Biomedical subjects

I D Dukes

Publications and source records attributed to I D Dukes.

30 records · Page 2Linked to original sources

PubMed1991

Divalent cations modulate the transient outward current in rat ventricular myocytes.

The modulation of the transient outward K+ current (Ito) by divalent cations was studied in enzymatically isolated rat ventricular myocytes with the whole cell patch-clamp technique. At holding potentials negative to -70 mV, 1 mM Cd2+ suppressed Ito, whereas, at potentials positive to -50 mV, the current was augmented. These effects were caused by shifts in the voltage dependence of both activation and inactivation of Ito toward more positive potentials. Cd2+ also slowed the activation kinetics of Ito by shifting the voltage dependence of its rate of activation, but the rate of inactivation was unaffected. Other divalent cations produced similar shifts but at markedly different concentrations. Thus, in the millimolar range, a rightward shift of approximately 20 mV was produced by 3 Co2+, 5 Ni2+, and 10 Ca2+, whereas 10 microM concentrations of Cu2+ and Zn2+ produced equivalent shifts. Similar effects were seen in hippocampal neurons with micromolar concentrations of Zn2+. Thus divalent cations have marked and specific effects on the kinetics and voltage dependence of Ito and may serve as a regulatory mechanism in its activation, particularly in cells with resting potentials positive to -60 mV.

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PubMed1990

Tedisamil blocks the transient and delayed rectifier K+ currents in mammalian cardiac and glial cells.

The potassium currents in rat and guinea pig ventricular myocytes and mouse astrocytes were studied using tedisamil, a novel antiarrhythmic agent. A 1 to 20 microM dosage of tedisamil caused marked prolongation of the action potential in isolated rat ventricular myocytes, mimicking its reported effects on multicellular rat heart preparations. Under voltage clamp conditions, tedisamil caused a dose-dependent increase in the speed of inactivation of the transient outward K+ current (Ito), the predominant outward current in rat ventricular myocytes. In cardiac myocytes, the tedisamil block was neither use- nor voltage-dependent. The slow reversibility of drug action when applied from the outside, and its effectiveness when applied intracellularly, suggested an internal site of drug action. In guinea pig ventricular myocytes, tedisamil blocked the slowly developing time-dependent delayed rectifier K+ current (IK) over the same concentration range as that found for Ito in the rat myocytes. Tedisamil reduced this current without changing the characteristics of its slow (tau approximately 1 sec) activation. The effects of tedisamil on Ito and IK were independent of the phosphorylation state of the channel, as assessed by the equal effectiveness of the drug in the presence or absence of isoproterenol. Tedisamil also blocked the transient K+ current and the delayed rectifier current (IK) in mouse astrocytes over the same concentration range as that found in the cardiac myocytes and by a process that accelerated (transient K+ current) or mimicked (IK) inactivation. At concentrations of up to 50 microM, tedisamil had little effect on the time-dependent inward rectifier K+ current, or inward calcium current in rat or guinea pig ventricular myocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

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PubMed1989

Tedisamil inactivates transient outward K+ current in rat ventricular myocytes.

The action of tedisamil, a new bradycardiac agent with antiarrhythmic properties, was investigated in single rat ventricular myocytes using the whole cell voltage-clamp technique. Under current clamp conditions, 1-20 microM tedisamil caused marked prolongations of the action potential. Over the same concentration range, in voltage-clamped myocytes, tedisamil suppressed the transient outward current (ito) and enhanced its inactivation in a dose-dependent manner. The half-maximal dose for the effect of tedisamil on ito was approximately 6 microM. Tedisamil had no significant effects on the inwardly rectifying potassium current and calcium current but did suppress the sodium current at concentrations greater than 20 microM. Our findings suggest that tedisamil represents a new type of antiarrhythmic agent that primarily suppresses the transient outward K+ current.

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PubMed1985

Cardiovascular effects of bevantolol, a selective beta 1-adrenoceptor antagonist with a novel pharmacological profile.

