Arrhythmias In Guinea Pigs Research Articles

Cardiac arrhythmias are ameliorated by local inhibition of angiotensin formation and bradykinin degradation with the converting-enzyme inhibitor ramipril

We investigated the influence of the angiotensin-converting enzyme (ACE) inhibitor ramipril on cardiac arrhythmias in guinea pigs and rats. Ramiprilat, the active moiety of ramipril, did not influence action potentials of isolated guinea-pig papillary muscle or rabbit sinus node, thereby excluding cellular electrophysiological evidence of anti-arrhythmic properties. Ramipril protected against cardiac arrhythmias induced by digoxin infusion in guinea pigs. This effect was comparable with that of lidocaine. In isolated perfused ischemic working rat hearts, angiotensin (ANG) I (3 x 10(-9) M/l) and ANG II (1 x 10(-9) M/l) aggravated reperfusion arrhythmias, accompanied by deterioration of cardiodynamic and metabolic events. Bradykinin (BK) (1 x 10(-10)-1 x 10(-8) M/l), in contrast, protected against reperfusion arrhythmias, which corresponded to an increase in energy-rich phosphates and glycogen stores and a decrease in lactate levels in myocardial tissue. Identical changes were seen in hearts from rats pretreated with ramipril (1 mg/kg PO) or perfused with ramiprilat (2.58 x 10(-7)-2.58 x 10(-5) M/l). Local ACE inhibition in these ischemic hearts antagonized ANG I but not ANG II effects and enhanced BK effects. The BK antagonist D-Arg-(Hyp2, Thi5,8, D-Phe7)BK abolished the beneficial effects of BK, ramipril, and ramiprilat. Increased concentrations of BK or ramiprilat were able to reverse the antagonism. The antiarrhythmic agent nicainoprol, a fast-sodium-channel blocking drug (class Ib), also protected isolated rat hearts against reperfusion arrhythmias, but was without beneficial effects on cardiac hemodynamics and biochemical parameters, in contrast to the ACE inhibitor. These results suggest that the beneficial effects of the ACE inhibitor ramipril on digoxin and reperfusion arrhythmias are not mediated by their direct actions on ionic channels in the cell membrane. It seems that other factors are responsible for its beneficial effects on reperfusion arrhythmias, cardiac function, and metabolism, which are associated with a reduction in ANG II generation and BK degradation by local ACE inhibition in the heart.

The effect of inhibitors of endogenous opioid degradation, bacitracin, bestatin, captopril, and D-phenylalanine, on digoxin-induced arrhythmias in guinea pigs.

The purpose of this study was to investigate the effect of inhibition of endogenous opioid degradation on digitalis-induced arrhythmias, utilizing the inhibitors bacitracin, bestatin, captopril, and D-phenylalanine. Guinea pigs, anesthetized with pentobarbital, 50 mg/kg i.p., and breathing spontaneously received intracerebroventricular (i.c.v.) injection of bacitracin (6.8 mg/kg), bestatin (1 mg/kg), captopril (2 mg/kg), D-phenylalanine (1.2 mg/kg) or the diluent, saline. Digitalis arrhythmias were induced by a 50 micrograms/kg i.v. bolus of digoxin followed by 500 micrograms.kg-1.h-1 i.v. Bacitracin and bestatin, but not captopril or D-phenylalanine, significantly (p less than 0.05) altered the relationship between the digoxin dose and the first occurrence of arrhythmias, i.e., digoxin-induced ventricular arrhythmias became manifest at lower digoxin doses. The mean digoxin dose and ED50s, at which arrhythmias first occurred, were significantly (p less than 0.05) reduced by bacitracin and bestatin. The findings were similar for fatal arrhythmias, although D-phenylalanine appeared to decrease the digoxin dose at the development of fatal arrhythmias. The opioid antagonist naloxone, in a 50 micrograms/kg bolus and 50 micrograms.kg-1.h-1 i.c.v., completely prevented these effects of bacitracin and reduced the effect of bestatin. The relationship to arrhythmias could not be ascribed to an effect on blood pressure, as the blood pressure response to digoxin was the same in bestatin, D-phenylalanine, and control groups. To examine whether systemic administration of an inhibitor of opioid degradation had similar effects, a second protocol was selected with systemic administration of bacitracin because it altered the dose effect relationship after i.c.v. administration and systemic concentrations could be readily attained. Bacitracin, in a 13.5 mg/kg i.v. bolus and 135 mg.kg-1.h-1 i.v., was followed by 100 micrograms/kg digoxin i.v. every 15 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of dantrolene sodium in rodent models of cardiac arrhythmia

