Protective activity of calcium entry blockers against ouabain intoxication in anesthetized guinea pigs

Several studies have suggested a central role for calcium in the pathogenesis of digitalis-induced arrhythmias. To test this hypothesis, the effects on ouabain-induced arrhythmia of intraarterial pretreatment with the calcium entry blockers nifedipine, flunarizine, verapamil, diltiazem, and bepridil, the calcium entry promotor Bay K 8644, and CaCl2 were compared with those of the currently applied digitalis antidotes phenytoin and lidocaine in urethane-anesthetized (1.5 g/kg i.p.) guinea pigs. Pretreatment with nifedipine (0.03 and 0.1 mg/kg), flunarizine (1 and 3 mg/kg), and phenytoin (10 mg/kg) doubled the time (from 10-20 to 20-40 min) required to provoke toxic ECG changes. Verapamil, diltiazem, and bepridil caused a slight but significant reduction of ouabain toxicity. Pretreatment with CaCl2 (10 mg/kg) enhanced all toxic effects of ouabain. None of the above-mentioned pretreatments as such changed the ECG parameters. Bay k 8644 (0.03 and 0.1 mg/kg) enhanced the effects of ouabain on ventricular rhythm, but abolished the ouabain-induced impairment of AV conduction. Bay k 8644 as such increased heart rate (from 318 +/- 11 to 376 +/- 6 beats/min at 0.1 mg/kg) and shortened the PR interval. The negative inotropic effects of the calcium entry blockers were quantified in electrically paced (3 Hz) guinea pig isolated left atria 15 min after pretreatment with ouabain (3 X 10(-7) M). The rank order of potency for the negative inotropic effect was nifedipine greater than verapamil greater than bepridil greater than diltiazem greater than flunarizine. In conclusion, nifedipine, flunarizine, and phenytoin showed obvious and equally effective protection against ouabain-induced arrhythmia.(ABSTRACT TRUNCATED AT 250 WORDS)     

The action of reserpine, 6-hydroxydopamine,and bretylium on digitalis-induced cardiotoxicity

This study determined whether the protective effect of reserpine against ouabain-induced ventricular arrhythmias in the cat is due to an action of the drug on the adrenergic nerve terminal. Rescrpine (5 mg/kg i.p.) administered 24 h prior to ouabain (2 μg/kg per min i.v., until death) increased the dose of ouabain to produce premature ventricular contractions, ventricular tachycardia, and death from 77.3 ± 5.2 to 105.0 ± 6.0; 84.9 ± 5.2 to 132.7 ± 9.1; and 108.8 ± 4.0 to 165.7 ± 10.4 μg/kg, respectively (P<0.05). When 6-hydroxydopamine (6OHDA; 20 mg/kg i.v.) was given 3 days prior to the experiment, the protective effect of reserpinc was not evident. When bretylium (20 mg/kg i.v., 2 h prior to ouabain) was administered to animals previously treated with reserpine, the dose of ouabain which produced premature ventricular contractions, ventricular tachycardia, and death was increased to 109.0 ± 72 146.1 ± 12.6; and 165.8 ± 7.6 μg/kg, respectively (P<0.05). However, the magnitude of this protective action was similar to that produced by rcserpine alone. Lathers et al. (Fed. Proc. 40, 672, 1981) reported that bretylium alone provides protection of a similar order of magnitude as reserpine. Thus, the effects of rescrpine and bretylium were not additive: this indicates that the two agents may be acting on the same locus or they may be acting at different sites with the action of one drug masking or blocking the action of the other. Since 60HDA prevented the action of rcserpine on ouabain-induced ventricular arrhythmia and since 60HDA only produces degeneration of adrenergic nerve terminals, it is probable that the protective effect of both reserpine and bretylium is due to an action at the adrenergic nerve terminal. The heart rate and blood pressure were not involved in the antiarrhythmic effects of rcserpine.     

Mechanism of neurotoxicity of cardiotonic glycosides.

