Ventricular Automaticity Research Articles

Nicorandil as a hybrid between nitrates and potassium channel activators

Nicorandil, although structurally a nitrate, differs from classic nitrates in several respects. It preferentially dilates resistive vessels. Its effect on venous return in dogs is not unanimously a decrease but rather an increase. In high doses or concentrations it suppresses myocardial contraction and ventricular automaticity, nearly sparing sinoatrial nodal automaticity and atrioventricular nodal conduction. It shortens the effective refractory period of myocardium. These cardiac effects of nicorandil have been explained by its mechanism of action as a potassium (K) channel activator. However, what part of the vascular effects of nicorandil this mechanism is responsible for has not been determined. BRL 34915 and pinacidil, nonnitrate vasodilators with a K-channel activator action, have essentially the same cardiovascular profile as nicorandil in isolated, blood-perfused canine heart preparations. In anesthetized, open-chest dogs the 2 K-channel activators decreased systemic blood pressure and increased venous return and cardiac output without elevating heart rate, unless the cardiodepressant effect emerged. The increase in venous return or cardiac output survived elimination of baroceptor functions. These results taken together with previous results on nicorandil suggest the following: (1) The property of nicorandil as a resistive vessel dilator highly selective for vasculature originates in its mechanism of action as a K-channel activator. The nonunanimous effect of nicorandil on venous return is a result of the opposing actions as a capacitive (action as a nitrate) and a resistive vessel dilator. Nicorandil, with its hybrid nature, is advantageous over specific K-channel activators and classic nitrates in therapeutic implications.

Theophylline antagonizes the effect of diazepam on ventricular automaticity

The effect of diazepam on ventricular automaticity induced by a local injury was investigated in the isolated right ventricle of the rat in the presence of the diazepam central antagonist, RO 15-1788, and of the adenosine antagonist, theophylline. Theophylline but not RO 15-1788 antagonized the inhibitory effect induced by diazepam on ventricular automaticity. The inhibitory effect of adenosine but not that of 2-chloroadenosine was potentiated in the presence of diazepam. The results suggest that the inhibitory effect of diazepam on ventricular automaticity results from the inhibition of adenosine uptake.

Sympathetic neural and alpha-adrenergic modulation of arrhythmias.

alpha 1-Adrenergic stimulation of the neonatal heart may induce either an increase or a decrease in ventricular automaticity, with the latter response predominating as age increases. We used isolated tissues from the hearts of neonatal and adult dogs and rats, as well as rat myocytes in tissue culture alone or in coculture with sympathetic nerves, to study the role of sympathetic innervation in modulating the alpha-adrenergic response. In the absence of sympathetic innervation, alpha-adrenergic stimulation uniformly increases automaticity. As the myocyte is innervated, an increased quantity of a GTP regulatory protein is detectable. That this protein is an essential transducer of alpha-adrenergic inhibition of automaticity is evidenced by the conversion of the alpha response from excitatory to inhibitory as the protein develops. ADP-ribosylation of the protein with pertussis toxin causes the alpha response to revert to excitation in both adult canine hearts and innervated myocytes in tissue culture. Hence, we have evidence for sympathetic modulation of cardiac rhythm via a regulatory protein whose function depends on normal neuronal development. Abnormal development of innervation may predispose to arrhythmogenesis via persistence of a primitive response to alpha stimulation.

Is the Cardiovascular Profile of BRL 34915 Characteristic of Potassium Channel Activators?

To see whether the cardiovascular profile of BRL 34915, a potent vasodilator, is characteristic of potassium channel activators, we investigated its cardiac effects by use of isolated, blood-perfused papillary muscle, sinoatrial (SA) node, and atrioventricular (AV) node preparations of dogs. BRL 34915 was injected intraarterially. It produced an increase in (coronary) blood flow in all preparations. In paced papillary muscle preparations, BRL 34915, although in large doses, produced a decrease in the force of contraction, leading nearly to abolition. The negative inotropic effect of BRL 34915 was accompanied by a marked acceleration of the repolarization of field cardiac action potentials. In some preparations, fibrillation occurred after profound negative inotropy and subsided spontaneously. In unpaced papillary muscles, BRL 34915 in large doses decreased rate of ventricular automaticity. In SA node preparations, BRL 34915 in large doses reduced sinus rate down to approximately 64% of the basal rate and produced atrial standstill in some. In AV node preparations, BRL 34915 in large doses slightly prolonged AV conduction time only when injected into the AV node artery. Nevertheless, it produced third-degree AV block in some. These cardiac effects of BRL 34915 are very similar to those of nicorandil and pinacidil, whose cardiac effects result exclusively from an increase in membrane K conductance in cardiac muscle cells. Like nicorandil and pinacidil, BRL 34915 was highly vasoselective.

