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Biomedical subjects

K A Kane

Publications and source records attributed to K A Kane.

At least 91 records · Page 5Linked to original sources
PubMed1983

Antiarrhythmic actions of meptazinol, a partial agonist at opiate receptors, in acute myocardial ischaemia.

1 The intravenous administration, to anaesthetized rats, of meptazinol (1 and 2 mg kg-1), a partial agonist at opiate receptors, greatly reduced the incidence of ventricular extrasystoles that resulted from acute coronary artery occlusion. The incidence of ventricular fibrillation (VF) was reduced from 50% (in the controls) to 10% and the mortality from 30% to zero. 2 In similar doses, pretreatment with meptazinol also reduced ventricular arrhythmias, including fibrillation, in conscious rats subjected to coronary artery occlusion. In this model, survival at 16 h was increased from 27% in the controls to 50% and 83% respectively in rats pretreated with 1 and 2 mg kg-1 of the drug. 3 In antiarrhythmic doses, meptazinol had little effect on either heart rate or systemic arterial blood pressure. 4 Intracellular action potential recordings from papillary muscle removed from rats given meptazinol (2 mg kg-1) 15 min previously showed an increase in APD50 and APD90 of more than 40%. There was no effect on dV/dtmax. When superfused with meptazinol in vitro normal rat papillary muscle stimulated at 1 or 3 Hz showed an increase in APD90 and a decrease in dV/dtmax. 5 The antiarrhythmic effect of meptazinol in these models can probably be explained by direct actions on the cardiac muscle action potential (increase in APD) although effects on opiate receptors cannot be ruled out. It is suggested that meptazinol might be useful in relieving pain, and in reducing the severity of arrhythmias in the early stages of acute myocardial infarction.

Action Potentials↗
PubMed1982

Influences of hypothermia, cold, and isolation stress on the severity of coronary artery ligation-induced arrhythmias in rats.

With a view to increasing the severity of the arrhythmias that arise following coronary artery ligation in anesthetized rats, the influences of exposure to lowered environmental temperature (LET) (21 to 13 degrees C) and isolation stress were examined. Housing rats singly for 48 hr, prior to the induction of arrhythmias, caused the most marked changes in the severity of the model; the incidence of ventricular fibrillation and mortality were increase from 43 to 90% and 9 to 60%, respectively. Exposure of multiply housed rats to LET for 48 hr also significantly increased mortality from fibrillation. A combination of LET plus isolation stress, however, did not further increase the severity of the arrhythmias following ligation. Acute hypothermia (body temperature reduced to 30 or 25 degrees C) did not significantly enhance the severity of the model.

Animals↗
PubMed1980

Coronary artery ligation in anesthetized rats as a method for the production of experimental dysrhythmias and for the determination of infarct size.

Coronary artery ligation in anesthetized rats was assessed as a method for the production of experimental dysrhythmias and for the determination of infarct size. Following occlusion of the left main coronary artery, very marked ventricular dysrhythmias occurred in two distinct phases, an early and a late phase, at 0-30 minutes and at 1 1/2--4 hours after ligation respectively. Infarct size was measured at 4 hours after ligation using nitroblue tetrazolium to stain for the depletion of two cytoplasmic enzymes, lactate dehydrogenase and NADPH diaphorase. In this model, lignocaine (10 mg/kg plus an infusion of 5 mg/kg/hr) and ORG 6001 (10 mg/kg plus an infusion of 2.5 mg/kg/hr) had marked antidysrhythmic activity but neither drug influenced infarct size. The model, because of its simplicity, reproducibility, and low cost, should be useful for the screening of potential antidysrhythmic agents and may also be used to determine infarct size following coronary artery ligation.

Androstanols↗
PubMed1980

Antidysrhythmic and electrophysiological effects of a new antianginal agent, bepridil.