1 In cats intracerebroventricular administration of 5, 10, 20 mug of peruvoside, a cardiac glycoside obtained from the plant, Thevetia neriifolia, and 10 and 20 mug of ouabain, produced marked neurotoxicity. This was dose-related. 2 Prior administration reserpine (2 mg/kg i.m., 500 mug i.c.v.) or tetrabenazine (25 mg/kg i.v., 50 mg/kg i.v. and 2 mg/,g i.c.v.) suppressed the neurotoxicity, but lithium carbonate (100 mg/,g i.p., 2 mg 2.c.v.) and haloperidol (200 mug i.c.v.) were ineffective. 3 Prior administration of 2-bromolysergic acid diethylamide (BOL-148, 200 mug i.c.v.) or p-chlorophenylalanine (PCPA) (400 mg/kg i.p.) suppressed the neurotoxicity induced by peruvoside and ouabain. 4 Perfusion of the lateral ventricles of cats with 10, 20 and 30 mug of peruvoside or ouqbain produced a massive release of 5-hydroxytryptamine (5-HT). This was dose-related. Prior administration PCPA suppressed the release of 5-HT. 5 The results of the findings indicate the involvement of 5-HT in the genesis of neurotoxicity induced by peruvoside or ouabain.     

Ouabain-Induced Coronary Vasoconstriction In Cats Is Not Neurally Mediated

1. Previous reports indirectly implicate a neural mechanism for coronary constriction to centrally administered digitalis. However, autoregulatory changes in coronary resistance due to changes in arterial pressure may have influenced the interpretation of these studies. 2. We tested directly the hypothesis that cardiac sympathetic innervation is responsible for coronary constriction to ouabain by examining the effects of ouabain (intravenous (i.v.) and intracerebroventricular (i.c.v.)) before and after bilateral stellate ganglionectomy. 3. Cats were anaesthetized and instrumented for the measurement of heart rate, blood pressure and coronary blood flow velocity using an epicardial-attached suction Doppler probe. Animals were treated with atenolol and the effects of either i.v. or i.c.v. injections of ouabain were examined. 4. In seven cats treated with atenolol, i.v. ouabain (0.11 mg/kg) produced maximal increases in arterial pressure and coronary vascular resistance index (CVRI) of 66 +/- 7 mmHg and 37 +/- 9%, respectively. Following bilateral stellate ganglionectomy (n = 7), ouabain produced similar increases in arterial pressure (70 +/- 9 mmHg) and CVRI (39 +/- 7%). A higher dose of i.v. ouabain (1.1 mg/kg) produced maximal increases in arterial pressure (115 +/- 4 mmHg) and coronary resistance (86 +/- 14%) in intact cats (n = 6) that were similar to responses seen in cats in which stellate ganglionectomy had been performed (n = 6; arterial pressure 104 +/- 13 mmHg; coronary resistance 114 +/- 6%). The increases in coronary resistance to ouabain at both doses were significantly greater than increases in coronary resistance to passive elevation of arterial pressure during aortic constriction. Thus, autoregulation does not explain fully the coronary constriction to ouabain. 5. To further examine a central mechanism, i.c.v. perfusion with 0.3 mmol/L ouabain was performed in six cats, resulting in increases in arterial pressure (122 +/- 7 mmHg) and coronary resistance (58 +/- 14%). Similar increases in arterial pressure (117 +/- 16%) and coronary resistance (84 +/- 20%) were seen in separate studies (n = 6) following stellate ganglionectomy. 6. These results indicate that coronary constriction to ouabain does not require intact cardiac sympathetic innervation, but probably involves a direct or humorally mediated effect.     

Indecainide: effects on arrhythmias, electrophysiology, and cardiovascular dynamics

The cardiovascular pharmacology of indecainide, a new class I antiarrhythmic agent, was studied in intact animals. Arrhythmias produced by ouabain were converted to sinus rhythm by indecainide (100 micrograms/kg/min, i.v.) at 0.7 +/- 0.1 mg/kg and a corresponding plasma concentration of 1.7 +/- 0.2 micrograms/ml at the time of conversion. Infusion at a slower rate (20 micrograms/kg/min) converted to sinus rhythm at 0.4 +/- 0.1 mg/kg and 0.4 +/- 0.2 micrograms/ml plasma. Arrhythmias produced by prior (24 h) coronary artery occlusion were converted to 50% sinus rhythm by indecainide (100 micrograms/kg/min, i.v.) at 1.3 mg/kg. In conscious dogs, 6 mg/kg indecainide p.o. prolonged the PR and QRS intervals by 31 +/- 5 and 13 +/- 3%, respectively, at a corresponding plasma concentration of 2.8 +/- 0.5 micrograms/ml. His bundle studies revealed that the PR interval prolongation was due to an increase in both A-H and H-V intervals. In anesthetized dogs, indecainide (1-5 mg/kg, i.v.) decreased cardiac contractility, however, this effect was comparable to or less than that produced by other class I agents and was likely due to the Na+-channel-blocking activity of the drug. The autonomic effects of indecainide were slight and no effects were produced on peripheral hemodynamics, the QTc interval, or the central nervous system. It was concluded that indecainide is a potent class I antiarrhythmic agent that would appear to have only minimal propensity for producing adverse side effects in humans.     

