Suppression of lethal ischemic ventricular arrhythmias by the class III agent E4031 in a canine model of previous myocardial infarction.

The antiarrhythmic efficacy of a new and potent class III agent E4031 [1-[2-(6-methyl-2-pyridyl)-ethyl]-4-(4- methylsulfonylaminobenzoyl)piperidine] was evaluated in several canine models of recent myocardial infarction. In anesthetized dogs with baseline inducible ventricular arrhythmias studied 4-10 days after anterior myocardial infarction, 30-300 micrograms/kg i.v. E4031 suppressed induction of ventricular tachyarrhythmias by programmed ventricular stimulation in 7 of 10 animals tested, while significantly prolonging refractoriness in both noninfarcted and infarcted ventricular myocardium. The incidence of lethal ischemic ventricular arrhythmias developing in response to acute posterolateral myocardial ischemia in the presence of previous anterior infarction was reduced from 10 of 10 (100%) in a vehicle pretreatment group to 3 of 10 (30%, p less than 0.01) in an E4031 (300 micrograms/kg intravenously, i.v.) pretreatment group. Neither the sizes of the underlying anterior myocardial infarctions (26.9 +/- 3.7 vs. 33.2 +/- 2.1% of left ventricle) nor the times to development of acute posterolateral myocardial ischemia (43 +/- 11 vs. 40 +/- 8 min) differed significantly between the vehicle and E4031 pretreatment groups, respectively, suggesting that the reduction in the incidence of lethal ischemic arrhythmias in the E4031 pretreatment group was not due to smaller underlying, electrically unstable myocardial substrates nor to a delay in onset of the acute ischemic insult. In conscious dogs with spontaneous ventricular ectopy at 48 h after myocardial infarction and in anesthetized dogs with no baseline inducible arrhythmias at 4-10 days after myocardial infarction, E4031 (30-3,000 micrograms/kg i.v.) produced no facilitation or aggravation of spontaneous or inducible ventricular arrhythmias. These findings suggest that pharmacologic agents such as E4031 that increase ventricular refractoriness (class III electrophysiologic activity) may provide significant protection against development of malignant ischemic ventricular arrhythmias in the setting of previous myocardial infarction.     

Antiarrhythmic actions of left stellectomy in digitalis-mediated malignant ventricular arrhythmias in the postinfarcted canine heart

Recently, this laboratory has demonstrated an enhanced susceptibility toward the development of ischemia-related lethal ventricular arrhythmias in the presence of therapeutic serum concentrations of digoxin in conscious dogs after myocardial infarction. The present study was performed to assess the effect of the interruption of cardiac sympathetic influences, via subacute left stellate ganglionectomy (LSGX), on digitalis-mediated ischemic ventricular arrhythmias. Commencing 4-5 days after anterior myocardial infarction, 11 dogs with LSGX and 14 sham controls were administered digoxin (0.0125 mg/kg/day i.v.) for 5-7 consecutive days. At baseline testing, programmed ventricular stimulation failed to initiate ventricular tachycardia in any postinfarction dog entered into this evaluation. After treatment, 11/11 digoxin + LSGX (1.33 +/- 0.10 ng/ml serum digoxin) and 14/14 digoxin-treated sham (1.23 +/- 0.14 ng/ml serum digoxin) dogs remained nonresponsive to programmed stimulation testing. The incidence of arrhythmic mortality in response to subsequent ischemia at a site remote from the infarcted anterior region was greater in the digoxin-treated sham group (1.22 +/- 0.21 ng/ml serum digoxin) than in the digoxin + LSGX group (1.33 +/- 0.10 ng/ml serum digoxin); mortality was 6/10 (60%) digoxin sham vs. 1/10 (10%) digoxin + LSGX, p less than 0.005. The underlying anterior myocardial infarct sizes (% of left ventricle: 6.8 +/- 2.3 vs. 6.6 +/- 1.1) did not differ between the digoxin sham and digoxin + LSGX groups. However, the digoxin sham controls developed larger posterolateral myocardial infarctions than did the digoxin + LSGX animals (% of left ventricle: 27.4 +/- 3.0 vs. 16.7 +/- 2.7, p less than 0.05). Norepinephrine concentrations in posterolateral through posteroseptal ventricular sections were not altered by LSGX in a separate group of digoxin-treated postinfarct dogs. The results suggest that left stellate ganglionectomy may reduce the incidence of digitalis-mediated malignant ventricular arrhythmias during ischemia, possibly due to a reduction in the severity of ischemic injury.     