The antidysrhythmic effects of a new antianginal agent, bepridil, were compared with those of disopyramide, a known antidysrhythmic drug. Bepridil (20, 50, and 100 mg/kg, i.p.) conferred little protection against aconitine-induced dysrhythmias in mice, whereas similar doses of disopyramide exerted a marked dose-dependent antidysrhythmic effect. Intravenous administration of either bepridil (2 mg/kg) or disopyramide (10 mg/kg) significantly reduced the number of ventricular extrasystoles and completely abolished the occurrence of ventricular fibrillation following coronary artery ligation in the rat. Local anesthetic and electrophysiological effects in vitro of bepridil were also investigated. A marked but slowly developing reduction in action potential height of desheathed frog sciatic nerves was observed at concentrations of 0.01-0.05 mM. In sheep Purkinje fibres, a similar decrease in action potential height, associated with a pronounced reduction in the maximum rate of depolarization of phase zero of the action potential (MRD) was seen with bepridil (0.5-2 X 10(-5) M). Higher concentrations (2-8 X 10(-5) M) were required to reduce MRD of guinea pig ventricular muscle. The antidysrhythmic actions of bepridil may at least in part be explained by the electrophysiological effects observed.

Aconitine↗
PubMed1980

Comparative electrophysiological effects of Org 6001, a new orally active antidysrhythmic agent, and lignocaine on human ventricular muscle.

1 The electrophysiological effects of Org 6001, a new orally active antidysrhythmic agent, have been compared with those of lignocaine on the human ventricular action potential in vitro.2 Org 6001 (4 to 16 mg/l) greatly reduced the maximum rate of depolarization (MRD) of the human ventricular action potential but had no effect on resting membrane potential or action potential amplitude.3 The action potential duration at the 50% repolarization level, but not at the 90% repolarization level, was significantly reduced by Org 6001. The absolute refractory period was unchanged.4 Lignocaine, at a concentration (4 mg/l) within the therapeutic range, had no significant effect on any measured parameter, either in muscle exposed to a normal (4.0 mM) or high (5.4 mM) extracellular potassium concentration ([K(+)](o)).5 Higher concentrations of lignocaine (8 to 16 mg/l) did, however, reduce MRD at both [K(+)](o) without changing resting membrane potential or action potential amplitude. The action potential duration was decreased slightly by these higher concentrations of lignocaine whilst the absolute refractory period was lengthened.6 Org 6001 was found to be more potent than lignocaine in reducing MRD but, unlike lignocaine, the absolute refractory period was not prolonged. These compounds, therefore, differed in their electrophysiological effects on human ventricular muscle although both are characterized as being class 1 antidysrhythmic drugs.

17-Ketosteroids↗
PubMed1979

The effect of aminosteroid, ORG 6001, on hypothermia induced ventricular fibrillation in the cat.

1 The effect of the antidysrhythmic aminosteroid, ORG 6001, on hypothermia-induced ventricular fibrillation was investigated in cats anaesthetized with pentobarbitone. 2 ORG 6001 (total dose, 10 mg/kg, by intravenous injection) reduced both the incidence of fibrillation and the temperature at which it occurred. The number of animals that survived to 16 degrees C was increased. 3 This protective effect of ORG 6001 could not be explained by changes in respiratory acidosis, plasma concentrations of sodium and potassium, or by changes in the action potential of excised hypothermic ventricular muscle. The hypothermia-induced elevation of blood lactate was less in cats treated with the aminosteroid. 4 Over a limited temperature range, ORG 6001 prolonged the P wave and QRS duration and shortened the QTc interval. ST segment elevation was slightly reduced in the drug-treated group. J deflections were observed but were not correlated with the development of fibrillation. 5 The onset of fibrillation was not considered to be due to temperature differences between the myocardium and arterial blood or between localized areas of the left ventricular wall.

17-Ketosteroids↗
PubMed1979

Myocardial function in feline endotoxin shock: a correlation between myocardial contractility, electrophysiology, and ultrastructure.