Bevantolol was more potent in blocking the chronotropic than the hypotensive effects of isoprenaline in pithed rats. Bevantolol itself induced bradycardia, so that it was not possible to estimate the pA2 from nonparallel dose-response curves relating isoprenaline concentration to tachycardia. Bevantolol caused hypertension in pithed rats, an effect attenuated by phentolamine, implying that bevantolol may be an alpha-adrenoceptor agonist. Bevantolol potentiated the pressor effects of noradrenaline, the maximum potentiation equalling that produced by prior chemical sympathectomy with guanethidine, implying that bevantolol may block noradrenaline uptake. In isolated atria bevantolol-induced bradycardia was associated with a positive shift in take-off potential, a reduction in the maximum rate of depolarization (Vmax), and a lengthening of action potential duration (APD). No change in the slope of the slow diastolic depolarization occurred except at the highest concentration (18 mumol l(-1). In atrial and ventricular muscle bevantolol reduced Vmax and overshoot potential, implying reduction of fast inward sodium current (Class I antiarrhythmic action). In pithed rats bevantolol lengthened the P-R interval in the ECG, and produced atrioventricular (A-V) block, and bundle-branch block. In isolated A-V nodal preparations, intranodal conduction time was greatly increased, implying restriction of inward current through calcium channels responsible for nodal depolarization. Bevantolol had no negative inotropic effect in pithed rats, or in isolated atria, and did not alter the positive inotropic effect of raised extracellular calcium concentration, implying absence of restriction of current through calcium channels controlling contraction of the myocardium.

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PubMed1984

An analysis of the rate-dependent action of lidoflazine in mammalian sino-atrial node and Purkinje fibres.

Lidoflazine is an anti-anginal drug whose beneficial effect is to reduce the heart rate increment on exercise. Micro-electrode recording was performed in the spontaneously-beating, isolated guinea-pig sino-atrial node. It was shown that low concentrations (less than 5 X 10(-6) M) of lidoflazine alone did not alter action potential configuration or beating frequency. However, the drug reduced the spontaneous rate and the slope of the diastolic depolarization in the presence of catecholamine. This effect of lidoflazine was more pronounced at higher catecholamine concentrations. The action of lidoflazine on the hyperpolarization-activated current if was studied using a 2-micro-electrode voltage-clamp technique on shortened sheep Purkinje fibres. The activation curve for if was not affected by the drug. The slope of the fully-activated current-voltage relation was reduced by a mean of 20.1% on exposure to 5 X 10(-6) M lidoflazine. Using a computer model of Purkinje fibre action potentials, the observed reduction in maximal if conductance was shown to account quantitatively for the effects of lidoflazine. It is proposed that lidoflazine slows the heart by reducing the conductance of the if channel. This may be brought about by a fall in intracellular calcium concentration.

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PubMed1984

Resistance to hypoxia-induced shortening of action potential duration of hypertrophied rabbit hearts.

Cardiac hypertrophy was induced in rabbits at atmospheric pressure by exposing them to hypoxia equivalent to an altitude of 6000 m for 280 to 350 h. Intracellular action potentials were recorded from Purkinje cells, and from atrial and papillary muscles, contractions of which were also measured. Hearts from normoxic littermates were used as controls. All the hypertrophied tissues studied had increased action potential durations (APD), but other electrophysiological parameters were little changed. During periods of acute exposure to hypoxia in vitro APD shortened less in the hypertrophied hearts than in the controls. During intervals of normoxia, interposed between the periods of acute hypoxia, recovery of contractions and of all electrophysiological changes was complete. It was concluded that the hypertrophy did not cause associated electrical alterations likely to increase the risk of arrhythmias.

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PubMed1984

The multiple modes of action of propafenone.

Previous studies of widely different concentrations of propafenone in various species have reported that in addition to having class 1 antiarrhythmic action, the drug was a beta adrenoceptor blocker and a calcium antagonist. High concentration shortened action potential duration in animal experiments, but Q-T interval was reported as being lengthened in man. It was thought desirable to study the effects of propafenone over a range of concentrations equivalent to those used clinically in various cardiac tissues of a single species, the rabbit. It was concluded that although the primary action of propafenone was on fast inward current, the drug being categorised as of group 1c, its potency as a beta blocker was sufficient for the effect to be of clinical significance. Its potency as a calcium antagonist was relatively weak. Action potential duration and effective refractory period were lengthened in both atrium and ventricle, the effects being long-lasting and persisting on wash-out of the drug when other measurements had returned to control values.