Influence of levosimendan, pimobendan, and milrinone on the regional distribution of cardiac output in anaesthetized dogs.

1. The distribution of cardiac output during administration of levosimendan, a new myofilament calcium sensitizer, is unknown. We examined and compared the effects of levosimendan, pimobendan, and milrinone on regional tissue perfusion by use of the radioactive microsphere technique in barbiturate-anaesthetized dogs. 2. Haemodynamics and regional blood flow were determined before and during infusions of levosimendan (0.75, 1.5, and 3.0 micrograms kg-1 min-1), pimobendan (10, 20, and 40 micrograms kg-1 min-1), or milrinone (1.0, 2.0, and 4.0 micrograms kg-1 min-1). 3. All three drugs caused similar increases in heart rate, cardiac output, and left ventricular +dP/dt and decreases in end-diastolic pressure and systemic vascular resistance. No changes in subendocardial, midmyocardial, and subepicardial blood flow occurred during administration of levosimendan. However, a redistribution of blood flow from subendocardium to subepicardium was observed. Pimobendan increased midmyocardial and subepicardial blood flow and reduced the endo/epi ratio to a greater degree than levosimendan. Milrinone did not affect myocardial perfusion. 4. Levosimendan increased blood flow to the renal medulla and decreased renal medullary and cortical vascular resistance. Levosimendan increased blood flow to the small intestine and liver and reduced vascular resistance in these organs. Pimobendan increased hepatic blood flow to a greater degree than levosimendan but did not alter small intestinal perfusion. All three drugs decreased splenic blood flow to similar degrees. Levosimendan and pimobendan reduced cerebral vascular resistance. Levosimendan and milrinone reduced skeletal muscle vascular resistance. 5. The results indicate that levosimendan, pimobendan, and milrinone cause subtlety different alterations in regional tissue perfusion while producing similar haemodynamic effects.     

Alpha-adrenergic influences in canine ischemic sudden death: effects of alpha 1-adrenoceptor blockade with prazosin

The antiarrhythmic and antifibrillatory actions of the alpha 1-adrenoceptor antagonist prazosin were evaluated in conscious dogs 4-7 days after anterior myocardial infarction. Both the intravenous (i.v.) low single dose administration of 100 micrograms/kg and the higher multiple dose administration of 500 micrograms/kg every 6 h for 24 h failed to alter electrocardiographic intervals, ventricular effective refractory periods, or the induction of ventricular tachycardia (VT) by programmed ventricular stimulation. During the first 30 min of a subsequent episode of acute posterolateral ischemia, the incidence of ventricular fibrillation (VF) was reduced from 13 of 16 (81%) in vehicle-pretreated control animals to 2 of 8 (25%, p less than 0.05) in animals pretreated with 100 micrograms/kg prazosin and 3 of 8 (37%, p less than 0.05) in animals pretreated with 500 micrograms/kg prazosin every 6 h for 24 h. The continued administration of prazosin in the higher dose regimen, every 6 h for 24 h, significantly enhanced survival at 24 h after the onset of posterolateral ischemia in postinfarction dogs relative to the vehicle group [24-h survival: 1 of 16 (6%) vehicle v 4 of 8 (50%) in higher dose prazosin group, p less than 0.05]. These findings suggest that the blockade of alpha 1-adrenoceptor stimulation may be efficacious in preventing lethal ventricular arrhythmias associated with acute ischemia, despite the lack of effect on electrophysiologic parameters and induction of VT in the postinfarction setting.     

