Failure of lidocaine to suppress lethal ischemic ventricular arrhythmias in a canine model of previous myocardial infarction.

The antiarrhythmic actions of high-dose intravenous (i.v.) lidocaine infusions were assessed in conscious dogs with spontaneous ventricular ectopy subacutely (48 h) after anterior myocardial infarction and in anesthetized dogs with ventricular tachyarrhythmias inducible by programmed ventricular stimulation at 4-11 days after anterior myocardial infarction. In conscious dogs administered cumulative doses of lidocaine at 48 h after myocardial infarction, a significant reduction in the frequency of spontaneous ventricular ectopic complexes (from 61 +/- 12 to 11 +/- 9% of total complexes) occurred only after administration of 10 mg/kg i.v. lidocaine. In anesthetized postinfarction dogs responding to baseline programmed stimulation with ventricular tachyarrhythmias, lidocaine administration (6 mg/kg i.v. loading dose + 100 micrograms/kg/min i.v. maintenance infusion) resulted in a selective increase in infarct zone conduction time (53.0 +/- 5.6 to 60.5 +/- 6.2 msec; p less than 0.05), increases in infarct zone relative refractory periods (RRPs 182 +/- 5 to 193 +/- 5 ms; p less than 0.05), and effective refractory periods (ERPs 156 +/- 4 to 165 +/- 3 ms; p less than 0.05), and an increase in noninfarct zone ERP (154 +/- 5 to 166 +/- 8 ms; p less than 0.05). The induction of ventricular arrhythmias by programmed stimulation was suppressed by lidocaine (6 mg/kg + 100 micrograms/kg/min i.v.) in 5 of 10 postinfarction animals tested, with an additional 3 animals displaying favorable stabilizations of induced arrhythmias.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of intracoronary lidocaine infusion on acetylstrophanthidin-induced ventricular arrhythmia in dogs

Antiarrhythmic drugs frequently cause extracardiac side effects that limit their use. If intracoronary delivery of a lower dose of drug to an electrically unstable focus can control arrhythmias, systemic adverse effects of these agents might be avoided. We investigated whether intracoronary lidocaine can suppress ventricular arrhythmia induced by acetylstrophanthidin, a rapidly acting digitalislike agent. We isolated and then cannulated either the left anterior descending or the left circumflex coronary artery in 12 pentobarbital-anesthetized dogs. Sustained ventricular tachycardia that persisted for 11.4 +/- 8.6 minutes was reliably induced by the intracoronary infusion. In all of 24 trials, an intracoronary lidocaine bolus at 2% of the usual systemic dose (0.77 mg/30 sec) abolished digitalis-induced ventricular tachycardia for an average of 2.0 +/- 1.8 minutes. This effect was not observed after a saline bolus. We conclude that an intracoronary bolus of low-dose lidocaine can suppress acetylstrophanthidin-induced ventricular arrhythmia.     

Cardioprotective effects of carbocromen in awake and anesthetized dogs with amitriptyline poisoning

We studied the effects of the antianginal drug carbocromen (4 mg/kg bolus plus 80 micrograms/kg/min i.v.) on amitriptyline (400 micrograms/kg/min i.v.) toxicity. In anesthetized dogs, amitriptyline increased heart rate, left ventricular (LV) end-diastolic pressure, and the PR and QT intervals, the QRS complex, and the S-T segments of the peripheral electrocardiogram. Blood pressure, LV pressure, and LV dP/dtmax fell considerably. Survival time was 37 +/- 4 min in amitriptyline-treated dogs and 64 +/- 3 min (p less than 0.05) in those receiving amitriptyline plus carbocromen. The amount of amitriptyline consumed until death increased from 14.8 to 25.6 mg/kg (p less than 0.05) with carbocromen. In conscious dogs, the hemodynamic impact of intraatrial amitriptyline was similar to that in anesthetized animals, and changes in stroke volume resembled those of dP/dt. Cardiac output was not altered, and peripheral resistance decreased moderately. Carbocromen prevented most of the typical amitriptyline effects on the heart and circulation. Sustained ventricular arrhythmia occurred at 29 +/- 4 min with amitriptyline infusion but was delayed to 58 +/- 3 min (p less than 0.05) when carbocromen was added. These experiments demonstrate (a) amitriptyline intoxication produced ventricular tachyarrhythmia and cardiac failure if high agent concentrations were achieved; (b) these rhythm disorders were associated with slowing of intraventricular conduction, which could be enhanced by carbocromen; and (c) carbocromen might be an effective therapy for amitriptyline-caused arrhythmia with cardiovascular collapse.     