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.

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.

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.

Transient increase in release of adenosine during rapid cardiac pacing; transient effects on overdrive suppression of ventricular automaticity.

A study was designed to test the hypothesis that endogenous adenosine concentration may increase during episodes of rapid ventricular pacing and, by virtue of its negative chronotropic effects, contribute to the transient suppression of automaticity that follows the period of overdrive. Isolated, perfused, rat ventricular preparations were subjected to periods of 6.0 Hz overdrive stimulation while adenosine release, oxygen consumption, and subsequent suppression of automaticity were measured. At the end of a 1 min episode of overdrive oxygen consumption and adenosine release were significantly increased, and the initial beating rate after 1 min overdrive was suppressed. At the end of 10 min overdrive oxygen consumption was still increased but adenosine release had returned to control values. Suppression of automaticity after 10 min overdrive was similar to that after 1 min overdrive. The relative magnitude of suppression after 1 min overdrive was decreased by theophylline (10(-4) mol.litre-1), and increased by the adenosine deaminase inhibitor, EHNA (10(-5) mol.litre-1). Neither theophylline nor EHNA had any discernible influence on suppression after 10 min overdrive. It its therefore concluded that endogenous adenosine may contribute to the suppression of ventricular automaticity that follows a 1 min episode of overdrive, but because of the transient nature of the increase in adenosine during overdrive endogenous adenosine does not contribute to the suppression that follows prolonged overdrive.

Effects of propafenone on sinus nodal and ventricular automaticity: In vitro and in vivo correlation

The electrophysiologic effects of the new antiarrhythmic drug, propafenone, were evaluated in anesthetized closed-chest dogs and on isolated cardiac tissues with the microelectrode technique. Propafenone (2 to 4 mg/kg intravenously) had no effect on sinus rate or on sinus nodal recovery time, but caused a dose-dependent significant decrease in the rate of idioventricular rhythm and increased the duration of ventricular overdrive suppression in dogs (n = 8) with complete atrioventricular block. On isolated canine Purkinje fibers (n = 8) manifesting automaticity with resting membrane potential less negative than −70 mV, propafenone reduced the slope of phase 4 depolarization and reduced the rate of automatic impulse initiation in a concentration-dependent manner (10 −6M–4.10 −5M). At these concentrations, propafenone had no effect on rabbit sinus nodal automaticity (n = 8) or on sinoatrial conduction. However, significant depression of sinus nodal automaticity occurred with propafenone concentrations above 5.10 −6M in the presence of cholinergic or complete autonomic blockade with atropine (10 −6M) and propranolol (5.10 −5M). Propafenone caused a concentration-dependent decrease in the disparity of Purkinje fiber-ventricular muscle action potential duration (APD), mainly by shortening Purkinje fiber APD. We conclude: (1) that propafenone suppresses idioventricular rhythm in the intact dog, most likely by depressing Purkinje fiber automaticity; (2) the depressant effect of propafenone on sinus nodal automaticity is evident only during cholinergic receptor blockade; and (3) the antiarrhythmic properties of propafenone may include removal of APD disparity by selective shortening of Purkinje fiber and not of ventricular muscle APD.

Voltage- and time-dependent block of iK1 underlying Ba2+-induced ventricular automaticity

The mechanism underlying the Ba2+-induced automaticity was studied in isolated guinea pig ventricular myocytes using the whole-cell clamp method and a patch electrode. In the presence of 0.1-0.3 mM Ba2+, application of a weak depolarizing current induced repetitive firing of spontaneous action potentials. Application of tetrodotoxin or Ca2+ channel blockers and removal of external Na+ and Ca2+ did not abolish the rhythmic activity, thereby suggesting that activation of inward currents played no crucial role in the generation of this rhythmicity. Voltage-clamp studies revealed that Ba2+ blocked the inward rectifier K+ current (iK1) in a voltage- and time-dependent manner with a greater and more rapid block at more negative potentials. This Ba2+ action could quantitatively be fitted with a model of the conventional bimolecular adsorption isotherm with a voltage-dependent dissociation constant. Simulation studies using this model showed that a membrane model, in which only the iK1 system and a small leak conductance were incorporated, could reproduce an automatic activity similar to that seen experimentally. Thus, in isolated ventricular cells, the voltage- and time-dependent block of iK1 by Ba2+ appears to be one important mechanism underlying the automaticity.