Effects of pimobendan (UD-CG 115 BS), a new positive inotropic agent, on ventricular tachycardia and ischemic ventricular fibrillation in a conscious canine model of recent myocardial infarction

Pimobendan (UD-CG 115 BS; 4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl- 3(2H)- pyridazinone) is a newly developed, structurally novel compound with positive inotropic as well as coronary and peripheral vasodilator activities. In vitro, pimobendan has been reported to prolong the duration of the cardiac action potential of ventricular myocardial tissue, suggesting the potential for this agent to increase myocardial refractoriness and possibly exert antiarrhythmic activity in vivo. In the present study, the effects of pimobendan upon cardiac electrophysiologic parameters, the induction of ventricular tachycardia by programmed ventricular stimulation, and upon the development of ischemic ventricular fibrillation were assessed in 16 conscious dogs 3 to 5 days after experimental anterior myocardial infarction. The intravenous administration of 0.3 mg/kg pimobendan to postinfarction dogs significantly reduced the rate-corrected QTc and paced QT intervals, and reduced the relative and effective refractory periods in normal noninjured ventricular myocardium. Electrophysiologic parameters in infarcted ventricular myocardium were not altered by pimobendan. Ventricular tachycardia remained inducible early after anterior myocardial infarction in eight of eight pimobendan-treated postinfarction dogs tested. Six of the eight pimobendan-treated animals that had nonsustained tachyarrhythmias elicited as initial responses to baseline programmed stimulation testing had sustained tachycardias induced at postdrug testing, with a reduction in the number of programmed extrastimuli required to induce the postpimobendan tachyarrhythmias occurring in three animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of digoxin on the extent of injury and the severity of arrhythmias during acute myocardial ischemia and infarction in the dog

Recently, this laboratory has demonstrated an enhanced susceptibility toward the development of lethal ventricular arrhythmias occurring in response to acute posterolateral ischemia in dogs with previous anterior myocardial infarction in the presence of therapeutic serum concentrations of digoxin. In the present study, acute posterolateral myocardial ischemia was produced in the absence of previous myocardial infarction in 15 digoxin-pretreated (1.19 +/- 0.21 ng/ml serum digoxin, 5-7 days pretreatment) and 11 vehicle-pretreated dogs. The incidences of sudden ventricular fibrillation and of 24 h arrhythmic mortality in response to posterolateral ischemia were 4/15 (27%) vs. 1/11 (9%) (p = 0.23) and 7/15 (47%) vs. 4/11 (36%) (p = 0.27) for digoxin- vs. vehicle-pretreated dogs, respectively. Ventricular ectopic activity at 24 and 48 h after the onset of posterolateral ischemia was reduced significantly by both intravenous lidocaine (1.0-5.0 mg/kg) and verapamil (50.0-500.0 micrograms/kg) in the vehicle-pretreated dogs, whereas neither antiarrhythmic agent significantly suppressed ventricular ectopy in the digoxin-pretreated dogs. The mean sizes for developing posterolateral myocardial infarctions (percentage of left ventricle) were greater for the digoxin-pretreatment group (31.9 +/- 2.8%) vs. vehicle-pretreatment group (14.8 +/- 2.0%, p less than 0.001). These findings suggest that uncomplicated acute myocardial ischemia in the presence of serum concentrations of digoxin that are considered clinically therapeutic may result in the development of larger areas of developing myocardial infarction and in the occurrence of ventricular arrhythmias that are less sensitive to suppression with conventional antiarrhythmic agents.     

Profibrillatory actions of pinacidil in a conscious canine model of sudden coronary death.

