Sinoatrial Node Preparations Research Articles

Cardiovascular profile of AN-132, a new diamine derivative antiarrhythmic agent, revealed in the isolated, blood-perfused dog heart.

The cardiac and coronary effects of AN-132, a new antiarrhythmic agent, were investigated in isolated, blood-perfused atrioventricular (AV) node, sinoatrial (SA) node and papillary muscle preparations of dogs. AN-132 was administered intraarterially. In AV node preparations, whether injected into the anterior septal artery (ASA; supplying the His-Purkinje-ventricular system) or the posterior septal artery (PSA; supplying the AV node), AN-132 prolonged AV conduction time and produced second- or third-degree AV block at large doses in some preparations. Moreover, only when injected into the ASA AN-132 produced a broadening and diminution of amplitude of bipolar electrograms obtained from the right bundle branch and the ventricular septum. In SA node preparations, AN-132 decreased sinus rate and produced atrial standstill at large doses in some preparations. In paced papillary muscle preparations, AN-132 reduced the force of contraction. In spontaneously beating papillary muscle preparations, AN-132 decreased the rate of automaticity and the force of contraction. In all preparations, AN-132 produced a transient increase in blood flow only at large doses. The order of potencies of AN-132 based on the doses that produced 15% suppressions of the above cardiovascular variables was as follows: cardiac muscle contraction greater than ventricular automaticity greater than or equal to intraventricular conduction greater than AV nodal conduction greater than or equal to coronary blood flow greater than SA nodal automaticity.

Are the Cardiovascular Effects of Gentamicin Similar to Those of Calcium Antagonists?

Cardiac and coronary vasodilator effects of gentamicin (GM) were investigated in isolated, blood-perfused papillary muscle, sino-atrial (SA) node and atrioventricular (AV) node preparations of dogs. GM (0.3-100 μmol) was injected intraarterially. GM produced an increase in coronary blood flow in all preparations. In paced papillary muscle preparations, GM reduced the force of contraction. In spontaneously beating papillary muscle preparations, GM decreased the rate of . automaticity and the force of contraction. In SA node preparations, GM decreased the sinus rate. In AV node preparations, GM injected into the posterior septal artery (which supplies the AV node) increased AV conduction time and in large doses, produced third-degree AV block. In the same preparations, GM 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) and reduced the amplitude of ventricular bipolar electrograms. The order of potencies of GM on the above cardiovascular variables is as follows: Coronary blood flow≥ventricular muscle contraction>ventricular automaticity>SA nodal automaticity>AV nodal conduction>intraventricular conduction. This cardiovascular profile is different from those of organic calcium-antagonists, but rather similar to that of manganese ions, reflecting its own mechanism of action.

Are the cardiovascular effects of gentamicin similar to those of calcium antagonists?

Cardiac and coronary vasodilator effects of gentamicin (GM) were investigated in isolated, blood-perfused papillary muscle, sino-atrial (SA) node and atrioventricular (AV) node preparations of dogs. GM (0.3-100 mumol) was injected intraarterially. GM produced an increase in coronary blood flow in all preparations. In paced papillary muscle preparations, GM reduced the force of contraction. In spontaneously beating papillary muscle preparations, GM decreased the rate of automaticity and the force of contraction. In SA node preparations, GM decreased the sinus rate. In AV node preparations, GM injected into the posterior septal artery (which supplies the AV node) increased AV conduction time and in large doses, produced third-degree AV block. In the same preparations, GM 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) and reduced the amplitude of ventricular bipolar electrograms. The order of potencies of GM on the above cardiovascular variables is as follows: Coronary blood flow greater than or equal to ventricular muscle contraction greater than ventricular automaticity greater than SA nodal automaticity greater than AV nodal conduction greater than intraventricular conduction. This cardiovascular profile is different from those of organic calcium-antagonists, but rather similar to that of manganese ions, reflecting its own mechanism of action.