SCH 58261 and ZM 241385 differentially prevent the motor effects of CGS 21680 in mice: evidence for a functional 'atypical' adenosine A(2A) receptor

The acute motor effects elicited by drugs acting upon adenosine A(2A) receptors, namely the highly selective agonist CGS 21680 or the antagonists SCH 58261 and ZM 241385, were investigated in mice. CGS 21680 dose-dependently (0.1-2.5 mg/kg i.p.) decreased horizontal and vertical motor activities. The depressant effect of CGS 21680 (0. 5 mg/kg i.p.) was maintained in mice pretreated by the adenosine receptor antagonist 8-(p-sulfophenyl)-theophylline (10-30 mg/kg i.p. ), which poorly penetrates the blood-brain barrier, but was completely lost in adenosine A(2A) receptor knockout mice. Thus, the adenosine A(2A) receptor is critically involved in motor activity. SCH 58261 (1-10 mg/kg i.p.) increased locomotion and rearing with a quick onset, but for a shorter period in mice habituated to the environment than in mice unfamiliar to it. ZM 241385 (7.5-60 mg/kg i. p.) stimulated horizontal and vertical activities with a slow onset at the two highest tested doses, similarly in naive and in habituated mice. The increase in locomotion elicited by ZM 241385 (15-30 mg/kg i.p. and 10-20 nM i.c.v.) was retained in mice treated by CGS 21680 (0.5 mg/kg i.p.) but that elicited by SCH 58261 (1-3-10 mg/kg i.p. and 10-20 nM i.c.v.) partially subsided. In conclusion, both 'striatal-like'/'SCH 58261-sensitive' adenosine A(2A) receptors and 'ZM 241385-sensitive'/'atypical' CGS 21680 binding sites may mediate CGS 21680-induced motor effects. Moreover, our results suggest that 'atypical' CGS 21680 binding sites could be adenosine A(2A) receptors with a peculiar pharmacological profile.     

Protective effects of dextromethorphan and tizanidine on ouabain-induced arrhythmias

The effects of the opioid agonist dextromethorphan and the alpha 2-adrenoceptor agonist tizanidine on ouabain-induced cardiac arrhythmias were investigated in rats. Ouabain (10 mg/kg i.v.) elicited ventricular arrhythmias in all of the control rats. Administration of dextromethorphan (25 mg/kg i.v.) and tizanidine (0.1 mg/kg i.v.) 30 min before ouabain treatment significantly reduced the incidence of arrhythmias. We suggest that dextromethorphan and tizanidine showed these effects by decreasing excitatory amino acid (EAA) activity. It can be speculated that opioids and other EAA antagonists may have antiarrhythmic actions through both their central and peripheral effects as well.     

Termination of ouabain-induced ventricular tachycardia by flunarizine in conscious dogs

The ability of flunarizine to terminate ouabain-induced ventricular tachycardia was investigated in conscious dogs. These arrhythmias result from triggered activity based on delayed afterdepolarizations. Sustained ventricular tachycardia was induced by ouabain (48 +/- 6 micrograms/kg) and pacing in 13 animals with surgically induced complete atrioventricular block. Flunarizine was administered i.v. when the arrhythmia had persisted for at least 20 min. Flunarizine induced an increase of the R-R interval from 300 +/- 30 to 410 +/- 50 ms (P less than or equal to 0.001) in all dogs. Flunarizine (2 mg/kg) terminated ventricular tachycardia with long R-R intervals (330 +/- 20 ms) in seven dogs. An additional dose of flunarizine (1 mg/kg) resulted in termination of the faster tachycardias (280 +/- 15 ms). The arrhythmias were not induced again by pacing for 27 +/- 18 min. Reinitiated tachycardias could be suppressed again by flunarizine. In conclusion, flunarizine (1) slows and terminates arrhythmias resulting from delayed afterdepolarizations, and (2) prevents their reinitiation.     