Pinacidil is one of a number of new antihypertensive agents possessing an action that involves an enhanced potassium efflux in cardiac and vascular smooth muscle. An associated feature of pinacidil is a shortening of the cardiac action potential duration, which may constitute a potentially proarrhythmic effect. The present study evaluated pinacidil (0.3 mg/kg/h i.v. for 6 h) on the postinfarcted canine heart in a subset of dogs unresponsive to programmed electrical stimulation during the subacute phase of anterior myocardial infarction, and known to be at low risk of ventricular fibrillation in response to acute posterolateral ischemia. Results were compared with a comparable control group of vehicle-treated, noninducible animals. Nonsustained ventricular tachyarrhythmia developed in 2 of 15 pinacidil-treated animals as compared to the initiation of ventricular tachycardia in 1 of 16 postinfarcted hearts (p = 0.96) in the control group. Thus, pinacidil did not alter the responsiveness of the postinfarcted heart with respect to the electrical induction of tachyarrhythmias. The subsequent development of an acute ischemic event at a site remote from the previous myocardial infarction was associated with a greater incidence of ventricular fibrillation within 1 h from the onset of ischemia in the pinacidil-treated animals (9/15; 60%) as compared to the control group (1/15; 6.7%; p = 0.007). The 24-h cumulative mortality, likewise, was greater in the pinacidil-treated group [13/15 (87%)] as compared to the vehicle-treated control group 3/15; 20%; p = 0.001. Significant cardiovascular and electrophysiologic effects of pinacidil included an increase in heart rate (124 +/- 6-143 +/- 10 beats/min, p less than 0.05) and reductions in the refractory periods of normal (178 +/- 2-166 +/- 4 ms, p less than 0.05) and peri-infarcted (170 +/- 5-185 +/- 5 ms, p less than 0.01) myocardial regions. It is concluded that pinacidil does not alter the responsiveness of the postinfarcted heart to programmed electrical stimulation. However, in the presence of a superimposed acute ischemic event, pinacidil increases the potential for the development of ventricular fibrillation in a subset of postinfarcted animals that otherwise show a low risk with respect to the development of lethal arrhythmias. It is hypothesized that the increased tendency to develop ventricular fibrillation is associated with the pinacidil-induced reduction in the ventricular refractory period. This conclusion is consistent with the known ability of pinacidil to enhance potassium efflux during myocardial repolarization and to decrease the duration of the action potential.     

急性心肌缺血—再灌注犬室性心律失常发生机制的实验研究

对１２只Ⅲ度ＡＶＢ模型犬建立心肌缺血（３０分）－再灌注模型的同时,进行心室程序电刺激（ＰＥＳ）,观察缺血－再灌注期间该模型犬对ＰＥＳ的反应特征,探讨在此期间室性心律失常的发生机制。１２只犬于实验性缺血期与再灌注期均出现室性心律失常（２０３次,２５３次）。ＰＥＳ均显示以搏周长（ＰＣＬ）为２００￣３００ｍｓ,刺激脉冲数为２０时期前逸搏百分率（％ＰＥＢｓ）最高。ＰＣＬ为６００￣８００ｍｓ,刺激脉冲数为５     

The effects of milrinone on action potential characteristics, conduction, automaticity, and reflected reentry in isolated myocardial fibers

Milrinone, a newly developed analogue of amrinone, possesses potent positive inotropic effects. Electrophysiologic actions of the drug have thus far been reported in only one study conducted on canine Purkinje fibers. The present study used microelectrode techniques to evaluate the electrophysiologic effects of milrinone on normal and depressed isolated ventricular myocardial fibers. At apparent therapeutic concentrations (0.1-0.2 microgram/ml), milrinone abbreviated action potential duration and refractory period in normal myocardial fibers, but caused no significant changes in any other parameter. At similar concentrations, the drug markedly altered the electrical activity of K+-depolarized preparations, producing an increase in action potential amplitude, duration, and dV/dtmax. Milrinone also restored regenerative activity in K+-inactivated ventricular fibers. The drug exerted important effects on conduction velocity, refractoriness, and reflected reentry generated in fibers mounted in a three-compartment chamber in which the central segment was depressed with an "ischemic" solution. Depending on the initial level of block, the drug concentration, and the segments of the preparation exposed to the drug, milrinone (a) suppressed the arrhythmia, (b) shifted its frequency dependence, or (c) induced reentry. Similar results were obtained in homogeneously depressed fibers. The drug produced no major changes in depolarization-induced automaticity. Thus, in addition to its inotropic actions, milrinone produces important electrophysiologic effects. By restoring or improving conduction through areas of depressed conductivity, the drug may alter the manifestation of arrhythmias.     

Effects of flecainide acetate on ventricular tachyarrhythmia and fibrillation in dogs with recent myocardial infarction