Prophylactic lidocaine: concentrations in plasma and myocardial tissue and antifibrillatoric efficacy during early ischemia in dogs and pigs

We investigated the antifibrillatoric efficacy of lidocaine and the time courses of lidocaine concentrations in plasma and nonischemic (NIM) and ischemic myocardium (IM) during early myocardial ischemia in anesthetized dogs and pigs. Lidocaine (2 or 3 mg/kg bolus + 50, 100, 150, or 500 micrograms/kg.min) was administered over 30 min to 29 dogs and 15 pigs. The left anterior descending coronary artery (LAD) was occluded 2 min after bolus application. Blood and myocardial biopsies were sampled for analysis by high-performance liquid chromatography (HPLC) up to 40 min. In 19 dogs and 6 pigs, we determined the ventricular fibrillation threshold (VFT) with and without lidocaine during acute LAD occlusion for 7-13 min. Dosages leading to therapeutic plasma levels (1.6-4.2 micrograms/ml) resulted in lidocaine concentrations always highest in the IM (IM greater than NIM greater than plasma). Under identical dosages, all lidocaine levels were higher in pigs than in dogs. The IM concentrations decreased less in the pigs. Lidocaine prevented the ischemic drop in VFT and spontaneous fibrillation only at persistent IM concentrations greater than 8 micrograms/g. With therapeutic dosages, this was achieved only in pigs, occluding the LAD as early as 2 or 10 min after bolus application. Lidocaine prophylaxis with clinically recommended dosages in humans will hardly result in myocardial concentrations sufficiently high to be antifibrillatorically effective during early acute ischemia.     

Beneficial effects of coronary venous retroinfusion of superoxide dismutase and catalase on reperfusion arrhythmias, myocardial function, and infarct size in dogs

The efficacy of coronary venous retroinfusion of superoxide dismutase and catalase was studied in anesthetized closed chest dogs with 90-min left anterior descending coronary artery (LAD) occlusion followed by 3-h reperfusion. In group A, superoxide dismutase (2.5 mg/kg) and catalase (2.5 mg/kg) were administered by a 30-min continuous right atrial infusion beginning 15 min before reperfusion and supplemented by a bolus injection of superoxide dismutase (2.5 mg/kg) and catalase (2.5 mg/kg) through the great cardiac vein immediately before reperfusion. The treatment in group B was similar to that in group A, except that the bolus injection was into the right atrium. In the control group (group C), saline was administered in the same manner as in group A. Infarct size, expressed as a percentage of the risk area, was significantly smaller in group A (11.3 +/- 8.9%) than in groups B (31.3 +/- 21.1%) and C (43.0 +/- 16.9%; p less than 0.05). Regional function of the ischemic zone measured by two-dimensional echocardiography exhibited significantly (p less than 0.05) greater recovery after 3-h reperfusion in group A (30.3 +/- 8.4%) versus groups B (12.5 +/- 13.7%) and C (12.1 +/- 11.7%). Moreover, there were significantly fewer postreperfusion ventricular arrhythmias in group A as compared with groups B and C. The results of this study indicate that coronary venous retroinfusion is an effective method for delivery of superoxide dismutase and catalase.     