Actions of a newly synthesized compound (711389-S) on various types of experimentally induced arrhythmias in mammalian species in situ

We examined effects of 711389-S, a new antiarrhythmic agent, on ouabain-induced arrhythmias in dogs and guinea-pigs, aconitine-induced arrhythmias in dogs and mice, adrenaline-induced arrhythmias in dogs under an anesthetized condition, and arrhythmias induced by coronary artery ligation and occlusion by a glass bead in dogs under conscious and un-restrained conditions. 711389-S (1-3 mg/kg, i.v.) decreased the number of ventricular extrasystoles induced by ouabain in dogs, and the doses of ouabain required to induce various types of arrhythmias were increased by pretreatment of guinea-pigs with intraduodenal application of 711389-S (5-10 mg/kg). In mice, 711389-S (3 mg/kg, i.v. or 10 mg/kg, p.o.) significantly prolonged the time to onset of arrhythmias induced by aconitine infusion. Atrial fibrillation induced by a topical application of aconitine on the atrium was blocked by 711389-S (1 mg/kg, i.v.) in dogs. 711389-S (1-3 mg/kg, i.v.) depressed arrhythmias induced by adrenaline and restored the sinus rhythm by significantly decreasing the number of ventricular ectopic beats induced by coronary ligation or occlusion in dogs. Oral administration of 711389-S (10-30 mg/kg) in dogs markedly depressed the ventricular ectopic beats induced by coronary ligation. The half decay time of 711389-S after a single bolus injection of 711389-S ranged from 60 to 80 min. Results indicate that 711389-S has similar antiarrhythmic effects to those of other Class I antiarrhythmic agents in situ, and they suggest that this compound might have potential usefulness as a new type of antiarrhythmic agent for clinical use.     

Effects of AH-1058, a new antiarrhythmic drug, on experimental arrhythmias and cardiac membrane currents

AH-1058 is a newly synthesized antiarrhythmic agent. We investigated the antiarrhythmic and electrophysiological effects of AH-1058 in experimental arrhythmia models and isolated cardiomyocytes. In the ouabain-induced arrhythmia model of the guinea pig, pretreatment with AH-1058 (0.1-0.3 mg/kg, i.v.) delayed the appearance of premature ventricular complex (PVC) and ventricular fibrillation (VF) induced by intravenous infusion of ouabain. However, disopyramide (10 mg/kg, i.v.) delayed only that of PVC, and verapamil (1 mg/kg, i.v.) failed to affect the ouabain-induced ventricular arrhythmias. In the reperfusion-induced arrhythmia model of the rat, in which 5-min coronary occlusion and 10-min reperfusion were produced, AH-1058 (0.1-0.3 mg/kg, i.v.) inhibited the incidence of both ventricular tachycardia (VT) and VF, whereas disopyramide (5 mg/kg, i.v.) inhibited only reperfusion-induced VF. On the other hand, a higher dose of AH-1058 (1 mg/kg, i.v.) did not affect the aconitine-induced arrhythmias in rats, which were inhibited by disopyramide (5 mg/kg, i.v.). We also confirmed oral activity of AH-1058 in the reperfusion-induced arrhythmia model of the rat. AH-1058, at doses of 2-4 mg/kg, dose-dependently inhibited VT and VF. Electrophysiological experiments with patch-clamp techniques revealed that AH-1058 potently suppressed the L-type Ca2+ currents in isolated cardiomyocytes of the guinea pig. These results suggest that AH-1058 is a potent antiarrhythmic drug having a Ca2+ channel-blocking action. The antiarrhythmic profile of AH-1058 is different from that of disopyramide and verapamil.     

Antiarrhythmic and hemodynamic effects of an aminosteroid (Org 3001) in the digitalized dog.