Cardiac and coronary vasodilator profile of pimobendan, a new cardiotonic drug, revealed by use of isolated, blood-perfused dog heart preparations

Cardiac and coronary vasodilator effects of pimobendan (UD-CG 115 BS) were assessed in isolated, blood-perfused papillary muscle, sinoatrial (SA) node, and atrioventricular (AV) node preparations of dogs. Pimobendan was administered intra-arterially. In paced papillary muscle preparations, the drug increased the force of contraction in a dose-dependent manner. In SA node preparations, the drug produced an increase in sinus rate. When the drug was injected into the artery supplying the AV node, the drug produced a decrease in AV conduction time by accelerating AV nodal conduction in AV node preparations. In spontaneously beating papillary muscle preparations, the drug increased the rate of ventricular automaticity. No ventricular arrhythmias were produced by the drug. In all preparations, the drug increased (coronary) blood flow. The order of effectiveness of pimobendan on the above cardiovascular variables was as follows: ventricular muscle contraction much greater than coronary blood flow greater than SA nodal automaticity greater than AV nodal conduction greater than ventricular automaticity. The results indicate that pimobendan is relatively specific for force and its cardiovascular profile is very similar to those of phosphodiesterase inhibitors. Therefore, it is likely that this cardiovascular profile would be determined by its inhibitory action on phosphodiesterase.

On the ionic mechanism of cyproheptadine-induced bradycardia in a rabbit sinoatrial node preparation

The effects of cyproheptadine (0.1–10 μM) on the membrane potentials and currents of rabbit sinoatrial node were examined with the double-microelectrode voltage clamp technique. Cyproheptadine reduced the heart rate, maximum rate of depolarization and action potential amplitude. It also decreased the slope of phase 4 depolarization. On the current systems, cyproheptadine decreased the slow inward current (I si), the time-dependent potassium outward current (I k) and the hyperpolarization-activated current (I h). The reduction of I si was the major effect. Furthermore, I si was progressively decreased by repetitive membrane depolarization during administration of cyproheptadine, an effect suggestive of frequency-dependent block of I s. These electrophysiological observations indicate that cyproheptadine has a calcium antagonistic property, and additionally, decreases I k and I h in rabbit sinoatrial node.

Coronary Vasodilator Versus Cardiac Effects of MCI-176, a Novel Quinazolinone Calcium Antagonist, in the Dog Heart

We compared the coronary vasodilator and cardiac effects of MCI-176, a novel quinazolinone calcium antagonist, in isolated, blood-perfused sinoatrial (SA) node, atrioventricular (AV) node, and papillary muscle preparations of dogs. The drug was administered intraarterially. In SA node preparations MCI-176 reduced sinus rate and produced atrial standstill in large doses. In AV node preparations MCI-176 prolonged AV conduction time and produced second- or third-degree AV block in large doses only when administered into the artery supplying the AV node, but failed to affect AV conduction when administered into the artery supplying the His-Purkinje-ventricular system. In paced papillary muscle preparations MCI-176 reduced the force of contraction. In spontaneously beating papillary muscles MCI-176 failed to change the beating rate. MCI-176 increased blood flow in all preparations. The dose that doubled blood flow was slightly larger than the dose that produced a 15% increase in AV conduction time, but about one-third the dose that produced a 15% decrease in sinus rate. The dose estimated to reduce the force of contraction by half was more than approximately 10 times the dose that doubled blood flow. The results indicate that MCI-176 can be classified as a nonvasoselective calcium antagonist but that it differs from others.

Inotropic Versus Chronotropic, Dromotropic, and Coronary Vasodilator Actions of DPI 201–106, a Novel Positive Inotropic Agent, in the Dog Heart

Inotropic versus chronotropic, dromotropic, and vascular effects of DPI 201-106 were assessed in isolated, blood-perfused papillary muscle, sinoatrial (SA) node, and atrioventricular (AV) node preparations of dogs. DPI 201-106 was administered intraarterially. In paced papillary muscles the drug produced an increase in developed tension. In spontaneously beating papillary muscles the drug slightly decreased the beating rate. In SA node preparations the drug decreased sinus rate, and atrial standstill ensued from the highest dose. In AV node preparations the drug affected AV conduction only when administered into the AV node artery, and in high doses second- or third-degree AV block occurred. In all preparations the drug increased blood flow. DPI 201-106 at the dose that produced a 50% increase in the force of contraction of ventricular muscle increased coronary blood flow by 8.4%, AV conduction time by 7.6%, and decreased sinus rate by 2.6%, indicating its high selectivity for force. When infused into the AV node artery, the drug in high doses produced dose-dependent prolongations of both the AV nodal conduction time and the functional refractory period of the AV node, which were pronounced with elevation of the pacing rate. These effects of DPI 201-106 are very similar to those of calcium channel blockers.