The nature of the myocardial depression observed in patients with septic shock, and in animals late in shock induced by endotoxin, is still under examination. These studies, in cats and kittens administered an LD80 dose of E coli endotoxin, were designed to examine the relationship between changes in myocardial contractility, in cellular electrophysiology and in ultrastructural morphology. There was no difference between tension developed in vitro by cardiac muscle removed from cats five hours after endotoxin administration and from cats not administered endotoxin. There was also no difference in their responses to calcium chloride or to anoxia. The action potential characteristics of ventricular muscle isolated from endotoxin treated cats were also not different from control, and ultrastructural damage was minimal and not extensive. Endotoxin (100 microgram/ml) had no effect on cardiac muscle in vitro, even after a one-hour contact time. It is concluded that the integrity of the myocardium is maintained even late in shock and that endotoxin has no direct effects on the heart.

Action Potentials↗
PubMed1976

Divergent changes in the rate of development of pressure in the left ventricle and in the performance of the heart as a pump.

Dog hearts were prepared in situ so that heart rate (HR), left ventricular end diastolic pressure (LVEDP) and mean aortic pressure (MAP) could be controlled separately during computation of left ventricular dP/dt max and external stroke work (SW). Progressive increases in HR consistently raised dP/dt max over a wide range, and consistently lowered SW except at low rates. Progressive increases in LVEDP or MAP consistently raised both dP/dt max and SW. Infusion of noradrenaline consistently raided both dP/dt max and SW, except at very high HR when only dP/dt max was consistently raised. Our results lead us to question the validity of equating changes in pre-ejection measurements with changes in performance of the heart as a pump under abnormal conditions and in the assessment of inotropic agents.

Animals↗
PubMed1974

Cardiovascular actions of prostaglandin C in the cat and dog.

1 Prostaglandin C(2) causes a prolonged fall in arterial blood pressure in the cat.2 At constant heart rate this fall in arterial pressure is accompanied by falls in stroke volume, left ventricular end diastolic pressure, and left ventricular dP/dt max.3 If mean aortic pressure and left ventricular end diastolic pressure are held constant as well as heart rate, prostaglandins C(2) and E(2) do not affect dP/dt max in the cat.4 In the dog, under similarly controlled conditions, prostaglandins C(2) and E(2) raise dP/dt max.5 We conclude that prostaglandins E(2) and C(2) have no direct inotropic action in the cat, but both have a direct positive inotropic action in the dog.

Animals↗
PubMedDate not supplied

The effects of prolonged oral administration of a new antidysrhythmic drug (Org 6001) on coronary artery ligation dysrhythmias in conscious and anesthetized rats.

We determined the antidysrhythmic activity of acute or prolonged administration of Org 6001 on dysrhythmias following coronary artery ligation in conscious and anesthetized rats. Intravenous doses of 5 and 10 mg/kg of Org 6001 markedly protected against postligation dysrhythmias in anesthetized rats, whereas a single oral dose of 10 mg/kg given 1 hr prior to ligation did not. Prolonged oral administration of Org 6001, 10 mg/kg twice daily for 10 days, the last dose given 1 hr before ligation, reduced the incidence of ventricular fibrillation and increased survival in both conscious and anesthetized animals. This effective antidysrhythmic dose regimen resulted in drug concentrations of 335 +/- 68 ng/ml in plasma and 2,940 +/- 408 ng Org 6001/g in the whole heart. At 24 hr after the last dose no protection against the dysrhythmias remained, and drug levels in both plasma and heart tissue were low. A good correlation was observed between the levels of Org 6001 in the heart and the reduction in the rate of rise of phase zero of cardiac action potentials obtained from drug-pretreated animals. It is concluded that prolonged administration of Org 6001 is effective against postligation dysrhythmias and that this effect may be associated with the drug's Class I activity.

Administration, Oral↗
PubMedDate not supplied

Supraventricular antidysrhythmic and electrophysiological effects of bepridil, a new antianginal agent.

