Blood-perfused Canine Atrium Research Articles

Inhibition by glibenclamide of negative chronotropic and inotropic responses to pinacidil, acetylcholine, and adenosine in the isolated dog heart.

The blocking effects of glibenclamide on the chronotropic and inotropic responses to K+ channel openers pinacidil (ATP-sensitive) and acetylcholine (ACh) or adenosine (receptor-operated) were investigated in the isolated, blood-perfused canine atrium or ventricle. Glibenclamide (0.1-3 mumol) induced no significant cardiac effects. Cumulative administration of pinacidil (0.03-3 mumol) dose-dependently decreased sinus rate much less than the contractile force of the atrial and ventricular muscles. Glibenclamide similarly inhibited the negative chronotropic and inotropic responses to pinacidil in a dose-related manner. A high dose of glibenclamide (3 mumol) slightly but significantly attenuated the negative chronotropic and inotropic responses to ACh and adenosine but not to verapamil. These results demonstrate that glibenclamide inhibits the negative chronotropic and inotropic responses to the ATP-sensitive K+ channel opener pinacidil and the receptor-operated K+ channel openers ACh and adenosine but more selectively antagonizes the responses to pinacidil in the dog heart and suggest that in contrast to ACh and adenosine, an ATP-sensitive K+ channel opener has a greater effect on the ventricle than on the sinoatrial node.

Anti-Nicotinic and Anti-Muscarinic Actions of Eperisone in the Isolated Canine Atrium.

The effects of eperisone, an antispastic agent, on the chronotropic and inotropic responses to acetylcholine, nicotine or stimulation of intracardiac autonomic nerves were evaluated in isolated, blood-perfused canine atrium. Eperisone (10-300 micrograms) injected into the sinus node artery of the isolated atrium produced dose-related negative chronotropic and inotropic effects, which were not affected by atropine. In the same doses, eperisone inhibited the negative chronotropic and inotropic responses to an injection of acetylcholine and intracardiac parasympathetic stimulation. Eperisone also suppressed the negative followed by positive cardiac responses to nicotine, but did not modify the positive responses to intracardiac sympathetic stimulation or norepinephrine. The inhibitory effect persisted much longer for the responses to nicotine or parasympathetic stimulation than for those to acetylcholine. These results suggest that eperisone at doses that induce direct cardiac depressant effects exerts its blocking action on nicotinic receptors at parasympathetic ganglia and sympathetic nerve terminals and on muscarinic receptors at the effector cells in the dog heart.

Pharmacologic Analysis of Ketamine-Induced Cardiac Actions in Isolated, Blood-Perfused Canine Atria

Effects of ketamine were investigated on atrial rate and contractile force in the isolated, blood-perfused canine atrium. When a relatively small dose (3 micrograms) of ketamine was injected into the sinus node artery, positive chronotropic and inotropic responses were consistently observed. With doses of 10-300 micrograms 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.

Attenuation of the responses to repeated cholinergic interventions in the isolated dog atrium.

In the isolated, blood-perfused canine right atrium, which was pretreated with propranolol, negative chronotropic and inotropic responses were evoked by stimulation of the intramural parasympathetic nerve fibers or by intra-arterial infusion of acetylcholine (ACh). Successive cholinergic interventions were applied; first, a conditioning intervention for 2 min was given, then this was followed by a test intervention for 4 min. The two interventions were separated by a rest period that varied from 15 to 240 s. The cardiac responses to the conditioning parasympathetic nerve stimulation quickly reached maximum levels, and then they "faded" or progressively diminished back toward the control level. The inotropic responses to the conditioning infusion of ACh (1 microgram/min) faded slightly but the chronotropic response did not. After the rest period, the test nerve stimulation evoked responses that also gradually faded with time. The maximal amplitude of the responses to the test stimuli were less than those to the conditioning stimuli. This reduction in the maximal amplitude of the cardiac responses to the test stimuli was more pronounced with high frequency stimulation (30 Hz) than with low frequency stimulation (5 Hz). The decrement was also more pronounced the shorter the rest period, and it was greater at earlier times after beginning the stimulation. Conversely, the maximal cardiac responses to test infusions of ACh were not appreciably less than the responses to the conditioning infusions. We conclude, therefore, that the diminution of the cardiac responses to the second test stimulation of the parasympathetic nerve fibers was mainly ascribable to a prejunctional rather than to a postjunctional mechanism.