The antiarrhythmic and antifibrillatory actions of the class IC antiarrhythmic agent flecainide acetate were examined in urethane-anesthetized dogs with recent myocardial infarction. The intravenous administration of flecainide in a loading dose of 1.0 mg/kg (n = 7) or 2.0 mg/kg (n = 6), followed by a maintenance infusion of 1.0 mg/kg/h to achieve plasma drug concentrations considered clinically therapeutic, failed to significantly elevate the electrical threshold current required to provoke ventricular fibrillation at infarct zone, border zone and non-infarct zone stimulation sites in postinfarction dogs. In 8 dogs which responded to baseline programmed stimulation with inducible sustained ventricular tachycardia, flecainide administered as 1.0 or 2.0 mg/kg loading doses followed by a 1.0 mg/kg/h maintenance infusion failed to prevent ventricular tachycardia initiation in any animal tested, although the post-treatment ventricular tachycardia cycle lengths were prolonged compared to baseline values (pre: 178 +/- 11 ms vs post: 202 +/- 17 ms, p less than 0.05). Flecainide administration apparently facilitated the induction of newly sustained ventricular tachycardia in 3 previously noninducible postinfarction dogs. The development of acute posterolateral ischemia at a site remote from previous anterior myocardial infarction resulted in the development of ventricular fibrillation in 4 of 11 (36%) saline-treated postinfarction dogs vs a cumulative 10 of 12 (83%) flecainide-treated, baseline noninducible postinfarction dogs (p less than 0.05 vs saline-treated). The incidence of sudden ischemic ventricular fibrillation was 7 of 7 (100%) among flecainide-treated baseline inducible postinfarction dogs. These data suggest that flecainide acetate may have only limited efficacy in preventing ventricular tachycardia or ventricular fibrillation soon after myocardial infarction.     

Comparative effects of R 80122, enoximone, and milrinone on left ventricular phosphodiesterase isoenzymes in vitro and on contractility of normal and stunned myocardium in vivo in dogs.

Using different subtypes of cyclic nucleotide phosphodiesterase (PDE) isoenzymes isolated from canine left ventricle, we identified R 80122, a 1,2,3,5-tetrahydro2-oxoimidazo[2,1-b]quinazoline derivative that was a more selective and potent inhibitor of PDE type III than milrinone or enoximone. Such substances improve cardiac contraction and relaxation, elicit vasodilation, and increase cardiac output (CO). To determine the extent to which these compounds affect the contractile force of stunned myocardium, the effects of enoximone, milrinone, and R 80122 on cardiac function were compared in anesthetized dogs subjected to 15-min occlusion of the left anterior descending coronary artery (LAD) followed by reperfusion, and treated beginning 30 min after reperfusion, with the compound being studied. During occlusion, all dogs exhibited passive systolic ventricular wall bulging in the ischemic area. Thirty minutes after reperfusion, systolic wall thickening was significantly decreased in the reperfused LAD segments and remained low (at 36% of baseline) in control animals. After enoximone administration, global left ventricular (LV) function was improved with i.v. doses greater than or equal to 0.64 mg/kg. Systolic wall thickening in the ischemic myocardium was restored less than or equal to 70% of baseline at 1.25 mg/kg i.v., but this dose also induced a marked decrease in arterial pressure and an increase in heart rate (HR). Milrinone and R 80122 significantly increased global LV function and systolic wall thickening in ischemic areas at doses greater than or equal to 0.16 mg/kg i.v. At the highest doses, HR increased slightly with both compounds.(ABSTRACT TRUNCATED AT 250 WORDS)     

Electrophysiology and antiarrhythmic actions of E-4031 in the experimental animal model of sudden coronary death.

The Class III agent E-4031 was evaluated for its antiarrhythmic and antifibrillatory actions in conscious dogs 3-5 days after anterior myocardial infarction that were responsive to the induction of tachyarrhythmia by programmed electrical stimulation. The administration of E-4031 as an intravenous loading dose (100 micrograms/kg) followed by an infusion for 90 min (10 micrograms/kg/min) suppressed the induction of ventricular tachycardia by programmed electrical stimulation in 6 of 12 dogs and prolonged the cycle length of the induced arrhythmia in 5 of the 6 remaining animals. Continued administration of E-4031 in a dose regimen of 1,000 microgram/kg every 2 h provided significant protection (8 of 10 dogs) against the development of ventricular fibrillation (sudden coronary death) within the first hour after the onset of myocardial ischemia in a region of the ventricle remote from the infarct-related vessel. The incidence of sudden coronary death was 80% in a comparable control group of electrically inducible postinfarcted dogs. Increases in ventricular myocardial refractoriness in the paced QT and QTc intervals suggest that Class III electrophysiologic actions contribute to the antiarrhythmic and antifibrillatory actions of E-4031. The findings suggest that E-4031 may be of clinical utility in the prevention of life-threatening arrhythmias in the setting of myocardial ischemia in the postinfarcted heart.     

