve stimulation and carbachol, to adenosine and to the K+ channel openers, pinacidil and nicorandil, were investigated in isolated, blood-perfused dog heart preparations. INO 2628 (0.1-10 mumol) injected into the sinus node artery of the isolated atrium induced negative chronotropic and small positive inotropic responses in a dose-dependent manner. INO 2628 antagonized the negative chronotropic and inotropic responses to intracardiac vagus stimulation and carbachol in a dose-dependent manner, whereas INO 2628 did not antagonize the negative cardiac responses to adenosine. Pinacidil and nicorandil caused dose-dependent negative inotropic and small negative chronotropic responses in isolated atria and ventricles, suggesting that pinacidil-related K+ channels are much sparser in SA nodal pacemaker cells than in cardiac muscle cells. INO 2628 dose dependently antagonized the negative inotropic responses to pinacidil and nicorandil, but it did not modify the nicardipine-, pentobarbital- or G-strophanthin-induced cardiac responses. These results suggest that INO 2628 inhibits the negative cardiac effects of acetylcholine at muscarinic receptors and directly inhibits K+ channels in the isolated dog heart.

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.

β‐Adrenoceptor blocking effects of a selective β2‐agonist, mabuterol, on the isolated, blood‐perfused right atrium of the dog

1 Effects of (±)−1‐(4‐amino‐3‐chloro‐5‐trifluoromethyl‐phenyl)−2‐tert.‐butylamino‐ethanol hydrochloride (mabuterol) on pacemaker activity and atrial contractility were investigated in the isolated and blood‐perfused right atrium of the dog. 2 Mabuterol, injected into the sinus node artery of the isolated atrium, dose‐dependently increased atrial rate and contractile force at doses of 0.01–10 nmol but the responses to over 10 nmol of mabuterol gradually decreased and mabuterol at higher doses induced biphasic cardiac responses, i.e., negative followed by positive cardiac responses. 3 The maximal increases in atrial rate and contractile force induced by mabuterol were 41.4% and 12.9%, respectively, of the maximal chronotropic and inotropic effects of isoprenaline. 4 Positive chronotropic and inotropic responses to mabuterol were dose‐dependently inhibited by a selective β2‐adrenoceptor antagonist, ICI 118,551. These responses were only slightly attenuated by atenolol. 5 Mabuterol (1–300 nmol) dose‐dependently inhibited both dobutamine‐ and procaterol‐induced positive chronotropic and inotropic responses. 6 These results indicate that mabuterol causes weak positive chronotropic and inotropic effects on the perfused canine right atrium by activating β2‐adrenoceptors, and that higher concentrations non‐selectively block both β1‐ and β2‐adrenoceptors.