Suppression of Strychnine on the Chronotropic and Inotropic Effects in the Isolated, Blood-Perfused Canine Atrium

In the isolated, blood-perfused dog atrium, strychnine evoked dose-dependent decreases in atrial rate and contractile force, and the negative cardiac effects were not influenced by atropine. Strychnine suppressed dose-dependently the negative chronotropic and inotropic responses to intramural parasympathetic nerve stimulation, but not the response to acetylcholine. These results suggest that strychnine has direct cardiac depressant properties and inhibits the release of acetylcholine from parasympathetic nerve terminals in isolated dog atrium.

Inotropic and chronotropic responses to inosine in isolated and blood-perfused dog atria

The effects of inosine on sinus rate and atrial contractile force were investigated using the isolated and blood-perfused canine atrium which was perfused with arterial blood from a donor dog. Injected inosine (100–3000 μg) consistently induced positive chronotropic and inotropic effects. However, the larger doses of inosine (1000 and 3000 μg) frequently produced slight and brief negative inotropic and chronotropic effects followed by long-lasting positive ones. Positive responses were not suppressed by treatment with propranolol. Negative responses were not inhibited by treatment with atropine. Adenosine-induced negative chronotropic and inotropic effects were potentiated by a continuous infusion of inosine at larger doses of 800–1000 μg/min. From these results, we concluded that inosine may have direct positive chronotropic and inotropic actions and that it potentiates adenosine-induced cardiac actions.

Chronotropic and inotropic effects of bradykinin on isolated, blood-perfused canine atrium.

Effects of bradykinin on SA node pacemaker activity and atrial contractility were studied, using isolated, blood-perfused dog atrium preparations. Bradykinin (0.1--100 micrograms) caused a slightly but consistently positive chronotropic action, although it did not produce a consistent inotropic action. When successive doses of bradykinin were given in a short period, these preparations displayed tachphylaxis. Bradykinin-induced action was not suppressed by a potent beta-adrenoceptor blocking agent, carteolol. In addition, kallikrein (0.1--3 units), was administered into the sinus node artery to investigate the effect of endogenous kinins. Kallikrein had no effect on SA node pacemaker activity nor atrial contractility at any examined doses. On the other hand, a kallikrein inhibitor, aprotinin, induced dose-relatedly a negative inotropic and chronotropic effect at a dose range from 100 to 3,000 units. These negative actions of aprotinin were not blocked by an adequate dose of atropine. From these results, it is concluded that bradykinin has a slight direct positive chronotropic effect, and that aprotinin has direct negative inotropic and chronotropic effects in the isolated, blood-perfused canine atrium in a wide dose range.

A pharmacologic analysis of chronotropic and inotropic responses to direct electrical stimulation of the isolated, blood-perfused canine atrium.

Electrical stimulation on the posterior portion in the caval margin of the right atrium caused a biphasic chronotropic and inotropic response, i.e., a negative response followed by a positive response, in the isolated blood-perfused canine atrial preparation. The threshold of pulse duration for inducing negative responses was approximately 0.05 msec at 2 v and 20 Hz, but that for inducing positive responses was approximately 0.5 msec. When the voltage and pulse duration of electrical stimulation were increased, both the degree of negative and positive responses became greater. However, muscle contracture was frequently induced by increasing the voltage or pulse duration. The optimal frequency was 20 to 40 Hz for inducing marked chronotropic and inotropic responses. The negative chronotropic and inotropic response to subthreshold electrical stimulation was significantly suppressed by the treatment with tetrodotoxin, hexamethonium or atropine, while it was enhanced by physostigmine treatment. These suggest that subthreshold electrical stimulation readily caused a release of acetylcholine by excitation of parasympathetic preganglionic fibers in this atrial preparation. The positive chronotropic and inotropic response was significantly suppressed not only by treatment with propranolol but also by tetrodotoxin, while it was enhanced by imipramine, hexamethonium, or atropine. From these results, it is indicated that this blood-perfused preparation is very suitable to evaluate both cardiac mechanisms controlled by autonomic nervous system and drug actions on effects of endogenous hormone.