Milrinone. A preliminary review of its pharmacological properties and therapeutic use

Milrinone is a bipyridine derivative of amrinone, with approximately 10 to 75 times greater positive inotropic potency, and separate direct vasodilatory properties. As with amrinone, the relative importance of these properties to treatment of congestive heart failure still remain controversial. The mode of action of milrinone appears to be due in part to selective inhibition of a specific cardiac phosphodiesterase with a subsequent increase in intracellular cyclic adenosine monophosphate and alteration in intracellular and extracellular calcium transport. Clinical experience has involved both short and long term treatment of a limited number of patients with moderate to severe congestive heart failure refractory to conventional therapy. Milrinone has usually been administered as intravenous bolus doses (12.5 to 75 micrograms/kg) and/or continuous intravenous infusion (0.5 microgram/kg/min), or orally (30 to 40 mg/day in divided doses). Milrinone rapidly improves cardiac performance by enhancing myocardial contractility, and by decreasing systemic vascular resistance (afterload), left ventricular filling pressure (preload), and pulmonary arterial pressure. Exercise performance improvement occurs with enhancement of left ventricular performance but without a significant increase in myocardial oxygen consumption or significant decrease in mean arterial pressure. Milrinone has been compared with dobutamine, nitroprusside and captopril in preliminary short term studies in patients with severe congestive heart failure. Milrinone significantly increased stroke work index and decreased left ventricular filling pressure compared to nitroprusside. When compared with dobutamine, both drugs improved cardiac index (to a similar degree), but milrinone significantly reduced right atrial pressure, pulmonary capillary wedge pressure and left ventricular end-diastolic pressure. One small study suggests that short term effects of intravenous milrinone may be superior to those of oral captopril, and it appears that the addition of captopril to milrinone therapy may produce a synergistic haemodynamic effect. Preliminary long term studies suggest that tolerance to the haemodynamic effects of milrinone does not occur, and that the drug is well tolerated and without the thrombocytopenic effects, fever and gastrointestinal complications observed with amrinone. However, it has not been demonstrated that milrinone improves the prognosis of the disease or the overall mortality and its propensity to produce arrhythmias has not been fully agreed upon.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of milrinone on systemic hemodynamics and regional circulations in dogs with congestive heart failure: comparison with dobutamine

Milrinone is a new bipyridine inotropic agent with direct vasodilator properties. To determine the role of the vasodilator action in mediating systemic and regional hemodynamic responses to milrinone, we administered two equipotent inotropic doses of either milrinone or dobutamine to dogs with chronic congestive right heart failure produced by tricuspid avulsion and pulmonary artery stenosis. Similar increases in cardiac output, right and left ventricular dP/dt, and left ventricular dP/dt/P were produced by milrinone and dobutamine; however, heart rate increased and mean aortic pressure decreased only with milrinone infusion. In addition, while total peripheral vascular resistance decreased with both agents, the decrease was greater with milrinone. Regional blood flows were measured by a radioactive microsphere method. Milrinone and dobutamine produced similar increases in myocardial blood flow and left ventricular oxygen consumption. Dobutamine infusion decreased quadriceps muscle vascular resistance and had no effect on renal and splanchnic circulations. In contrast, milrinone infusion increased vascular resistance in quadriceps muscle and decreased it in renal and splanchnic beds. Thus, when milrinone was used in inotropic doses similar to those of dobutamine, the responses in systemic and regional hemodynamics in congestive heart failure differed. Milrinone produced a greater decline in total peripheral, renal, and splanchnic vascular resistances, probably resulting from its direct vasodilator action.     