Serial production of controlled periods of temporary heart block used to unmask and assess latent ventricular automaticity during experimental acute myocardial ischemia

This study examined the onset, time course of development and response to overdrive stimulation of ventricular tachycardia in 10 dogs that underwent a Harris two-stage ligation of the left anterior descending coronary artery. Transient (12 +/- 3 minutes) complete atrioventricular (AV) block was produced 2, 3, 4, 5, 8, 12, 16, 20 and 24 hours after onset of infarction through selective injection of physostigmine salicylate into the AV node artery. Seven of the 10 dogs had early transient arrhythmic episodes that occurred within 20 to 40 minutes after coronary occlusion but none of the dogs had any spontaneous ventricular tachycardia in the ensuing 2 hours. Two hours after left anterior descending coronary artery ligation, complete AV block unmasked in every dog a slow (37 +/- 9 beats/min) AV junctional rhythm readily suppressed by overdrive. Three hours after coronary ligation, AV block revealed a monomorphic ventricular tachycardia (106 +/- 10 beats/min) in 3 of the 10 dogs. Four and five hours after coronary ligation, five and eight dogs, respectively, had ventricular tachycardia during AV block and in three the tachycardia was polymorphic. The two remaining dogs did not develop ventricular tachycardia during the 24 hours of observation. Ventricular tachycardia always began abruptly, first with brief and then longer bursts. Soon after onset the rate of tachycardia began to increase to reach a plateau 2 to 3 hours later at frequencies 21 +/- 9% greater than the initial tachycardia rate. Concomitant with this increase in rate there was a steady decline of overdrive suppressibility and during the plateau phase there was little or no overdrive suppression.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Inhibition of rat ventricular automaticity by adenosine.

This study was designed to characterize adenosine's negative chronotropic effect on ventricular pacemakers. The spontaneous beating rate of isolated, isovolumic rat ventricular preparations perfused with Krebs-Henseleit solution decreased as the adenosine concentration was increased [log M effective concentration 50% (EC50) = -5.22 +/- 0.17]. The lack of effect of propranolol or atropine on this adenosine response eliminates the involvement of endogenous neurotransmitters. Support for the involvement of an external cell surface receptor was provided by findings that theophylline and 8-(4-sulfophenyl)theophylline, an analogue thought to act solely at the cell surface, significantly increased the adenosine log M EC50 to -3.94 +/- 0.22 and -3.61 +/- 0.22, respectively. An increase in spontaneous beating rate induced by theophylline, but not by its analogue, was blocked by the addition of propranolol. The relative chronotropic potency of the adenosine analogues R-PIA, S-PIA, and NECA suggests that the cell surface receptors may be of the Ri type. The negative chronotropic effects of adenosine and its analogues occurred at concentrations that had no effect on the developed pressure of the paced preparation. Electrocardiographic evaluations indicate that at high agonist concentrations, there was an abrupt alteration in electrical properties of the preparation, which could be blocked by theophylline and its analogue.

Ectopic ventricular tachycardia sensitive to calcium antagonists in acute myocardial infarction in dogs

The effects of antiarrhythmic agents on automatic ventricular tachycardia (VT), which emerged in the early stage of acute myocardial infarction (AMI), were examined in 30 closed-chest mongrel dogs. Antiarrhythmic agents were administered intravenously when the rate of VT became almost equal to sinus rate (5.6 ± 1.4 hours). VT was slowed significantly by verapamil (0.15 or 0.3 mg/kg), diltiazem (0.2 or 0.4 mg/kg), propranolol (0.1 mg/kg) and amiodarone (5 mg/kg), but not by procainamide (20 mg/kg), lidocaine (2 or 4 mg/kg), nifedipine (0.01 mg/kg) and nicorandil (0.03 mg/kg). The number of ventricular premature complexes was reduced most effectively by verapamil. The significant suppressive effects of calcium antagonist drugs (verapamil and diltiazem) and propranolol indicate that an inward calcium current during diastole may play a critical role In the abnormal enhancement of ventricular automaticity in the early stage (4 to 8 hours) of AMI.