Org 6001 (3alpha-amino-5alpha-androstan-2beta-ol-17-one-hydrochloride) is an orally non-hormonal aminosteroid possessing antiarrhythmic activity. In 13 dogs the efficacy of the drug against ouabain-induced ventricular tachycardia (VT) was studied. VT was produced by a mean dose of 67.5 +/- 18.7 mug/kg ouabain, administered by continuous infusion of 25 mug/min. 20 min after the onset of VT an 0.125 mg/kg/min infusion of Org 6001 was initiated, doubling the dose every 10 min. In all dogs VT was reverted into normal sinus rhythm (NSR) by a dose of 9.72 +/- 7.07 mg/kg (0.87-20.75 mg/kg) Org 6001. The duration of VT ranged from 27-61 min (mean 47.1 +/- 11.4 min), including the 20 min waiting period. NSR persisted in 8 dogs until the experiment was terminated (90 min after onset of VT), while in 5 dogs VT returned after 3-23 min sufficient to revert VT into NSR. A bolus injection of Org 6001 (10 mg/kg) gave an immediate return to NSR in 3 dogs, in which VT was provoked again by administration of a second dose of ouabain after the 90 min period had elapsed. Though the interaction of ouabain makes a quantitative analysis of the negative inotropic effects difficult, it appeared that there uas no major hemodynamic deterioration during and after treatment with Org 6001. During digitalization there was a significant increase in the first derivative of left ventricular systolic pressure (peak LVdP/dt) from 2340 +/- 600 to 3650 +/- 1070 mm Hg/sec and in peripheral resistance, while heart rate decreased. During VT, left ventricular systolic pressure (LVSP) and mean aortic pressure (MAP) dropped by approximately 20 mm Hg, while heart rate increased significantly. After treatment with Org 6001, LVSP and MAP further decreased to 128 +/- 30 mm Hg (p less than 0.05) areased to 128 +/- 30 mm Hg (p less than 0.05) and 112 +/- 20 mm Hg respectively. Peak LVdP/dt fell from 3650 +/- 1390 to 2780 +/- 970 mm Hg/sec (p less than 0.05). Heart rate had dropped to 126 +/- 22 beats/min (p less than 0.05). During the first 30 min after Org 6001 infusion was stopped none of the parameters showed significant changes, although peak LVdP/dt rose slightly. It is shown in the present investigation that Org 6001 has effective antiarrhythmic properties in controlling ouabain-induced VT with acceptable cardiodepressant actions.     

Effects of the new class-III antiarrhythmic drug D-sotalol on contractile function of postischemic myocardium.

The hemodynamic effects of the new class-III antiarrhythmic drug D-sotalol (2 mg/kg i.v.) on postischemic myocardium were investigated in comparison with the actions of the racemic D,L-sotalol (2 mg/kg i.v.) in rats. Drug infusion (7 min) was started 20 min after 3 x 4 min of global ischemic injury (oxygen deficiency). The left ventricular isovolumic pressure-generating capacity at the beginning of infusion was reduced by 15%, indicating postischemic dysfunction. Infusion of D-sotalol caused a highly significant (p less than 0.01) reduction of the left ventricular pressure-generating capacity (to 58 +/- 5%), as well as of the dp/dtmax (to 21 +/- 3%). Stroke volume (to 66 +/- 6%), ejection fraction (to 62 +/- 7%), and cardiac output (to 51 +/- 6%) were also decreased (p less than 0.01). Fifteen minutes after infusion a partial renormalization of the hemodynamic measures (dp/dtmax 41 +/- 5%; stroke volume 94 +/- 8%) was observed. Infusion of the racemic D,L-sotalol caused similar hemodynamic changes (left ventricular pressure-generating capacity 60 +/- 2%, dp/dtmax 25 +/- 2%), indicating its cardiodepressant action. In contrast to prior findings on normal myocardium, our present results indicate that D-sotalol, a potential new class-III antiarrhythmic drug, has a considerable negative inotropic effect on postischemic myocardium.     

Inhibition of the vascular actions of IgG aggregates by BN 52021, a highly specific antagonist of paf-acether

The effect of BN 52021, a selective antagonist of paf-acether (Braquet GB patent 8, 418, 424 July 19, 1984), was studied in normotensive rats challenged with different doses of paf-acether. Sudden death was observed in animals receiving an i.v. dose of 10 micrograms/kg of paf-acether and this was prevented by prior treatment with BN 52021 (5 mg/kg, i.v.). Animals receiving 2.5 micrograms/kg of paf-acether had a fall of mean arterial pressure of 92.5 +/- 4.7 mmHg which recovered to the prechallenge level 20.5 +/- 0.2 min thereafter. Previous treatment with BN 52021 (5 mg/kg, i.v.) reduced the mean arterial pressure fall to 47 +/- 0.9 mmHg and the time of recovery to 5.7 +/- 1.7 min. The extravasation of 125I-bovine serum albumin under the above conditions was reduced by BN 52021 from 36 +/- 3 to 18 +/- 3%. A lower dose of BN 52021 (1 mg/kg, i.v.) was also effective in reducing later extravasation, but was unable to prevent the extravasation which appears up to 10 min after the injection of paf-acether. To extend these findings to a model of endogenous production of paf-acether, other animals were challenged with soluble aggregates of human IgG (40 mg/kg, i.v.; I?arrea et al., Immunopharmacology 6:7, 1983).(ABSTRACT TRUNCATED AT 250 WORDS)     