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PubMed1984

Electrophysiological effects of alpha-adrenoceptor antagonists in rabbit sino-atrial node, cardiac Purkinje cells and papillary muscles.

The effects of prazosin, labetalol, and medroxalol were studied in the rabbit sino-atrial node, Purkinje cells and papillary muscles. At concentrations producing similar bradycardia, labetalol and medroxalol reduced the maximum rate of depolarization (Vmax) and overshoot potential in the sinus node. Prazosin had no such effects. These large and highly significant reductions in Vmax and overshoot in sinus node cells were observed at concentrations of medroxalol and labetalol which had no negative inotropic effect. If depolarization in the sinus node was due to the second inward current, this would imply that such currents in the sinus node and contracting cardiac muscle are pharmacologically distinct. All three drugs prolonged action potential duration in the sinus node, Purkinje cells and papillary muscles in a dose-related manner. Recovery after 1 h in drug-free solution from the effects of medroxalol and labetalol was only partial in the sinus node, but almost complete in Purkinje cells and papillary muscle. Recovery from prazosin was complete in all tissues. All three drugs depressed Vmax in Purkinje cells and papillary muscles in a dose-related manner, and recovery was complete. It is concluded that all three drugs had class 1 and class 3 antiarrhythmic actions, which could contribute to their protective effects in ischaemia and reperfusion independently of blockade of myocardial alpha-adrenoceptors.

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PubMed1984

Effects of selective alpha 1-, alpha 2-, beta 1-and beta 2-adrenoceptor stimulation on potentials and contractions in the rabbit heart.

Selective adrenoceptor agonists and antagonists have been used to analyse the effects of stimulation of individual types of adrenoceptor in various parts of the rabbit heart. The selective alpha 1- and alpha 2-adrenoceptor agonists used were St 587 and BHT 933 respectively, and the antagonists were prazosin (alpha 1) and WY 25309 (alpha 2). The selective beta 1- and beta 2-adrenoceptor antagonists were atenolol and ICI 118551, respectively. Pirbuterol was a highly selective beta 2-adrenoceptor agonist. The non-selective agonists noradrenaline, adrenaline and isoprenaline were also employed with various combinations of antagonists. Phenylephrine was found to stimulate beta- as well as alpha-adrenoceptors. Rimiterol was a beta-adrenoceptor agonist, partially selective for beta 2-adrenoceptors. In the sinus node beta 1-, but not beta 2-adrenoceptor stimulation increased the fast phase of depolarization (Vmax). Both beta 1- and beta 2-adrenoceptor stimulation increased the slope of slow diastolic depolarization, accelerated repolarization and increased maximum diastolic potential. After blockade of both beta 1- and beta 2-adrenoceptors alpha 1-adrenoceptor stimulation caused bradycardia, due exclusively to delayed repolarization. alpha 2-adrenoceptor stimulation had no effect. In Purkinje cells and papillary muscle both beta 1- and beta 2-adrenoceptor stimulation accelerated repolarization. Stimulation of alpha 2-adrenoceptors had no effect. Beta 1-, not beta 2-adrenoceptor stimulation augmented peak contractions 3-5-fold, and greatly increased rate of development of tension. After beta-blockade alpha 1-adrenoceptor stimulation moderately increased peak contractions (up to 47%), but increased time-to-peak and duration of contractions. These patterns of adrenoceptor-mediated effects were unchanged in animals pre-treated with sufficient 6-hydroxydopamine to eliminate responses to sympathetic nerve stimulation. The results would be consistent with beta 1-, and beta 2-adrenoceptor stimulation increasing inward calcium current, and with stimulation of alpha 1-adrenoceptors delaying its inactivation, rather than increasing its magnitude.

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PubMed1983

The absence of effect of chemical sympathectomy on ventricular hypertrophy induced by hypoxia in young rabbits.