Ventricular fibrillation during coronary angiography: An analysis of mechanisms

To investigate the mechanisms of ventricular fibrillation (VF) during coronary angiography, we assessed ventricular automaticity, local QT intervals, local conduction characteristics, and the ability to induce arrhythmias with premature ventricular stimulation in 30 dogs after intracoronary injections of 4 to 6 cc of Renografin 76 (RG 76). Ventricular automaticity was measured in six dogs as the idioventricular escape rate following intense vagal stimulation and was unchanged (51 ± 6 vs 52 ± 6 bpm, p > 0.05) with 6 cc of RG 76. In addition, 8 of 10 injections of 6 cc of RG 76 produced VF at a heart rate of 200 bpm compared to only 2 of 10 injections at a heart rate of 80 bpm ( p < 0.05). Composite and bipolar plunge electrodes were placed in the region perfused by the left anterior descending coronary artery (LAD) and circumflex coronary artery to assess QT intervals and conduction characteristics. RG 76, 4cc, produced a 116 ± 18 msec increase in the QT intervals recorded from the region perfused by the LAD, resulting in a marked dispersion in repolarization. Both local bipolar and composite electrograms showed minimal conduction delay, which rarely extended beyond the QRS of a lead II ECG during atrial paced rhythm. As premature beats (spontaneous or induced) conducted through the region of QT prolongation, marked conduction delay was recorded from bipolar electrograms, while composite electrograms recorded continuous fractionated electrical activity spanning the diastolic interval at the onset of VF. An early cycle premature impulse applied after every fourth atrial paced beat in the circumflex region produced VF in 23 of 25 injections of 4 cc of RG 76. The addition of CaCl 2 (40 mEq/L) to RG 76 markedly attenuated the QT prolongation, local fractionation, and conduction delay and totally prevented VF in response to premature stimulation. We conclude that the regional QT prolongation produced by RG 76 renders the myocardium vulnerable to VF by increasing the temporal dispersion of repolarization. VF appears to result from slow conduction of premature beats through incompletely repolarized myocardium leading to the formation of multiple reentrant pathways. However, the mechanism of the first premature beat in spontaneous VF remains unknown.

The beta-agonist drug tulobuterol decreases cardiac automaticity in the rat: Comparison with isoproterenol

1. The effect of the new beta-agonist drug tulobuterol, has been compared with isoproterenol in an experimental model of ectopic cardiac automaticity induced by local injury in the isolated right ventricle of the rat. 2. Isoproterenol significantly increases ventricular automaticity even with the lowest concentrations tested (10 −9 M). 3. Tulobuterol, at concentrations ranging from 10 −9 M to 10 −6 M do not induce any change on the automatic ventricular frequency. 4. Nevertheless, at higher concentrations (10 −5 and 5 × 10 −5 M), tulobuterol decreases the experimentally induced ventricular automaticity. 5. Our results suggest that the new beta-agonist drug tulobuterol does not increase ventricular automaticity but, in fact, decreases it.

実験的心筋こうそくにおける急性期心室性不整脈に対するＣａｒｔｅｏｌｏｌ Ｈｙｄｒｏｃｈｌｏｒｉｄｅの抑制効果の検討

The effects of carteolol, a β-blocking agent, on the incidence of ventricular arrhythmias and ventricular automaticity were studied in a canine acute myocardial infarction model. Carteolol (10 μ g/kg) was given intravenously 5∼ 30 minutes before balloon occlusion of the left anterior descending coronary artery in anesthetized, closed chest dogs (Group I). The total incidence of ventricular arrhythmias during the first 30 minutes of coronary occlusion was 91% (10/11) in group I, similar to control dogs without pretreatment of carteolol (Group II; 92%, 12/13, NS).However, ventricular fibrillation or sustained ventricular tachycardia was not observed in Group I, compared to 2 cases in the Group II dogs.Ventricular escape interval (VET), used as an index of ventricular automaticity, progressively shortened in the periods between 1 and 4 hours post-occlusion in both groups. However, the mean value of VET at 4 hours after coronary occlusion in Group I was significantly longer than.that of the Group II dogs (1549 ± 1259 msec vs 610 ± 224 msec, P<0.05).It was suggested that carteolol prevented the occurrence of malignant ventricular arrhythmia in the acute phase (within 30 minutes) and suppressed the enhancement of ventricular automaticity in the delayed phase (4 hours) of myocardial infarction.

P2H0106) - Effects of E-747, a new antiarrhythmic drug, on arrhythmias, abnormal ventricular automaticity and delayed conduction in experimental myocardial infarction in anesthetized dogs

P2H0106) - Effects of E-747, a new antiarrhythmic drug, on arrhythmias, abnormal ventricular automaticity and delayed conduction in experimental myocardial infarction in anesthetized dogs

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.