The cardiac effects of amiloride, a potassium-sparing diuretic, were investigated in isolated, blood-perfused atrioventricular (AV) node, sinoatrial (SA) node, and papillary muscle preparations of dogs. In AV node preparations, when infused into the posterior septal artery (which supplies mainly the AV node), amiloride in a blood concentration of 0.2 mumole/ml gradually prolonged the functional refractory period at atrial pacing rates of 100, 150, and 200 stimuli/min. The lower the pacing rate, the greater was the prolongation. AV conduction time was increased only with pacing at 200 stimuli/min. In the same preparation, when infused into the anterior septal artery (which supplies the His-Purkinje-ventricular system), amiloride did not appreciably prolong AV conduction time, indicating that intraventricular conduction was unaffected. The configuration of ventricular bipolar electrograms was also unchanged. In SA node preparations, amiloride had a negative chronotropic action which was not antagonized by atropine. In papillary muscle preparations, amiloride had a positive inotropic action and prolonged the effective refractory period but did not change ventricular automaticity. The positive inotropic action of amiloride was not antagonized by carteolol, a beta-adrenoceptor-blocking agent. These results indicate that amiloride may have antiarrhythmic properties.

Amiloride↗

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Effects of antiarrhythmic drugs on AV nodal and intraventricular conduction as assessed in the isolated, blood-perfused AV node preparation of the dog.

The effects of seven antiarrhythmic drugs on atrioventricular (AV) nodal and intraventricular (His-Purkinje-ventricular muscle) conduction were investigated in the isolated, blood-perfused AV node preparation of the dog. When injected into the posterior septal artery (PSA), which supplies mainly the AV node, quinidine, ajmaline, disopyramide, lidocaine, mexiletine, phenytoin, and procainamide increased AV nodal conduction time; and in high doses, these drugs produced second- or third-degree AV conduction block. However, quinidine, ajmaline, disopyramide, and lidocaine had less propensity to induce second- or third-degree AV conduction block than did phenytoin, mexiletine, and procainamide. When injected into the anterior septal artery (ASA), which supplies the His-Purkinje-ventricular muscle, all seven drugs prolonged intraventricular conduction time. The relative suppressant effects of these drugs on AV nodal and intraventricular conduction varied. Quinidine, disopyramide, and ajmaline suppressed AV nodal conduction as much as intraventricular conduction. Lidocaine and mexiletine suppressed AV nodal conduction more than intraventricular conduction, and phenytoin suppressed AV nodal conduction much more than intraventricular conduction. In contrast, procainamide suppressed intraventricular conduction rather than AV nodal conduction. All drugs increased blood flow in the ASA and the PSA.

Animals↗

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Comparison of the responses of the simian and canine coronary circulations to autonomic drugs.

We studied Japanese monkeys, an anubis baboon, and dogs to determine possible differences in the responsiveness of the simian and the canine coronary vasculature to autonomic drugs. Under ketamine and pentobarbital anesthesia the left anterior descending coronary artery was perfused with autologous blood at constant pressure. All drugs were injected intraarterially. In monkeys, acetylcholine and methacholine produced vasoconstriction followed by vasodilatation, and vasoconstriction was marked after large doses. Both responses were antagonized by atropine. In dogs, the two muscarinic receptor agonists produced only vasodilatation. In the baboon, acetylcholine injected into the femoral artery produced only vasodilatation. These results indicate that vasoconstriction mediated by muscarinic receptors is characteristic of the simian coronary vasculature. In monkeys, norepinephrine produced vasoconstriction followed by vasodilatation. The former response was abolished and the latter enhanced by phentolamine. In dogs, norepinephrine produced only vasodilatation. This response was reduced and preceded by vasoconstriction after atenolol. Methoxamine produced only vasoconstriction, which was weaker in dogs than in monkeys. These results indicate that alpha-adrenoceptors in the coronary vasculature are more important in subhuman primates than in dogs.

Adrenergic alpha-Agonists↗

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Modification by islet-activating protein of direct and indirect inhibitory actions of adenosine on rat atrial contraction in relation to cyclic nucleotide metabolism.