Antiarrhythmic and arrhythmogenic actions of methyl lidocaine during the recovery phase after canine myocardial infarction

Programmed electrical stimulation was used to evaluate the electrophysiologic and antiarrhythmic actions of methyl lidocaine in both conscious and anesthetized dogs, 4-7 days after myocardial infarction. When administered to animals demonstrating sustained ventricular tachycardia (n = 6), methyl lidocaine (5 and 10 mg/kg i.v.) prevented the induction of the original ventricular tachycardia in 2 dogs, and in the remaining 4 dogs slowed the tachycardia (cycle length 163 +/- 18 ms vs. 198 +/- 11 and 219 +/- 11 ms, respectively, p less than 0.05). New morphologic forms of sustained tachycardia were observed after drug administration in 4 of 6 experiments. When administered to animals developing only nonsustained ventricular tachycardia or no arrhythmias with programmed stimulation, methyl lidocaine administration enabled programmed stimulation to produce monomorphic sustained ventricular tachycardia in 10 of 13 experiments. The drug increased activation delays in both normal and ischemically injured epicardium, with larger activation delays always observed in ischemically injured tissue. The drug increased refractoriness in ischemically injured myocardium without altering refractoriness in normal tissue. The data suggest that the depression of conduction and prolonged refractoriness produced by methyl lidocaine in ischemically injured tissue may extinguish or slow some forms of ventricular arrhythmia while promoting the formation of new reentry pathways.     

Interaction of metoprolol and lidocaine on the ventricular fibrillation threshold in the anesthetized dog

In the present study, we evaluated the antiarrhythmic interaction (s) of metoprolol and lidocaine in 16 dogs using the ventricular fibrillation threshold (VFT) method. The right ventricle was stimulated with a 100 Hz train of 12.4 ms pulses delivered after every eighth atrial paced beat at a basic cycle length of 300 ms. Lidocaine dosage was 2 mg/kg followed by a 70 micrograms/kg/min infusion and metoprolol dosage was a 75 micrograms/kg bolus. In Group 1, lidocaine was followed by metoprolol; in Group 2, first lidocaine then metoprolol and again lidocaine were given; and in Group 3, dogs received first metoprolol, then lidocaine, and subsequently metoprolol. Drug dose intervals were 45 min. In Group 1, lidocaine elevated the VFT to 149% +/- 20% and metoprolol to 204% +/- 30% of control, (p less than 0.01). In group 2, the VFT remained elevated after the second lidocaine administration (p less than 0.05 vs. Group 1). In Group 3, the VFT was increased by metoprolol to 227% +/- 30% of control (p less than 0.01). Interestingly, defibrillation induced by the combination of metoprolol and lidocaine occurred after 3.2 +/- 0.5 s in four out of 16 animals (p less than 0.05). This "chemical" defibrillation never occurred when only metoprolol or lidocaine alone was administered. Fibrillation was often more organized in the presence of the combination of metoprolol plus lidocaine, which might relate to the observed defibrillation associated with metoprolol plus lidocaine. In conclusion, the combination of metoprolol and lidocaine has no proarrhythmic effects and may enhance the electrical stability of the ventricles as measured by the VFT method.     

Effect of sulfinpyrazone on ventricular arrhythmia, prostaglandin synthesis, and catecholamine release following coronary artery occlusion in the cat

We examined if inhibition of endogenous prostaglandin (PG) synthesis reduced the severity of ventricular arrhythmia and the incidence of ventricular fibrillation (VF) following occlusion of the left anterior descending coronary artery (LAD) in anesthetized cats. We also determined whether the PGs were interacting in a facilitory manner with the sympathetic nervous system to produce arrhythmia and VF after LAD occlusion. Sulfinpyrazone, an inhibitor of cyclo-oxygenase enzyme, or vehicle was administered intravenously to cats 1 h before LAD occlusion. Sulfinpyrazone completely (p less than 0.001) inhibited the release of 6-keto-PGF1 alpha into the great cardiac vein following LAD occlusion. Sulfinpyrazone (100 mg/kg) significantly (p less than 0.001) reduced the amount of ventricular arrhythmia and the incidence of VF (p less than 0.05) in the 1st h after LAD occlusion. In addition to 6-keto-PGF1 alpha sulfinpyrazone also (p less than 0.001) inhibited the increase in plasma norepinephrine from the heart due to sympathetic nervous system stimulation following LAD occlusion. Since sulfinpyrazone was ineffective in increasing the dose of digoxin required to produce arrhythmia and death, sulfinpyrazone apparently did not depress cardiac excitability. Finally, the extent of infarction resulting from LAD occlusion was not different in sulfinpyrazone-treated animals compared with control. These data indicate that sulfinpyrazone, by inhibiting endogenous PG synthesis in the heart following LAD occlusion, may prevent a facilitory interaction between PGs and the sympathetic nervous system that contributes, in part, to the development of ventricular arrhythmia and VF normally associated with this event.     