Dantrolene sodium has been compared with reference antiarrhythmic agents in rodent models of cardiac arrhythmia. In a coronary-artery-ligation model in rats, dantrolene sodium (3, 10 and 20 mg/kg i.v.) significantly decreased extrasystoles, episodes of ventricular tachyarrhythmia, and frequency, duration, and total episodes of ventricular fibrillation in a dose-dependent manner. In an electrically induced fibrillation model in rats, dantrolene sodium (10 and 20 mg/kg i.v.) significantly raised ventricular fibrillation threshold in a dose- and time-dependent manner. In contrast to its activity in these models, dantrolene sodium was not active in two chemically induced models involving automaticity. Aconitine-induced arrhythmias in rats and mice and ouabain-induced arrhythmias in guinea pigs were not suppressed by i.v. (10 or 20 mg/kg) or i.p. (100–300 mg/kg) doses of the drug. These results show that the antiarrhythmic potential of dantrolene sodium, predicted by in vitro Class III and Class IV electrophysiological effects, is expressed in whole animal models.

Pharmacological studies of indole alkaloids obtained from domestic plants, Uncaria rhynchophylla Miq. and Amsonia elliptica Roem. et Schult

Pharmacological studies on hirsutine (HS), hirsuteine (HST), rhynchophylline (RP), isorhynchophylline (IRP) and dihydrocorynantheine (DCT) which were isolated from the domestic plant Uncaria rhynchophylla Miq. and beta-yohimbine (beta-Y) which was isolated from the domestic plant Amsonia elliptica Roem. et Schult. were carried out. These alkaloids showed a mild central depressive effect in mice, a week non-competitive anti-spasmodic action in the mouse intestine, and a hypotensive effect in rats. Since beta-Y showed alpha-adrenoceptor blocking action, the hypotensive effect of beta-Y may be partly due to the vasodilative effect induced by its alpha-adrenoceptor blocking action. HS and beta-Y showed a preventive effect on the development of gastric erosions in mice. HS had antiarrhythmic effects on both aconitine-induced arrhythmias in mice and ouabain-induced arrhythmias in guinea pigs. The potency of the antiarrhythmic effects induced by HS was approximately the same as that of ajmaline, an indole alkaloid. Since HS did not show beta-adrenoceptor blocking action, the antiarrhythmic effects of HS would not be due to its beta-adrenoceptor blocking effect.

Effects of thromboxane synthetase inhibitor (UK 38,485) and thromboxane receptor antagonist (ICI 185,282) on digoxin-induced arrhythmias in anaesthetized guinea-pigs.

1. Increased local thromboxane (Tx) formation has been considered to be a contributing factor in digitalis-induced arrhythmias. 2. A potent Tx synthetase inhibitor (TxSI), UK 38,485 (0.1, 1.0 or 10.0 mg/kg per h, administered intravenously) and a Tx receptor antagonist (TxRA), ICI 185,282 (1, 2 or 10 mg/kg bolus and 1, 2 or 10 mg/kg per h, administered intravenously) were tested for their ability to reduce digoxin-induced arrhythmias in anaesthetized guinea-pigs. 3. Electrocardiograms, mean blood pressure, heart rate and arrhythmias were recorded, starting 30 min before digoxin administration and continued for 60 min afterwards. 4. ICI 185,282, at the doses used, significantly delayed the time of onset of arrhythmias, and reduced the incidence of ventricular fibrillation, mortality and arrhythmia score. In contrast, UK 38,485 was found to be effective on all measured variables only at the dose rate of 1.0 mg/kg per h, except for time required for the development of arrhythmias. These protective effects of both TxSI and TxRA were not found to be dose-dependent. 5. Arterial blood pressure and heart rate changes caused by either UK 38,485 or ICI 185,282 infusions did not have any marked effects on digoxin-induced arrhythmias. 6. These data suggest that endogenously released TxA2 and prostaglandin endoperoxides may play an important role in digoxin-induced arrhythmias in guinea-pigs.

Effect of some non-steroidal anti-inflammatory drugs on ouabain-induced arrhythmias in guinea-pigs.