Absence of Acute Cardiac Effect of Triiodothyronine in Isolated, Blood-perfused Canine Atrium

Effects of triiodothyronine (T3) on SA node pacemaker activity, atrial contractility and on chronotropic and inotropic responses to norepinephrine were investigated, using 9 isolated, blood-perfused dog atrium preparations. T3 (0.001 pg--0.1 microgram) did not cause a significant direct action injected into the cannulated sinus node artery. When T3 (10 pg/min, 40 pg/min, 0.1 microgram/min, or 0.4 microgram/min) was continuously infused into the sinus node artery, both positive chronotropic and inotropic actions of norepinephrine (0.03 microgram--0.3 microgram) were not influenced. From these results, it is concluded that T3 has neither acutely direct chronotropic nor inotropic effects, and also T3 does not have an acute effect on responses to norepinephrine in the isolated, blood-perfused canine atrium.

Direct positive chronotropic and inotropic effects of ouabain in the isolated and blood-perfused canine atrium.

Using isolated, blood-perfused canine atrial preparations the effects of ouabain on sinus rate and contraction were investigated in 20 preparations. A continuous infusion of ouabain (1 microgram/min) usually induced a significant increase in sinus rate but occasionally a slight but no significant decrease followed by a clear increase, and then finally decrease followed by atrial arrest. On the inotropy, ouabain induced only distinct positive inotropic effect from the earlier stage, and the time to the maximum positive inotropic effect was much earlier than that to the maximum chronotropic effect. The positive chronotropic effect of norepinephrine was not affected by ouabain in the dose for inducing marked positive inotropic effect. On the other hand, the positive inotropic effect of norepinephrine was suppressed in percent changes by ouabain but not abolished. The negative chronotropic and inotropic effects of ACh were not significantly affected by ouabain in the dose for inducing marked positive inotropic effect. During atrial arrest by ouabain infusion, distinct staircase phenomenon disappeared. In this condition, atrial muscle responded more readily to higher frequencies of electric pacing (above 2 Hz) than to lower frequencies (under 1 Hz).

Positive chronotropic and negative inotropic actions of vasopressin in isolated blood-perfused canine atrium.

Effects of vasopressin on SA nodal pacemaker activity and atrial contractility were investigated, using 5 isolated, blood-perfused canine atrium preparations. Vasopressin produced a dose-related positive chronotropic and negative inotropic effect, which was not influenced by treatments with an adequate dose of atropine or an adrenergic beta-blocking agent, alprenolol. From these results, it is concluded that vasopressin has a direct stimulating property on SA nodal pacemaker activity and a direct suppressive property on atrial contractility.

217) - Effect of histamine on the isolated, blood-perfused canine atrium

217) - Effect of histamine on the isolated, blood-perfused canine atrium

79) - Frequency-force relationship in the isolated, blood-perfused canine atrium: modification by ACh or ouabain

79) - Frequency-force relationship in the isolated, blood-perfused canine atrium: modification by ACh or ouabain

Comparison of the Effects of Norepinephrine and Acetylcholine Between Intraarterial and Extravascular Administration to the Isolated, Blood-Perfused Canine Atrium

Effects of acetylcholine (ACh) and norepinephrine on atrial contractility and pacemaker activity were investigated in isolated and blood-perfused canine atrium preparations with a support dog which were suspended in the blood-filled bath kept at 37°C. The drug was given in two forms of administration, i.e., intraarterial injection into the cannulated sinus node artery or direct administration into the bath. ACh administered into the bath produced a significant decrease in the developed tension from a concentration of 10−5 g/ml and norepinephrine produced a significant increase in the developed tension from 3 × 10−6 g/ml. An injection via the sinus node artery resulted in 300 and 100 times greater response to ACh and norepinephrine, respectively, in the tension development. In atrial pacemaker activity, ACh given into the bath did not produce a dose-related decrease while norepinephrine produced a dose-related increase frequently accompanied by an irregularity of rhythmicity.