Effects of S-dobutamine on venous blood return and organ nutrient blood flow.

The selective contractile effects of s-dobutamine were studied in vitro in selected canine arteries and vein preparations; propranolol was included to block potential beta-mediated vasodilation. These in vitro data were expanded by quantifying the in vivo effects of s-dobutamine on venous blood return and redistribution of regional nutrient blood flow (NBF) and non-nutrient blood flow (non-NBF) in anesthetized dogs. In in vitro studies with isolated canine arteries and veins, s-dobutamine exhibited vein-selective constriction. At maximally efficacious concentrations of agonist, contractions of carotid, coronary, and femoral arteries in response to s-dobutamine were only 7, 25 and 45% as great as those elicited by norepinephrine (NE). Similarly, in jugular vein, s-dobutamine-mediated contractions were 55% as great as those obtained in response to NE. Coronary and femoral arteries precontracted with NE were relaxed in a dose-related manner by increasing concentrations of s-dobutamine. Effects of NE and s-dobutamine on venous blood return (VR) were compared in dogs. s-Dobutamine increased VR by 49 +/- 10 ml, whereas NE increased VR by 14 +/- 6 ml during 5-min infusion. s-Dobutamine significantly increased coronary NBF in left ventricular (LV) endocardium from 115 +/- 10 to 194 +/- 13 and 263 +/- 9 ml/min/100 g at doses of 10 and 20 micrograms/kg/min, respectively. In addition, LV epicardium flow was increased from 87 +/- 8 to 189 +/- 15 and 262 +/- 11 ml/min/100 g at 10 and 20 micrograms/kg/min, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of vasodilator drugs on coronary occlusion and reperfusion arrhythmias in anesthetized dogs

The effect of vasodilator drugs on the incidence of ventricular arrhythmias induced during 30 min of occlusion and 15 min of reperfusion of the left anterior descending coronary artery (LAD) was studied in 65 pentobarbital-anesthetized open-chest dogs. Intravenous administration of captopril (0.5 mg/kg), enalapril (0.5 mg/kg), felodipine (4 micrograms/kg), or ketanserin (0.1 mg/kg) 30 min before LAD occlusion reduced mean arterial blood pressure by 15.5 +/- 0.6% (mean +/- SEM). Nifedipine (5 micrograms/kg bolus + 1 microgram/kg min-1) infusion reduced mean arterial blood pressure by 24.8 +/- 1.8%. In none of the dogs was the diastolic blood pressure reduced below 70 mm Hg. During LAD occlusion, reduction in arterial blood pressure by these drugs was associated with a reduced incidence of ventricular premature depolarizations, ventricular tachycardia, and ventricular fibrillation (VF). During LAD reperfusion, the incidence of VF in saline-treated animals was 6/9, whereas for captopril it was 6/9, enalapril 1/9, felodipine 7/9, nifedipine 3/8, and ketanserin 3/9 animals. Thus, only enalapril significantly lowered the incidence of VF (p less than 0.05). The mechanism responsible for this antifibrillatory effect of enalapril is unknown. The muscle mass of the left ventricle supplied by the LAD distal to the site of occlusion in dogs which survived was similar to that of dogs which developed ventricular fibrillation.     

Cardiovascular effects of a novel calcium entry blocking and selective beta 1-adrenoceptor blocking agent, YM-16151-4, in anesthetized and conscious dogs.