Ischemia-induced conduction delay and ventricular arrhythmias: comparative electropharmacology of bethanidine sulfate and bretylium tosylate

Bretylium tosylate and bethanidine sulfate were studied in two models of experimental myocardial ischemia. In anesthetized dogs, left anterior descending coronary artery occlusion during rapid atrial pacing (180-200 min-1) produced ventricular tachycardia and fibrillation within 5 min in 9 of 11 dogs studied. In all cases, arrhythmias were preceded by and appeared to be temporally related to progressive fractionation and delay of electrograms recorded from the ischemic zone. In four dogs, bretylium (10 mg/kg) did not alter the time course of electrogram changes nor the time to onset of arrhythmia. However, in five dogs bethanidine (10 mg/kg) markedly exacerbated conduction changes in the ischemic zone and decreased the time to onset of ventricular arrhythmias (173 +/- 35 vs. 262 +/- 34 s control, mean +/- SEM, p less than 0.05). Bethanidine administration also facilitated ischemia-induced ventricular tachycardia and fibrillation in two dogs that did not exhibit ischemia-induced arrhythmias before receiving the drug. In isolated perfused rabbit hearts, global ischemia produced conduction slowing, depolarization of resting membrane potential, and decreases in amplitude and Vmax that were reproducible in serial 10 min ischemic episodes. Bretylium (10 mg/L) did not affect these parameters under either perfused or ischemic conditions. Although bethanidine (10 mg/L) also did not affect these parameters during perfusion, conduction slowing and depression of Vmax during ischemia were accelerated without affecting the time course of change in resting membrane potential. Both bretylium and bethanidine prolonged action potential duration under perfused conditions, but after 10 min of ischemia this effect was no longer evident. The results demonstrate that differences in the electrophysiologic effects of bretylium and bethanidine are markedly accentuated in the setting of acute ischemia. Although both these agents have been demonstrated to have antifibrillatory effects in other experimental settings, under the conditions of this study, bretylium failed to protect against ischemia-induced arrhythmias and acute bethanidine administration produced a proarrhythmic effect in association with an exacerbation of ischemia-induced conduction changes.     

Lack of concordance between the antiarrhythmic and antifibrillatory actions of UM-424, a quaternary ammonium analogue of propranolol

UM-424, 1-dimethyl isopropylamino-3-(2-phenylphenoxy)-propan-2-ol chloride, is a quaternary ammonium derivative of propranolol. Previous studies have demonstrated UM-424 to suppress the development of ventricular arrhythmias in a variety of experimental canine models, while lacking significant beta-adrenergic blocking and cardiodepressant actions. In the present studies, slight and transient reductions in heart rate, coronary flow, and indices of cardiac force and pressure developed only after the intravenous administration of 10.0 mg/kg UM-424. The positive inotropic response to intravenous isoproterenol was not altered significantly by 1.0-10.0 mg/kg UM-424. In conscious dogs 4-7 days after anterior myocardial infarction, UM-424 administered intravenously in a single (5.0 mg/kg) or multiple (5.0 mg/kg q 6 h for 24 h) dose schedule increased the ventricular refractory period from 146 +/- 4 to 180 +/- 3 ms (p less than 0.01), and suppressed the initiation of ventricular tachycardia by programmed ventricular stimulation in six of nine postinfarction dogs tested. However, the incidence of subsequent ventricular fibrillation developing in response to acute ischemia at a site remote from previous myocardial infarction was 100% in both UM-424 (n = 8)- and vehicle (n = 8)-treated postinfarction dogs. These findings suggest UM-424 is ineffective in preventing the development of ischemic ventricular fibrillation in the presence of previous myocardial injury, despite the efficacy of this agent in suppressing other experimentally induced ventricular arrhythmias.     

Antiarrhythmic and electrophysiologic actions of CK-3579 and sematilide in a conscious canine model of sudden coronary death.

The antiarrhythmic and antifibrillatory actions of the CK-3579 and sematilide, two new class III antiarrhythmic drugs, administered in a multiple-dose regimen were evaluated in conscious dogs 3-5 days after anterior myocardial infarction. The study population consisted of three groups of 10 dogs each, in which all animals entered into the final protocol developed nonsustained or sustained ventricular tachycardia in response to programmed electrical stimulation using one, two or three premature stimuli. Each drug was administered intravenously in a dose of 3.0 mg/kg every 3 h for a total of six doses. Sematilide significantly suppressed the induction of ventricular tachyarrhythmia by programmed electrical stimulation in six of 10 postinfarcted dogs, whereas CK-3579 suppressed the induction of tachyarrhythmia in only two of 10 animals. Despite its ineffectiveness in preventing electrical induction of tachycardia, CK-3579 produced a significant increase in the cycle length of the induced ventricular rhythm. The administration of each drug was associated with an increase in the ventricular refractoriness and in the paced QT interval, suggesting that class III electrophysiologic properties contribute to the antiarrhythmic action of each drug. In addition, CK-3579 was shown to have beta 1-adrenoceptor blocking properties. The subsequent induction of an acute ischemic event in a region remote from the infarct-related artery was associated with a high incidence (80%, eight of 10 postinfarcted dogs) of ventricular fibrillation within the first hour after the onset of myocardial ischemia in the vehicle-treated control group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antiarrhythmic and antifibrillatory actions of the levo- and dextrorotatory isomers of sotalol