We investigated the potential antidysrhythmic effects of bepridil, a new antianginal agent, on dysrhythmias of supraventricular origin. Intravenous bepridil (5 mg/kg) suppressed dysrhythmias evoked by local application of aconitine to the left atria of anesthetized cats. After the aconitine-induced dysrhythmias had subsided, cardiac function was better maintained in animals given bepridil than in the controls. The effects of bepridil on the maximum following frequency (MFF) and transmembrane action potentials of isolated guinea pig atria and on cells displaying phase 4 depolarization were also examined. Both bepridil (5--120 microM) and verapamil (0.02--1 microM) induced a dose-dependent reduction in contractility of driven left atria, whereas only bepridil reduced MFF. The effects of bepridil (10--40 microM) on the cellular action potentials of left atria were a dose-dependent decrease in the maximum rate of depolarization of phase 0 associated with a reduction in action potential height and a marked prolongation of the action potential duration. In similar concentrations, bepridil reduced the spontaneous rate of the right atrium and reduced the slope of phase 4 depolarization. We conclude that the action of bepridil in suppressing supraventricular dysrhythmias may be partly explained by depression of automaticity together with a reduction in the intensity of the inward sodium current.

Aconitine↗
PubMedDate not supplied

Creatine phosphate suppresses ventricular arrhythmias resulting from coronary artery ligation.

The effects of various doses of creatine phosphate have been examined in a rat model of acute myocardial ischaemia. When given directly into the lumen of the left ventricle in pentobarbitone-anaesthetised male rats, creatine phosphate (50 and 100 mg/kg) markedly reduced the incidence of ventricular ectopic beats, and especially the incidence and duration of ventricular tachycardia and fibrillation which normally resulted from acute coronary artery ligation in this model. This protection was observed even if 1 of 2 h elapsed between creatine phosphate administration and coronary artery ligation. Electrophysiological studies on papillary muscles removed from rats 1 h after administration showed that creatine phosphate both decreased the maximum rate of depolarisation and prolonged the duration of the action potential. These results confirm our previous work in dogs that creatine phosphate is effective against early postinfarction ventricular arrhythmias, at least if given locally. It is suggested that these effects are due, at least in part, to a prolongation of the cardiac muscle action potential. Whether this is the result of maintaining energy production early in myocardial ischaemia is unclear.

Action Potentials↗
PubMedDate not supplied

Electrophysiological effects of lidocaine, l-chlorpheniramine, and bepridil on rabbit sinus node pacemaker cells.

We compared the electrophysiological effects of lidocaine, l-chlorpheniramine, and bepridil on rabbit sinus node pacemaker cells. Only bepridil (0.25-2.0 mg/L) caused a marked reduction in the automaticity of the sinus node. Action potential amplitude, overshoot, and maximum rate of depolarization of phase O (MRD) were all reduced in a dose-dependent manner by bepridil. Decreases in maximum diastolic potential (MDP) and take-off potential were also observed, the former falling to approximately -40 mV when automaticity ceased. On the other hand, lidocaine (12-48 mg/L) depressed the upstroke of the action potential without significantly affecting MDP or take-off potential. The action potential duration was also prolonged at these concentrations. Both MDP and take-off potential were markedly reduced by l-chlorpheniramine (2.9-11.6 mg/L) and these changes were accompanied by reductions in amplitude, overshoot, and MRD of the action potential. A prolongation of the action potential duration was also observed. Pacing the sinus node preparations at a frequency of 4.5 Hz depressed the upstroke of the action potential and led to postoverdrive suppression. l-Chlorpheniramine abolished the postoverdrive suppression, whereas in the presence of lidocaine and bepridil a marked reduction and alternation in action potential amplitude occurred on pacing which made the accurate assessment of sinus node recovery time impossible.

Action Potentials↗
PubMedDate not supplied

Electrophysiological effects of lidocaine, l-chlorpheniramine, and bepridil on normal and ouabain-intoxicated canine Purkinje fibers.