Cardiovascular effects of YM-16151-4, a combined calcium entry blocking and beta 1-adrenoceptor blocking agent, were evaluated in dogs. In anesthetized dogs, YM-16151-4 (0.01-1 mg/kg intravenously, i.v.) dose-dependently increased coronary blood flow (CBF) and decreased mean blood pressure (MBP), total peripheral resistance (TPR), dP/dtmax, double product, and left ventricular (LV) work without increasing heart rate (HR) and cardiac output (CO). YM-16151-4 increased vertebral blood flow as well as CBF, but had no effect on carotid, mesenteric, renal, and femoral blood flow. Coronary vasodilating activity of YM-16151-4 was also observed after intracoronary artery injection (i.a.). In anesthetized and vagotomized dogs, YM-16151-4 dose-dependently inhibited isoproterenol (0.2 micrograms/kg i.v.)-induced tachycardia and decrease in diastolic BP (DBP), with ED50 values of 0.039 and 0.52 mg/kg i.v., respectively. In conscious dogs, YM-16151-4 (0.1-1 mg/kg i.v.) produced a dose-dependent hypotensive effect with no effect on HR or PQ-interval. The hypotensive effect of YM-16151-4 (0.3 and 1 mg/kg i.v.) reached its maximum approximately 1-2 h after each dosing and lasted 6-8 h. These results suggest that YM-16151-4 actually behaves as a hybrid compound, combining calcium entry blocking and beta 1-adrenoceptor blocking activities, and that this compound could be a novel long-acting antianginal and antihypertensive agent.     

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.     

The anaphylatoxins C3a and C5a are vasodilators in the canine coronary vasculature in vitro and in vivo.

The effect of complement fragments on coronary blood flow in vivo and the contraction of coronary arteries in vitro was determined. In pentobarbital anesthetized dogs, intraarterial bolus injection of C3a and C5a, zymosan-activated serum and methylcholine in the coronary vascular bed caused transient and dose-dependent increases in coronary blood flow. Similar increases were obtained with 25 micrograms of C3a (104 +/- 13%, n = 5) and 0.1 microgram of methylcholine (102 +/- 4%, n = 3). Smaller increases in blood flow were elicited by 25 micrograms of C5a (41 +/- 18%, n = 4) and 0.2 ml of zymosan-activated serum (48 +/- 5%, n = 4). None of these responses were associated with significant changes in left ventricular contractile force measured with a strain gauge, arterial blood pressure, and heart rate. C3a dilated the coronary vascular bed in conscious dogs with an activity equal to or greater than that observed in anesthetized dogs. Isolated canine coronary arteries that were precontracted with serotonin relaxed in response to C3a, whether or not the endothelium was intact. Overall these data suggest that physiologically high doses of anaphylactic complement fragments vasodilate the canine coronary circulation.     

Antiarrhythmic effects of optical isomers of cibenzoline on canine ventricular arrhythmias.

Antiarrhythmic effects of (+)-cibenzoline and (-)-cibenzoline were examined using two canine ventricular arrhythmia models. Digitalis arrhythmia, which is suppressed by Na channel blockers, was induced by intermittent intravenous (i.v.) injection of ouabain in pentobarbital-anesthetized dogs. Adrenaline arrhythmia, which is suppressed by Ca channel blockers, was induced by adrenaline infusion in halothane-anesthetized dogs. Ten and 5 mg/kg i.v. (+)-cibenzoline suppressed digitalis- and adrenaline-induced arrhythmias, respectively. The minimum effective plasma concentrations of (+)-cibenzoline for digitalis- and adrenaline-induced arrhythmias were 1.4 +/- 0.4 and 2.0 +/- 0.6 micrograms/ml, respectively (mean +/- SD, n = 6). A lower dose of 1 mg/kg i.v. of (-)-cibenzoline suppressed the digitalis-induced arrhythmia, whereas 5 mg/kg i.v. was needed to suppress adrenaline-induced arrhythmias. The minimum effective plasma concentrations of (-)-cibenzoline for digitalis- and adrenaline-induced arrhythmia were 0.06 +/- 0.04 and 0.7 +/- 0.1 micrograms/ml, respectively (mean +/- SD, n = 6). The stronger antiarrhythmic effect of (-)-cibenzoline indicates that (-)-isomer may have an effect nearly 5-20 times stronger in suppressing Na channels, but effects of both drugs on Ca channels may be almost equipotent.     