1. Effects of some non-steroidal anti-inflammatory drugs on ouabain-induced arrhythmias in guinea-pigs were studied. 2. Ventricular premature beats, ventricular fibrillation and cardiac arrest were induced in pentobarbitone-anaesthetized guinea-pigs by a slow intravenous infusion of ouabain. 3. Aspirin and indomethacin were found to accord a significant protection to the guinea-pigs against arrhythmias whereas ketoprofen was found to be ineffective. 4. It is concluded that the protective effect of aspirin and indomethacin may be due to inhibition of synthesis and release of thromboxane A2 from the myocardium.

Analysis of antiarrhythmic effect of ryanodine in guinea-pigs

The effects of ryanodine on (1) ventricular arrhythmias in guinea-pigs in vivo, (2) delayed afterpotentials and aftercontractions and (3) spontaneous oscillations of the membrane potential (SOP) and of resting tension (SOT) of guinea-pig papillary muscle under ouabain intoxication have been studied. After addition of ouabain (1 microM), the afterpotentials, aftercontractions and the amplitude of SOP and SOT were significantly increased. The power spectra of SOT and SOP under these conditions had a resonance harmonic with a frequency of about 5 Hz. The afterpotentials, aftercontractions, SOP and SOT were abolished 3 to 5 min after ryanodine addition (0.1 to 0.5 microM), suggesting a close relationship between these oscillations and the oscillatory activity of sarcoplasmic reticulum. During in vivo experiments, ouabain-induced (75 to 115 micrograms/kg) ventricular arrhythmias were terminated 4 to 5 min after the intravenous injection of ryanodine (15 micrograms/kg) and within 8 to 10 min, the sinus rhythm was completely restored. We conclude that the antiarrhythmic effect of ryanodine is related to the inhibition of the diastolic fluctuations of the membrane potential.

The effect of the specific PAF antagonist BN 52021 and the calcium blocker diltiazem on PAF induced arrhythmogenicity

Platelet-activating factor (PAF) in a concentration of 10 −11 mole per animal decreased the threshold doses for onsets of arrhythmia, ventricular flutters and fibrillation in ouabain induced arrhythmia in guinea-pigs in a statistically significant manner. The specific PAF antagonist BN 52021 (20 mg/kg, orally) completely inhibited the PAF effect for all types of arrhythmia, while the Ca 2+ antagonistic drug diltiazem (0.1 mg/kg, i.v.) failed to counteract the PAF action. BN 52021 (20 mg/kg, per os) alone did not exert any effect on ouabain induced arrhythmia, but as expected, diltiazem (0.1 mg/kg, i.v.) showed antiarrhythmic effects. These results confirm the specific PAF antagonistic activity of BN 52021, its usefulness for PAF related cardiac rhythm disturbances and indicate that the method used could be a further useful tool to screen PAF antagonistic substances.

Do endogenous lipoproteins modulate the sensibility of animals against arrhythmogenic drugs?

The present study suggests that a diminished level of HDL is connected with an enhanced susceptibility to arrhythmogenic stimuli only in rats pretreated with a diet deficient in polyunsaturated fatty acids (PUFA), but not after a PUFA-rich or pellet diet. The endogenous level of total cholesterol did not influence the thresholds for ventricular flutter or ventricular fibrillation in aconitine-induced arrhythmia in rats or in ouabain-induced arrhythmia in guinea pigs.

The effect of PAF (platelet-activating factor) on experimental cardiac arrhythmias and its inhibition by substances influencing arachidonic acid metabolites

Platelet-activating factor (PAF), 10–11 mol decreased the threshold of ouabain induced arrhythmia in guinea-pigs. The thresholds inducing premature ventricular beats and ventricular flutter were statistically significantly decreased by 27.4 % and 15.6 %, respectively. BM 13.177 (30 mg/kg), a thromboxane receptor antagonizing substance, and esculetin (1.2 mg/kg), a lipoxygenase inhibitor, abolished this arrhythmogenic effect of PAF. Acetylsalicylic acid (10 mg/kg) showed only a tendency to inhibit the PAF effect. These results suggest that PAF could play a role in cardiac arrhythmias under special conditions and it supports the hypothesis that PAF action is mediated by the release of leukotrienes and thromboxane.

Antiarrhythmic effects of DPI 201-106.