We compared the electrophysiological effects of lidocaine, l-chlorpheniramine, and bepridil on both normal and ouabain-induced automaticity of canine Purkinje fibers. All three drugs suppressed the automaticity of spontaneously beating Purkinje fibers, but only lidocaine and bepridil reduced the amplitude of delayed afterdepolarizations induced by ouabain. Whereas lidocaine caused equal decreases in delayed afterdepolarization amplitude initiated at cycle lengths of stimulation between 1,000 and 250 ms, bepridil reduced their amplitude more at short than at long cycle lengths. Similarly, bepridil's but not lidocaine's effects on action potential characteristics were also dependent on the cycle length of stimulation; more marked decreases in amplitude and rate of rise of the action potential being observed at short cycle lengths. Lidocaine, alone, also markedly prolonged the period of overdrive suppression.

Action Potentials↗
PubMedDate not supplied

Effects of prolonged administration of oxprenolol on severity of ischaemic arrhythmias, enzyme leakage, infarct size, and intracellular cardiac muscle action potentials.

We examined the effects of prolonged oral administration of oxprenolol (twice daily for 6 weeks) to male Sprague-Dawley rats. At two times (1 or 16-18 h) after the last oral dose, the rats were anaesthetised and subjected to acute coronary artery ligation, and the severity of the resulting arrhythmias was assessed. Ischaemic damage was measured histochemically (using frozen section analysis by toluidine blue dye in nitrobluetetrazolium ) and by myocardial enzyme release. Cardiac muscle (atria and papillary muscle) was also removed and the transmembrane action potentials recorded using conventional microelectrode techniques. When coronary artery ligation was performed 1 h after the last oral dose (at which time there was evidence of substantial myocardial beta 1-adrenoceptor blockade), there was significant reduction in the severity of early arrhythmias, but no evidence that the severity of ischaemic damage was reduced or that the intracellular cardiac action potentials were modified. No protection was observed when coronary artery ligation was carried out 16 h after the last oral dose of oxprenolol. These results support our previous studies with acutely administered beta-adrenoceptor blocking drugs that myocardial beta-adrenoceptor blockade is the main factor involved in the protection afforded by such drugs against early ischaemic arrhythmias and that other possible effects, such as membrane stabilisation and action potential prolongation, are relatively unimportant in this model.

Action Potentials↗
PubMedDate not supplied

Antiarrhythmic and electrophysiological effects of ICS 205-930, an antagonist of 5-hydroxytryptamine at peripheral receptors.

We assessed the antiarrhythmic activity of ICS 205-930 [(3 alpha-tropanyl)-1H-indole-3-carboxylic acid ester], a selective antagonist at neuronal 5-hydroxytryptamine M-receptors, against the arrhythmias that occur following occlusion of the left main coronary artery in anaesthetised rats and subsequent release (reperfusion). The incidence of reperfusion-induced ventricular fibrillation and ventricular tachycardia was significantly reduced by pretreatment with ICS 205-930 (0.3 and 1.0 mg kg-1 i.v. and 10 and 30 mg kg-1 p.o.). The arrhythmias that occurred during 30 min of coronary artery occlusion were also less severe in animals given ICS 205-930 (1.0 and 5.0 mg kg-1 i.v.). Arterial blood pressure was not altered by the drug, and heart rate was only slightly reduced by the highest intravenous dose. In vitro, ICS 205-930 reduced the maximum rate of rise of phase 0 of normal sheep Purkinje fibre action potentials in concentrations from 0.5 to 5.0 mg L-1. Action potentials depressed by superfusion with a physiological salt solution modified to mimic the conditions occurring during mild ischaemia were similarly affected by ICS 205-930. The highest drug concentration studied under these conditions was 1.5 mg L-1 since, in combination with the modified physiological salt solution, this rendered some of the Purkinje fibres inexcitable. These results indicate that ICS 205-930 possesses marked antiarrhythmic activity against ischaemia-induced arrhythmias in anaesthetised rats and that a direct electrophysiological effect of the drug may, at least in part, underlie its protective action.

Action Potentials↗