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)     

Effects of two nonsulfhydryl angiotensin-converting enzyme inhibitors, CGS 14831 and CGS 16617, on myocardial damage and left-ventricular hypertrophy following coronary artery occlusion in the rat

The present study was designed to examine the effects of two new angiotensin-converting enzyme (ACE) inhibitors, CGS 14831 and CGS 16617 (3 mg/kg i. v. 1 min prior to occlusion and 4 and 24 h after occlusion), on myocardial ischemic (MI) damage and left-ventricular hypertrophy in rats. Administration of CGS 14831 or CGS 16617 inhibited angio-tensin-I-induced pressor responses by 40-100% for 4 h after each dose. Myocardial creatine phosphokinase (CK) levels were 10.6 +/- 0.6 U/mg protein in sham-MI animals, and following coronary artery occlusion for 48 h were decreased to 4.1 +/- 0.2 U/mg protein in MI + vehicle animals (p less than 0.01). CGS 14831 and CGS 16617 attenuated the decrease in CK content and resulted in 47 and 40% sparing, respectively, of the left-ventricular free wall. Neither agent attenuated the left-ventricular hypertrophy which developed following coronary artery occlusion. These data indicate that the nonsulfhydryl ACE inhibitors CGS 14831 and CGS 16617 have a significant cardioprotective effect in rats surviving 48 h, and suggest a potential therapeutic usefulness of these agents for the treatment of ischemia-induced heart failure.     

Central effect of histamine and peripheral effect of histidine on the formalin-induced pain response in mice

1. The present study was designed to investigate the role of brain histamine in modulating pain transmission in mice. 2. In conscious mice implanted with an intracerebroventricular (i.c.v.) cannula, the effects of i.v.c. injections of normal saline (control) and low and high doses histamine (2 and 40 microg/mouse, respectively) were investigated on the duration of paw licking and biting induced by subcutaneous (s.c.) injection of formalin (20 microL; 5%) into the plantar surface of the left hindpaw. 3. To clarify the involvement of histidine in the pain response, the effects of intraperitoneal (i.p.) injections of low and high doses of histidine (50 and 1000 mg/kg, respectively) alone or before i.c.v. injection of histamine were also examined. 4. Intraplantar injection of formalin induced a biphasic pain response (first phase: 0-5 min after injection; second phase: 20-40 min after injection). 5. Histamine (2 microg/mouse, i.c.v.) had no effect on the first phase of the pain response, but suppressed the second phase. The higher dose of histamine (40 microg/mouse, i.c.v.) suppressed both phases of the pain response. 6. Histidine, at 50 mg/kg, i.p., had no effect on the pain response, but the higher dose (1000 mg/kg, i.p.) suppressed the both phases of the pain response. 7. Pretreatment with the low dose of histidine (50 mg/kg, i.p.) prior to administration of 2 microg/mouse, i.c.v., histamine did not change the antinociception induced by low-dose histamine. However, pretreatment with the high dose of histidine (1000 mg/kg, i.p.) prior to 2 microg/mouse, i.c.v., histamine produced antinociception that resembled that seen following administration of the high dose of either histidine or histamine. Pretreatment with the low dose of histidine (50 mg/kg, i.p.) prior to administration of 40 microg/mouse, i.c.v., histamine has no effect on the pain response following high-dose histamine. Pretreatment with 1000 mg/kg, i.p., histidine prior to administration of 40 microg/mouse, i.c.v., histamine strongly suppressed both phases of the formalin-induced pain response, particularly the second phase. 8. The results of the present study indicate that: (i) activation of brain histamine produces antinociception in the mouse formalin test; (ii) peripheral loading with a high dose of histidine (1000 mg/kg, i.p.) alone exerts the same effect as that seen following 40 microg/mouse, i.c.v., histamine; and (iii) pretreatment with a high dose of histidine potentiates central histamine-induced antinociception.     

Investigation of electrophysiologic mechanisms for the antiarrhythmic actions of R 56865 in cardiac glycoside toxicity.