Hemodynamic profile of BM 14.478: a new positive inotropic and vasodilating agent

BM 14.478 (7,7-dimethyl-2-(4-pyridyl)-6,7-dihydro-3H,5H pyrrolo [2,3-f]benz-imidazol-6-one) was investigated in anesthetized rats and cats and conscious dogs. Left ventricular dp/dt was increased after intravenous injection of 0.01-0.1 mg/kg in rats (7,200 +/- 300 to 10,700 +/- 500 mm Hg/s), 0.001-0.3 mg/kg in cats (2,800 +/- 200 to 4,500 +/- 100 mm Hg/s) and 0.01 +/- 3.0 mg/kg in dogs (2,400 +/- 100 to 4,400 +/- 500 mm Hg/s). The inotropic potency was about 5- to 18-fold higher than that of milrinone. Effects persisted for more than 6.5 h in dogs after administration of 1 mg/kg p.o., which was definitely longer than that of milrinone. Hypotension and a moderate tachycardia were observed in the same dose range. In conscious dogs the compound increased cardiac output by 39 +/- 10%, and stroke volume by 17 +/- 7% and lowered total peripheral resistance by 45 +/- 5% and right atrial pressure by 3.0 +/- 0.3 mm Hg. BM 14.478 induced no tolerance after repeated administration in dogs when administered in a dose of 1 mg/kg p.o. b.i.d. for 10 days.     

Nifedipine prevents sympathetic vasoconstriction distal to severe coronary stenoses

Cardiac sympathetic nerve stimulation ( CSNS ) can induce vasoconstriction distal to severe coronary stenoses by activation of vascular alpha 2-adrenoceptors. Whether nifedipine can antagonize this CSNS -induced vasoconstriction was tested in 11 anesthetized, vagotomized dogs. CSNS decreased the end-diastolic resistance of intact coronary arteries from 0.76 +/- 0.07 to 0.56 +/- 0.05 mm Hg x min x 100 g/ml (p less than 0.05). In contrast, the resistance distal to severe stenoses, which were defined by a reduction of the postocclusive reactive hyperemia to almost zero, was increased during CSNS from 0.52 +/- 0.06 to 0.87 +/- 0.14 mm Hg x min x 100 g/ml (p less than 0.05). This increase in resistance was associated with severe ischemia, as indicated by a net lactate production of the circumflex-perfused myocardium and a decrease in systolic segment shortening from 8.4 +/- 0.7 to 7.0 +/- 0.7% (p less than 0.05). Both intracoronary (10 micrograms) and intravenous (10 micrograms/kg) administration of nifedipine did not change the poststenotic resistance at rest, but did prevent the CSNS -induced increase in resistance, the decrease in regional contraction, and the net lactate production. We conclude that nifedipine can prevent the deleterious role of alpha-adrenoceptor-mediated vasoconstriction in the genesis of myocardial ischemia.     

Cardiovascular effects of the new cardiotonic agent 1,2-dihydro-6-methyl-2-oxo-5-(imidazo[1,2-a]pyridin-6-yl)-3-pyridine carbonitrile hydrochloride monohydrate. 2nd communication: studies in dogs

The cardiovascular effects of 1,2-dihydro-6-methyl-2-oxo-5-(imidazo[1,2-a]pyridin-6-yl)-3-pyridine carbonitrile hydrochloride monohydrate (E-1020), a new nonglycoside, noncatechol cardiotonic agent, were investigated in dogs. In anesthetized dogs, E-1020 (10-100 micrograms/kg i.v.) dose-relatedly increased cardiac contractility (LV dP/dtmax), enhanced cardiac index and decreased systemic vascular resistance accompanying relatively small reduction in mean aortic pressure and a mild increase in heart rate. Coronary and femoral arterial blood flow were increased by either systemic intravenous or topical administration of E-1020. The degree of increase in myocardial oxygen consumption was only slight (10% at 30 micrograms/kg i.v.). The inotropic effect of E-1020 was not markedly affected by pretreatment with beta-adrenoceptor blockade, reserpine or other cardiotonic agents such as dobutamine or ouabain. In two experimental heart failure models induced by an excessive dose of propranolol or by coronary occlusion following volume-loading, E-1020 (30 micrograms/kg i.v.) rapidly reversed the cardiac depression. In chronically instrumented conscious dogs, E-1020 (30-100 micrograms/kg i.v. or 0.3-10 mg/kg p.o.) produced dose-dependent increases in LV dP/dtmax with minor increases in heart rate. E-1020 did not exacerbate arrhythmias of several experimental models in anesthetized dogs even at high dose of 100 micrograms/kg i.v. These results indicate that E-1020 is an intravenously and orally effective cardiotonic agent with vasodilating property, and that it may be beneficial in the treatment of acute and chronic congestive heart failure.     