Adenosine decreased the force of contraction of isolated rat left atria (direct action) and inhibited the positive inotropic action of isoproterenol (indirect action). The direct action of adenosine was not accompanied by changes in cyclic nucleotide levels, while the isoproterenol-induced increase in cyclic AMP level was reduced by the nucleoside. Reserpine pretreatment and pindolol did not affect the direct action of adenosine. Both the direct and indirect actions of adenosine were enhanced by dipyridamole and dilazep and inhibited by 1-methyl-3-isobutylxanthine and theophylline. Among adenosine derivatives, N6-phenylisopropyladenosine was most potent, and 2'-deoxyadenosine was least effective in inducing the negative inotropic action in the absence and presence of isoproterenol. In atria pretreated with islet-activating protein (IAP) both the direct and indirect actions of adenosine, and the actions of N6-phenylisopropyladenosine were markedly attenuated compared with those in nontreated atria. The isoproterenol-induced increase in cyclic AMP level was not reduced by adenosine in IAP-treated atria. These results indicate that adenosine produces a dual action on rat atria: it decreases the force of contraction directly by a mechanism independent of cyclic AMP metabolism, and inhibits the positive inotropic action of isoproterenol by reducing the drug-induced accumulation of cyclic AMP. IAP attenuates both of these inhibitory actions of adenosine on rat atria.

Adenosine↗

PubMedDate not supplied

Cardiac versus coronary vasodilator actions of KB-944, a new calcium antagonist, assessed in isolated, blood-perfused heart preparations of dogs.

We compared the cardiac and coronary vasodilator actions of a new calcium-antagonistic vasodilator, KB-944, in isolated, blood-perfused heart preparations of dogs. In all preparations KB-944 injected intra-arterially produced an increase in blood flow. In sinoatrial (SA) node preparations KB-944 decreased sinus rate and in large doses produced atrial standstill. In atrioventricular (AV) node preparations KB-944 increased AV conduction time and in large doses produced second- or third-degree AV block only when injected into the artery supplying the AV node. In the same preparations KB-944 had virtually no effect on AV conduction when injected into the artery supplying the His-Purkinje-ventricular system. In papillary muscle preparations KB-944 in medium and large doses depressed force of contraction, the depressant action being greater at high rates of contraction. In the same kind of preparations KB-944 affected automaticity slightly and inconsistently. Depression by KB-944 of SA nodal automaticity and AV nodal conduction occurred pari passu with coronary vasodilation, whereas force of contraction was depressed to a lesser extent in coronary vasodilator doses. In these respects, KB-944 resembles verapamil and diltiazem rather than nifedipine and nicardipine.

Animals↗

PubMedDate not supplied

Profile of coronary vasodilator and cardiac actions of bepridil revealed by use of isolated, blood-perfused heart preparations of the dog.

We investigated the coronary vasodilator and cardiac actions of bepridil in various isolated, blood-perfused dog heart preparations. Intra-arterial bepridil increased blood flow in all preparations. In sinoatrial (SA) node preparations bepridil decreased sinus rate and produced atrial standstill in large doses. In paced atrioventricular (AV) node preparations, bepridil injected into the posterior septal artery (which supplies the AV node) increased AV conduction time (i.e., AV nodal conduction time) and in large doses produced second- or third-degree AV block. In the same preparations, bepridil in large doses injected into the anterior septal artery (which supplies the His-Purkinje ventricular system) prolonged AV conduction time (i.e., intraventricular conduction time). In paced papillary muscle preparations, bepridil reduced force of contraction only in large doses. In spontaneously beating papillary muscle preparations, bepridil decreased the rate of automaticity and the force of contraction as well. The order of effectiveness of bepridil on the above cardiovascular variables is as follows: coronary blood flow greater than AV nodal conduction greater than SA nodal automaticity much greater than ventricular automaticity ventricular muscle contraction much greater than intraventricular conduction. The results indicate bepridil to have a pharmacological profile different from that of verapamil, diltiazem, nifedipine, nicardipine, or KB-944.

Animals↗