R 56865 is an experimental compound that has been shown to ameliorate the effects of cardiac glycoside toxicity and myocardial ischemia. We evaluated the direct electrophysiological effects of R 56865 and its effects on the electrophysiological sequelae of ouabain toxicity in vivo and in vitro. In normal anesthetized dogs, R 56865 alone at doses of 0.04 to 0.16 mg/kg i.v. had no effect on atrial, AV nodal, or ventricular conduction times and refractoriness, but at doses of 0.64 to 2.5 mg/kg it tended to increase these parameters. In ouabain-pretreated dogs, R 56865 (0.08 to 0.32 mg/kg i.v.) dose-relatedly reduced ouabain-induced ventricular arrhythmias. In normal isolated canine Purkinje fibers, R 56865 (1-10 microM) reduced Vmax at short pacing cycle lengths and decreased the action potential duration at concentrations of 0.1 to 10 microM. R 56865 at concentrations through 10 microM had no significant effect on normal action potentials of canine ventricular muscle and slow response action potentials in guinea pig papillary muscles. In Purkinje fibers exposed to toxic concentrations of ouabain, R 56865 (1 microM) reduced the delayed after depolarization (DAD) amplitude and inhibited triggered activity. R 56865 had no effect on normal automaticity in canine Purkinje fibers at 1 microM, but 10 microM significantly slowed it. R 56865 at 10 microM did not affect isoproterenol-enhanced automaticity and only slightly reduced barium-induced abnormal automaticity that occurred at reduced membrane potentials. These results demonstrate that R 56865 reverses cardiac glycoside-induced arrhythmias in anesthetized dogs at doses that do not significantly affect conduction or refractoriness. Suppression of ouabain-induced DAD and triggered activity in isolated Purkinje fibers, at concentrations not affecting normal or abnormal automaticity, may be the mechanism of R 56865's antiarrhythmic actions in vivo. Suppression of DAD does not appear to be associated with blockade of voltage-dependent calcium channels, but R 56865 may prevent intracellular sodium overload by limiting excessive sodium entry during ouabain intoxication.     

Functional reactivity of different central opioid receptor systems following clomipramine treatments

Intracerebroventricular administration of the enkephalinase inhibitor, phosphoramidon (PHA, 3.7 X 10(-7) moles, i.c.v.) induced distinct wet-dog-shakes (WDS) behaviour. Naltrexone (NX) given in a low dose (0.25 mg/kg, i.p.) did not antagonize the WDS induced by PHA. A higher dose of NX (2.5 mg/kg i.p.) decreased WDS behaviour. Morphine (25 mg/kg, i.p.) induced marked catalepsy. Ketocyclazocine (0.01-1.0 mg/kg, i.p.) induced a dose related decrease in spontaneous locomotor activity. Chronic (20 mg/kg, i.p. daily for 10 days and withdrawn, 24 h prior, C.CLO) and acute (20 mg/kg, i.p., 60 min prior, A.CLO) clomipramine treatments decreased PHA-induced WDS compared to saline pretreatments. However, C.CLO treatments antagonized the morphine-induced catalepsy and ketocyclazocine-induced sedation whereas A.CLO did not alter the opiate-induced cataleptic/sedative behaviours. It is suggested that chronic clomipramine treatment induced a functional deficiency of central mu and kappa opioid receptor systems without altering the delta opioid mechanisms.     

Effect of SC-40230, a new class I antiarrhythmic agent,on canine ventricular tachycardias

SC-40230, α-[2-[acetyl(1-methylethyl)amino]ethyl]-α-(2-chlorophenyl)-1-piperidinebutanamide, a new class I antiarrhythmic agent, was tested for efficacy against coronary ligation-induced arrhythmias and ouabain toxicity arrhythmias in dogs. Doses of 9mg/kg i.v. and 15, 25, and 35 mg/kg p.o. significantly reduced ectopic rate in conscious dogs that had undergone ligation of the left anterior descending coronary artery 24 hr prior to testing. Plasma concentrations of SC-40230 ranging from 3 to 9 μg/ml corresponded with ectopic rate reductions of 10–82% in the coronary ligation model. SC-40230 was well tolerated at all doses tested in the conscious dogs. A 5 mg/kg i.v. dose of SC-40230 converted ouabain-induced ventricular tachycardias to normal sinus rhythm in anesthetized dogs. The antiarrhythmic effect of SC-40230 in the ouabain toxicity model was reversed by large (? 240 U) doses of insulin. The experiments described in this study demonstrated that SC-40230 is a well-tolerated new class I antiarrhythmic agent with intravenous and oral effectiveness against ventricular arrhythmias.     

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.