The cardiotonic agent DPI 201-106 (4-[3-(4-diphenylmethyl-1-piperazinyl-2- hydroxypropyl]-1H-indole-2-carbonitrile) which modifies the sarcolemmal Na+ channel gating system and has electrophysiological properties of class III antiarrhythmics was investigated for local anaesthetic and antiarrhythmic activity. The compound action potential amplitude of cat cervical vagus nerves in vitro was decreased by DPI 201-106 in a concentration-dependent manner, the IC50 being 1.82 X 10(-5) M. This was paralleled by a slowing in conduction velocity and demonstrates local anaesthetic effects. Ventricular fibrillation which occurs in response to coronary artery reperfusion in rats was prevented by intravenous infusions of 0.3 mg kg-1 min-1 of DPI 201-106. The arrhythmogenic intravenous doses of aconitine in rats were increased following pretreatment with DPI 201-106 in a dose-dependent manner. DPI 201-106 did not protect against ouabain-induced arrhythmias in guinea-pigs. The results demonstrate that DPI 201-106 has local anaesthetic effects and is a potential antiarrhythmic.

Effects of alpha-adrenoceptor agonists and antagonists on ouabain-induced arrhythmias and cardiac arrest in guinea-pig.

Effects of alpha-adrenoceptor agonists and antagonists with different affinity for alpha 1- and alpha 2-receptors on ouabain-induced arrhythmias in guinea-pigs were studied. Early arrhythmias, ventricular fibrillation and cardiac arrest were induced in anaesthetized guinea-pigs by the slow intravenous infusion of ouabain. Phenylephrine and yohimbine potentiated the cardiotoxicity of ouabain significantly whereas prazosin and clonidine showed significant antiarrhythmic effects and delayed the cardiac arrest. It is concluded that selective alpha 1-receptor stimulation and alpha 2-receptor blockade increases the cardiotoxic effects of ouabain and selective alpha 2-receptor stimulation and alpha 1-receptor blockade inhibits ouabain-induced arrhythmias and cardiac arrest in guinea-pigs.

Mechanism of coupled arrhythmias in guinea pig perfused heart and isolated ventricular tissue models of ischemia-reperfusion

We recently developed an in vitro model of ischemia and reperfusion in which isolated canine ventricular tissues were superfused with Tyrode’s solutions modified to mimic ischemia and reperfusion (1,2). Intracellular microelectrode recordings demonstrated that reperfusion induced a regular, orderly sequence of mechanisms of arrhythmia in Purkinje tissue but not in muscle. The mechanisms in order of appearance were: oscillatory afterpotentials (OAP, also known as delayed afterdepolarizations), conduction block, and depolarization-induced automaticity (DIA, also known as early afterdepolarizations). OAP occasionally reached threshold and induced extrasystoles early in reperfusion (2 min). DIA regularly induced extrasystolic activity but only after approximately 20 min of reperfusion. Our superfused tissue model did not exhibit the characteristic time course of arrhythmic activity seen in coronary ligation and release (3,4) or perfused heart models of ischemia and reperfusion (5,6). In these latter models, ectopic activity frequently appeared as a rapid burst of activity within the first minute of reperfusion. A valid model of reperfusion arrhythmias should mimic this characteristic response. It is possible that “ischemic Tyrode’s” mimics the essential components of ischemia but that slow interstitial exchange of solutions attenuates the reperfusion response.

O-236 - The effects of sodium succinate on adrenaline-, ouabain- or aconitine-induced arrhythmia in guinea pigs

O-236 - The effects of sodium succinate on adrenaline-, ouabain- or aconitine-induced arrhythmia in guinea pigs

Protective effects of Na salicylate against digoxin- and BaCl 2-induced arrhythmias in guinea-pigs

In pentobarbital-anaesthetized (60 mg/kg i.p.) guinea-pigs injections of Na salicylate (50 and 100 mg/kg i.v.) had a protective effect against arrhythmias induced by digoxin or BaCl 2. A lower (25 mg/kg) and a higher (200 mg/kg) dose exerted no clearcut antiarrhythmic effect. Plasma concentrations of Na salicylate up to 1 mg/ml influenced neither the heart rate nor the ECG parameters. The antiarryhythmic effect of the drug may be explained by an inhibition of cardiac cyclooxygenase.