The electrocardiographic responses to programmed ventricular stimulation and acute posterolateral myocardial ischemia were studied in conscious dogs treated with the resolved optical isomers of sotalol. Studies were conducted 3-7 days after anterior myocardial infarction to determine the relative contributions of beta-adrenergic receptor blockade and direct Class III electrophysiologic actions in the antiarrhythmic and antifibrillatory actions of the isomers. With cumulative i.v. administration of up to 8 mg/kg, both the beta-blocking levorotatory isomer and the dextrorotatory isomer suppressed the induction of ventricular tachyarrhythmias by programmed stimulation in at least 50% of dogs tested. Both isomers produced equivalent 15-20% increases in normal zone ventricular refractoriness, thereby preventing propagation of programmed ventricular extrastimuli of sufficient prematurity to elicit tachyarrhythmias. The levorotatory isomer of sotalol prolonged the PR interval; the administration of the dextrorotatory isomer increased QTc and, in several dogs, was associated with the development of ventricular ectopy. The prior administration of 8 mg/kg of either optical isomer of sotalol prevented the immediate spontaneous development of ventricular fibrillation in response to ischemia at a distance from the previous site of infarction. These results suggest that alterations in ventricular refractoriness may underlie the antiarrhythmic and antifibrillatory actions of the optical isomers of sotalol and of racemic sotalol.     

Interplay between milrinone and adenosine in the inhibition of human platelet response

• 1.1. In this study, we investigated the influence of the isotropic agent and coronary vasodilator milrinone on platelet aggregation and intracellular levels of 3′,5′ cyclic adenosine monophosphate (cAMP) in human platelet-rich plasma (PRP) and whole blood (WB). Furthermore, we evaluated the influence of milrinone on the effects of adenosine, which reduces the platelet aggregation through an elevation of intraplatelet cAMP levels.
• 2.2. Milrinone decreased the platelet aggregation in response to agonists in both PRP and WB. A dose-dependent increase of intraplatelet cAMP levels was demonstrated: this result is in accordance with an effect on platelet phosphodiesterases.
• 3.3. Milrinone at low concentration and adenosine exerted additive effects on platelet aggregation and intraplatelet cAMP levels.
• 4.4. An interplay between milrinone and adenosine was shown in WB. Furthermore, dipyridamole, which prevents the uptake of endogenous adenosine, markedly enhanced the milrinone antiaggregating effect, whereas the adenosine receptor blocker, theophylline, decreased it.
• 5.5. The present data provide evidence that milrinone modulates the platelet function through an influence on intraplatelet levels of cAMP and it is able to interplay with substances stimulating adenylyl cyclase.
• 6.6. The interplay between milrinone and adenosine in the inhibition of the human platelet function could be effective during milrinone administration in the treatment of heart failure, when blood adenosine levels are significantly increased. These milrinone effects could be advantageous from a therapeutic point of view, since patients with heart failure are at risk of thrombosis and ischemic heart disease.

     

Nonsteroidal cardiotonics. 1. 2-Pyridyl-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-ones, a novel class of cardiotonic agents

A series of substituted 2-pyridyl-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-ones 1-24 were synthesized and evaluated for positive inotropic activity. In rats, cats, and dogs most of these tricyclic heterocycles produced a dose-related increase in myocardial contractility with little effect on heart rate and blood pressure. The increase in contractility was not mediated via stimulation of beta-adrenergic receptors. Compound 1 (BM 14.478) was more potent than milrinone (25) and enoximone when administered intravenously to rats, cats, and dogs. After oral administration of 1 mg/kg, compound 1, milrinone, and pimobendan were equipotent. However, only 1 and pimobendan were still active after 6 h. The structural requirements necessary for optimal cardiotonic activity within this novel class of heterocycles were investigated.