Inhibition of Ca 2+ inward current in rabbit sinoatrial node by bunazosin, an α-adrenoceptor antagonist

The electrophysiological effects of bunazosin, a novel α-adrenoceptor antagonist, were examined on isolated spontaneously beating sinoatrial node preparations of the rabbit by means of a double-microelectrode voltage clamp method. Bunazosin (above 10 μM) reduced the beating frequency, and the maximum rate of rise and the amplitude of action potentials. The slope of the diastolic depolarization (phase 4) was also decreased by the drug whereas the action potential duration at 50% repolarization was prolonged. Bunazosin decreased the slow inward current (I si) and the time-dependent potassium outward current (I K). However, the major effect was the reduction of I si. The results indicate that bunazosin, an α-adrenoceptor antagonist, depresses the action potential and automaticity of the sinoatrial node by inhibition of Ca channels.

Inhibitory action of 711389-S on the electrical activity of rabbit sinoatrial node.

The effects of 711389-S (0.1-10 mumol.litre-1) on membrane potentials and currents of rabbit sinoatrial node preparations were studied using a conventional double microelectrode voltage-clamp method. The agent 711389-S decreased the heart rate, the maximum rate of depolarisation, and the amplitude of the action potential and increased the action potential duration in a dose dependent manner. The slope of the diastolic depolarisation was also reduced. Of the current systems of sinoatrial node, 711389-S depressed the slow inward current (Isi), the potassium outward current (IK), and the hyperpolarisation activated current (Ih) dose dependently. The kinetics of IK were not altered significantly by the drug. It is concluded that 711389-S does not have an effect on a single current system but that the drug exerts a depressant effect on the electrical activity of the sinoatrial node.

Differences in cardiovascular profile among calcium antagonists

Calcium antagonists constitute a group of organic compounds with diverse chemical structures. Although their main pharmacodynamic actions are vasodilatation and myocardial depression, they are not uniform in producing these effects. Based on comparison of the potencies in producing negative inotropic, chronotropic and dromotropic effects to the coronary vasodilator potency of individual calcium antagonists determined by use of isolated, blood-perfused papillary muscle, sinoatrial node and atrioventricular node preparations of dogs, calcium antagonists are classified into 2 major groups. The dihydropyridines, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, PN 200-110 (isradipine) and PY 108-068, are generally far more potent in producing coronary vasodilatation than in producing negative inotropic, chronotropic and dromotropic (first-degree atrioventricular block) effects, although there are minor differences among them. The non-dihydropyridine calcium antagonists, verapamil, diltiazem, KB-944, bepridil and MCl-176, are nearly equipotent in producing coronary vasodilatation and a negative dromotropic effect, although all of them are less potent in producing negative inotropy. The non-dihydropyridine calcium antagonists can be further divided into 2 subgroups. Verapamil, diltiazem and KB-944 are nearly equipotent in producing negative dromotropic and chronotropic effects. Bepridil and MCI-176 are less potent in producing negative chronotropy than in producing negative dromotropy.

Cardiac versus Coronary Vasodilator Actions of Isobutylmethylxanthine in Dogs: Comparison with Theophylline

Cardiac and coronary vasodilator effects of isobutylmethylxanthine (IBMX) and theophylline were compared in isolated, blood-perfused papillary muscle, si no-atrial (SA) node and atrioventricular (AV) node preparations of dogs. IBMX (1 nmol-1 μmol) and theophylline (30 nmol-10 μmol) were injected intra-arterially. In paced papillary muscle preparations, both agents increased the force of contraction. In spontaneously beating papillary muscle preparations, both agents increased the rate of ventricular automaticity. In SA node preparations, both agents increased sinus rate. In AV node preparations, both agents decreased AV conduction time only when they were injected into the artery supplying the AV node. In all preparations, both agents increased coronary blood flow. However, both agents were not homogeneously effective on these cardiovascular variables, but showed selectivity in the following order: Ventricular muscle contraction ≒ coronary blood flow>SA nodal automaticity ≒ AV nodal conduction>ventricular automaticity. These results indicate that IBMX and theophylline have almost an identical profile in their cardiac and coronary vasodilator effects. The two agents were different in that IBMX was 40–50 times as potent as theophylline in producing these effects. Thus, both agents appeared to express their cardiovascular profiles mainly through inhibition of cyclic AMP phosphodiesterase, although theophylline has been claimed to have additional actions.

Cardiovascular profile of Bay K 8644, a presumed calcium channel activator, in the dog.