Antiarrhythmic effects of tocainide and lidocaine in dogs

To compare the antiarrhythmic activities of tocainide and lidocaine in dogs, a protocol was designed where the drug plasma levels were increased stepwise. This was achieved by computerizing bolus doses and infusion rates, using pharmacokinetic equations with constants, derived from previous experiments in similar animals. In conscious coronary-ligated dogs with ischaemic arrhythmias both compounds were active, causing a 50% reduction in VPB's at plasma concentrations of 5.0 micrograms/ml (tocainide) and 3.5 micrograms/ml (lidocaine). "Clearing" of catecholamine-induced arrhythmias was not obtained in any of six dogs given tocainide and only in two out of six dogs given lidocaine.     

Cardiovascular effects of R- and S-enantiomers of Ro 22-9194, (2R)-2-amino-N- (2,6-dimethylphenyl)-N-[3-(3-pyridyl)propyl]propionamide D-tartrate and (2S)-2-amino-N-(2,6-dimethylphenyl)-N-[3-(3-pyridyl)propyl]propionamide L-tartrate, in dog heart preparations.

A newly synthesized compound, Ro 22-9194, relates in part of to the chemical structure of lidocaine. The cardiac effects of R- and S-enantiomers of Ro 22-9194 were investigated on isolated right atrial and left ventricular (LV) preparations which were cross-perfused with blood from another donor dog and an anesthetized open-chest dog. Each enantiomer (1-1,000 micrograms) decreased dose-dependently the sinus rate and atrial developed tension in the isolated right atrium (RA). The negative chronotropic responses to R- and S-enantiomers were not significantly different, and the negative inotropic responses to R- and S-enantiomers were also generally comparable. Both R- and S-enantiomers (10-3,000 micrograms) also decreased the ventricular developed tension in a dose-related manner similarly. In neurally decentralized, anesthetized, open-chest dogs, R- and S-enantiomers (0.1-3 mg/kg) injected into the femoral vein dose-dependently prolonged atrioventricular (A-V) conduction time and decreased heart rate (HR) and arterial blood pressure (ABP). Each enantiomer (3 mg/kg intravenously, i.v.) prolonged the interval between His bundle and ventricle rather than the interval between atrium and His bundle. There was no significant difference between R- and S-enantiomer-induced negative dromotropic actions. The duration of the negative dromotropic response to each enantiomer (3 mg/kg i.v.) was longer than that of the decrease in BP. These results suggest that the negative chronotropic, inotropic, and dromotropic effects of R- and S-enantiomers of Ro 22-9194 are not stereospecific in dog heart.     

Cardiovascular actions of DPI 201-106, a novel cardiotonic agent

DPI 201-106 (4-[3-(4-diphenylmethyl-1-piperazinyl)-2-hydroxypropoxy]-1H-indole -2- carbonitrile) is characterized by a marked cardiotonic activity. The compound exerted positive inotropic effects in anesthetized and conscious dogs, pithed open-chest cats, and isolated hearts of cardiomyopathic hamsters and vanadate-treated guinea-pig atria. Left ventricular dP/dtmax was increased in anesthetized dogs after i.v. injection of 0.2 and 2 mg/kg DPI 201-106 (34 +/- 6 and 104 +/- 18%, respectively) and in unanesthetized dogs after oral doses of 2-8 mg/kg (22 +/- 3 to 50 +/- 5%, respectively). In most experiments, the compound lowered blood pressure and heart rate. Stroke work and left ventricular work were almost unaffected by DPI 201-106, and oxygen consumption and cardiac efficiency remained unchanged in open-chest dogs. Studies of the mechanism of action of DPI 201-106 lead to the conclusion that its positive inotropic effect is not explainable either by beta-stimulation or by liberation of catecholamines. This was shown in anesthetized dogs and pithed open-chest cats pretreated with propranolol and reserpine.