Protective effect of prostaglandin E1, but not prostacyclin, on ouabain induced ventricular fibrillation in guinea-pigs

Various prostaglandins(PGs) are effective against arrhythmias induced by chemicals or coronary artery obstruction in experimental animals. These findings have led to the assumption that PGs may act as endogenous antiarrhythmic agents. Prostacyclin(PGl2) is the main PG released from guinea-pig heart. However, there is some controversy regarding the effect of PGI2 on the arrhythmias induced by coronary artery obstruction. Therefore, the present study was undertaken to test the effect of PGIg on ouabain induced ventricular fibrillation(V.F.) in guinea-pigs. Animals were anaesthetized with pentobarbital sodium. II-lead ECG and blood pressure were continuously recorded. Ouabain,200 μg/kg,was rapidly injected into jugular vein. The time(sec) was recorded for the occurrence of first V.F. and cardiac arrest. PGE1,5 μg/kg.and PGI20.5~5 μg/kg,markedly reduced the blood pressure, but the heart rate was not altered. Propranolol,0.5 mg/kg,slightly reduced blood pressure, but the heart rate was markedly decreased. The pretreatment with PGE1,5 μg/kg,or propranolol,0.5 mg/kg,lengthened the time to produce V.F. and significantly reduced the incidence of V.F. Also, a significant number of animals pretreated with PGE1 or propranolol spontaneously reversed to sinus rhythm from V.F. and survived more than 20 min after the first appearance of V.F. On the contrary, the pretreatment with PGI2,0.5 or 5μg/kg, shortened the time to produce V.F. and did not influence the incidence of V.F. All animals pretreated with PGI2 died within 20 min after the first appearance of V.F. The finding shows that PGI2 has no protective action on ouabain induced arrhythmias in guinea-pigs.

Effects of adrenergic beta-blockers and a membrane stabilizing agent on ouabain-induced cardiac arrhythmias in anaesthetized guinea pigs.

The antiarrhythmic effects of dl'propranolol, d-propranolol, metoprolol and lidocaine against ouabain-induced cardiac arrhythmias were studied. It was found that contrary to earlier findings in the dog, the effects of the adrenergic beta-blockers against ouabain-arrhythmias in guinea pigs were due to beta-blocking activity and not the membrane-stabilizing activity of the compounds. The cardioselective beta-blocker, metoprolol, was more or equally effective as dl-propranolol against ouabain-induced arrhythmias in guinea pigs.

Thyrotoxicosis induced by iodine contamination of food--a common unrecognised condition?

The incidence of thyrotoxicosis in northern Tasmania rose significantly in 1964, two years before an epidemic of iodine-induced thyrotoxicosis was precipitated by the addition of iodate to bread to prevent goitre. Each time older patients accounted for most of the increase. The 1964 increase was probably iodine-induced as the use of iodophor disinfectants on dairy farms, which causes iodine residues in milk, began in 1963 and a fall in the prevalence of goitre in young children suggested an increase in dietary iodine at about that time. A further small increase in thyrotoxicosis in 1971 may also have been iodine-induced as it followed an extension of the use of iodophors. Dietary iodine is rising substantially in many places because of high iodine levels in milk and the use of iodine compounds in automated bread making, and this may be causing unsuspected iodine-induced thyrotoxicosis. Dietary iodine should be monitored regularly and clinicans alerted to any rise. Contamination of common foods with iodine should be more strictly controlled.

Studies on A New 1, 5-Benzothiazepine Derivative (CRD-401): V. Antiarrhythmic Actions

The effect of CRD-401 on several types of experimentally induced arrhythmias in guinea-pigs and dogs and the antagonistic effect against isoproterenol in the isolated atrium of guinea-pig were studied and compared with quinidine and propranolol. In epinephrine-induced arrhythmias of guinea-pigs, propranolol had a notable but brief depressive effect, which was observed only 5 min after administration of the drug. Although the potency of CRD-401 was weaker than that of propranolol in these arrhythmias, the effect persisted for more than 35 min after administration. In ouabain-induced arrhythmias of guinea-pigs, CRD-401 and propranolol showed similar depressive effects. Quinidine had little effect on both epinephrine- and ouabain-induced arrhythmias. Both CRD-401 and propranolol failed to reverse the arrhythmias produced by two-stage coronary artery ligation. Propranolol showed a competitive antagonism against the positive chronotropic effect of isoproterenol, while CRD-401 revealed a non-competitive β-blocking action. Quinidine produced no blocking effect in the present experiments.