Bay k 8644, although belonging to dihydropyridines, has been reported to exert effects directionally opposite to those of dihydropyridine calcium channel blockers such as nifedipine. The present experiments were carried out to elucidate whether this is indeed true. All experiments were done on isolated, blood-perfused dog-heart preparations described below, and Bay k 8644 was administered intra-arterially. In sinoatrial (SA) node preparations Bay k 8644 increased sinus rate by about 37% of the basal value at the highest dose (10 micrograms). In atrioventricular (AV) node preparations Bay k 8644 decreased AV conduction time by accelerating AV nodal but not intraventricular conduction. However, the decrease in AV conduction time remained at about 10 ms (about 7.8% of the basal value) even at the highest dose (10 micrograms). In papillary muscle preparations driven at a fixed rate of 120 stimuli/min Bay k 8644 increased the force of contraction by about 100% of the basal value at the highest dose (10 micrograms). In spontaneously beating papillary muscle preparations Bay k 8644 failed to increase the rate of automaticity although it increased the force of contraction. In all preparations Bay k 8644 decreased (coronary) blood flow down to about 20% of the basal value at the highest dose (10 micrograms). The positive chronotropic and dromotropic effects of Bay k 8644 reached respective peaks nearly at the same time as its vasoconstrictor effect, whereas its positive inotropic effect reached a peak after the vasoconstrictor effect had nearly worn off.(ABSTRACT TRUNCATED AT 250 WORDS)

Separation of the coronary vasodilator from the cardiac effects of PN 200-110, a new dihydropyridine calcium antagonist, in the dog heart.

Coronary vasodilator and cardiac effects of PN 200-110 were compared by use of isolated, blood-perfused sinoatrial (SA) node, atrioventricular (AV) node, and papillary muscle preparations of dogs. PN 200-110 was administered intraarterially. In all preparations PN 200-110 produced an increase in coronary blood flow. In SA node preparations, the drug produced a decrease in sinus rate and atrial standstill as well, but only in large doses. The dose that produced a 15% (nearly half-maximum) decrease in sinus rate was about three times the dose that doubled coronary blood flow. In AV node preparations, the drug produced an increase in AV conduction time and, in large doses, second- or third-degree AV block only when it was injected into the artery supplying the AV node. The dose that produced a 15% (nearly half-maximum) increase in AV conduction time was approximately 12 times the dose that doubled coronary blood flow. In paced papillary muscle preparations, the drug produced a decrease in the force of contraction. However, the dose that produced a 50% decrease in the force of contraction of the papillary muscle was approximately 14 times the dose that doubled coronary blood flow. These effects of PN 200-110 were of long duration. The drug was entirely ineffective in changing the rate of ventricular automaticity. The order of selectivity of PN 200-110 was as follows: coronary blood flow greater than SA nodal automaticity greater than AV nodal conduction greater than ventricular muscle contraction. This cardiovascular profile of PN 200-110 is slightly different from that of PY 108-068, a compound closely related to PN 200-110 in chemical structure.

Differential effects of Bay k 8644, a presumed calcium channel activator, on sinoatrial nodal and ventricular automaticity of the dog heart.

Bay k 8644 is suggested to increase calcium influx through the voltage-dependent calcium channel. In isolated, blood-perfused sinoatrial node preparations of the dog. Bay k 8644 injected intra-arterially increased sinus rate as isoprenaline did. In isolated, blood-perfused papillary muscle preparations of the dog isoprenaline injected intra-arterially increased both the force of contraction of the papillary muscle and its spontaneous beating rate. In these preparations, however, Bay k 8644 failed to increase the beating rate, although it increased the force of contraction. These results are consistent with the concept that the slow inward current plays a role in sinoatrial nodal automaticity but not in automaticity of Purkinje fibres which was reflected as ventricular automaticity of the papillary muscle preparations used here.

Actions of alinidine and AQ-A 39 on rate and contractility of guinea pig atria during beta-adrenoceptor stimulation.