Young rabbits, eight at a time, were exposed to 203 and 208 h (groups I and II) and 283 and 298 h (groups III and IV) of hypoxia (O2 at 70 to 80 mmHg), at atmospheric pressure. The animals were injected ip with 25 mg X kg-1 on the first day, and with 50 mg X kg-1 on the second day and every 48 h thereafter of guanethidine (G) or 6-hydroxydopamine (6-OHDA) (O), or an equivalent volume of saline (H = hypoxic controls, or N = normoxic controls). This regime of treatment abolished, in normoxic and hypoxic animals alike, the effect of sympathetic nerve stimulation on the pupil at voltages which produced maximum dilatation in control animals. Injection of atenolol reduced heart rate by 32% in control animals, but had no effect in the guanethidine treated animals, and a very small effect in the 6-OHDA treated group. The animals in each group were litter mates of those in the other groups. In the first series the dry weight of the hypoxic right ventricles increased, relative to the normoxic controls, by 38.8% (H), 40.5% (G) and 40.9% (O). There was no left ventricular hypertrophy in the hypoxic animals, but there was a small, but not statistically significant, rise in the haematocrit (Hct). In the second series the right ventricular hypertrophy was greater (+98% (H), +89% (G) and +102% (O]. There was also a significant left ventricular hypertrophy (+38% (H), +40.3% (G) and +41% (O] and a highly significant increase in haematocrit in all the hypoxic groups. The right atria were only slightly hypertrophied in the first series, but greatly hypertrophied in the second series (+103%, H), an effect attenuated by the treatment (+34%, G, and +39%, O). When each treated hypoxic animal was compared with its untreated hypoxic littermate (n = 12), the mean treated/untreated ratio for the right ventricular dry weight was 0.991 +/- 0.022 for the guanethidine group (n = 11) and 1.023 +/- 0.043 for the 6-hydroxydopamine (n = 11). Such identity of the extent of the hypertrophy in all the hypoxic groups, irrespective of the duration of hypoxia, implies that the hypertrophy was not conditional upon sympathetic activity.

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PubMed1983

Hypoxia-induced cardiac hypertrophy in rabbits treated with verapamil and nifedipine.

Young rabbits were exposed, eight at a time, to 310 h of hypoxia (O2 at 70-80 torr), at atmospheric pressure. The animals were injected with 1 mg kg-1 nifedipine (F) or 5 mg kg-1 verapamil (V) or an equivalent volume of the vehicle (H) (Cremophor EL), i.p. twice a day. A fourth group (N), also injected with vehicle, was not made hypoxic. The animals were from 6 litters, 6 rabbits in each litter, and were distributed so that every group had litter mates in the other groups. Right ventricular hypertrophy was induced in all the hypoxic groups (H, +39%; V, +46%; F, +44%). Differences between groups were not statistically significant, but all were significantly hypertrophied relative to their normoxic litter mates (N). The right atria were less hypertrophied (H, +3.6%; V, +20%; F, +21.6%), but there was no left ventricular or left atrial hypertrophy. There was also a small increase in haematocrit in the hypoxic groups (H, +20.6%; V, +17.5%; F, +28.8%). The doses administered were equivalent to the highest used clinically producing blood levels of verapamil and nifedipine within or above the clinical range and had no effect on the development of cardiac hypertrophy.

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PubMedDate not supplied

Electrophysiological and cardiovascular effects of pirmenol, a new class 1 antiarrhythmic drug.

Pirmenol, a new antiarrhythmic agent, has been studied in the pithed rat and in the sinoatrial (SA) node, atrium, atrioventricular (AV) node, Purkinje cells, and ventricular muscle of the isolated rabbit heart. It resembles disopyramide chemically and in its electrophysiologic effects. Pirmenol decreased the maximum rate of depolarization (MRD) and overshoot potential in isolated rabbit atrium, Purkinje cells, and ventricle. Pirmenol caused bradycardia in pithed rats and isolated rabbit SA nodes. In the latter, repolarization was delayed, but there was little change in MRD or in the slope of the slow diastolic depolarization. Like disopyramide, but unlike lidocaine, pirmenol lengthened APD in all cardiac tissues studied. The above effects were dose-related and were reversed on washout. Pirmenol did not lengthen conduction time within the AV node. Unlike disopyramide, pirmenol had no negative inotropic action, and did not alter the relation between contractile force and extracellular calcium concentration. This suggests, as does the absence of effect on sinoatrial MRD or AV conduction, that pirmenol does not block calcium channels.

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