We studied two new agents, alinidine (St 567, 2-[N-allyl-N-(2,6-dichlorophenyl)-amino]-2-imidazoline) and AQ-A 39 (5,6-dimethoxy-2-[3[[alpha-(3,4-dimethoxy)-phenylethyl] methylamino]propyl]phthalimidine), in isolated guinea pig atria with respect to their specificity to decrease heart rate but not contractility during beta-adrenoceptor stimulation. Spontaneous electrical activity in sinoatrial node preparations was increased by perfusion with isoprenaline (0.1 micrograms/ml); addition of alinidine (3 micrograms/ml), AQ-A 39 (3 micrograms/ml), or propranolol (0.03-0.3 micrograms/ml) reduced sinus rate to the control values. The same concentrations of these drugs were tested in electrically driven (1 Hz) left atria. The positive inotropic effect of isoprenaline was not affected by alinidine and AQ-A 39; however, it was markedly reduced or abolished by propranolol. The experiments, therefore, demonstrated the bradycardic specificity of alinidine and AQ-A 39 under conditions of beta-adrenoceptor stimulation. A cumulative concentration-response curve for the positive chronotropic effect of isoprenaline was established in spontaneously beating atria. AQ-A 39, 1 and 10 micrograms/ml, reduced the control sinus rate but did not affect the following concentration-response curve of isoprenaline. A similar result was published earlier for alinidine and excludes an interaction of both drugs with isoprenaline on a possible subgroup of selective beta-adrenoceptors in the sinoatrial node.

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.

Cycle length dependence of the chronotropic effects of adrenaline and acetylcholine in the rabbit sinoatrial node

Under the influence of adrenaline (Adr) and acetylcholine (Ach), pacemaker dominance in the sinoatrial node moves from one site to another. The Adr-center is located in the inferior part of the sinoatrial node. The Ach-center, an elongated cell group in the periphery of the sinoatrial node, is located nearer to the crista terminalis and is often more caudally located than the leading center under standard conditions. Under the combined influence of Ach and Adr, the Ach-center is dominant. The sinoatrial node preparation shows a cycle length-dependent chronotropic response to Adr. A greater shortening of cycle length is related to a longer basic cycle length. This agrees with previously reported findings concerning the positive chronotropic action of high calcium. The chronotropic response to Ach is not cycle length-dependent. In the presence of Ach, the effect of Adr remains cycle length dependent, although no shift of the pacemaker occurs. This demonstrates that cycle length dependence of chronotropic responses can be the property of one and the same cell group, and is not necessarily caused by different chronotropic responses of different cell groups.

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.

Effects of timing of vagal stimulation on the sinoatrial nodal cell discharge

The effects of vagal stimulation on the activity of the isolated rabbit sino-atrial (SA) node preparation were studied using electrophysiological techniques. Brief stimulus trains, which were subthreshold for the myocardial cells, were applied in order to release acetylcholine (ACh) from the nerve terminals. Transmembrane potentials were recorded from the follower cells located at the exit site near the pacemaker region. As the time from peak of the action potential to delivery of the vagal stimuli was progressively increased, the sinus cycle length first became progressively prolonged, and then was rapidly reduced to the control value. In order to resolve the underlying mechanisms for the phase-dependency, the effects of vagal stimulation were examined in a quiescent SA node preparation. When one stimulus was applied, membrane hyperpolarization began after a latency of 70 msec and developed slowly, reaching its peak value after about 270 msec, and its total time course was about 630 msec. Oscillatory potentials were observed after the recovery of the vagal-induced hyperpolarization; such oscillations were not observed in atrial myocardial cells. It is concluded that the slow-onset long-lasting response of the SA node cell membrane to ACh may play a role in the phase-dependent effect of vagal stimulation.

Cardiac actions of AQ-A 39, a bradycardic agent.

Cardiac and coronary vasodilator actions of AQ-A 39, a new bradycardic agent which resembles verapamil in chemical structure, were investigated in various isolated, blood–perfused dog-heart preparations. AQ-A 39 was injected intra–arterially. In all preparations, AQ-A 39 increased blood flow. In sino-atrial(SA) node preparations, AQ-A 39 decreased sinus rate, but rarely produced atrial standstill even in large doses. In paced atrioventricular(AV) node preparations AQ-A 39 injected into the posterior septal artery supplying the AV node rather increased AV conduction time in large doses, but produced neither second- nor third-degree AV block. In the same preparations, AQ-A 39 injected into the anterior septal artery supplying the His-Purkinje-ventricular system rather prolonged AV conduction time in large doses. In paced papillary muscle preparations, AQ-A 39 reduced force of contraction only in large doses. In spontaneously beating papillary muscle preparations, AQ-A 39 decreased rate of automaticity and force of contraction as well. The order of effectiveness of AQ-A 39 on the cardiovascular variables is as follows: Ventricular automaticity = SA nodal automaticity >> AV nodal conduction = intraventricular conduction = coronary blood flow = ventricular muscle contraction. These results indicate that AQ-A 39 has a pharmacological profile entirely different from that of verapamil.