Treating venous leg ulceration with complementary therapy.
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Acupressure↗
Biomedical subjects
M Gwilt
Publications and source records attributed to M Gwilt.
Pharmacological studies of K+ loss from ischaemic myocardium in vitro: roles of ATP-dependent K+ channels and lactate-coupled efflux.
Perfused guinea-pig hearts were rendered ischaemic by 95% reductions in coronary flow. K+ and lactate release over the first 6 min of ischaemia were reduced by glibenclamide (described as a K+ATP channel blocker), 2-deoxyglucose (inhibitor of lactate synthesis) and alpha-cyano-4-hydroxycinnamic acid (inhibitor of lactate transport). Glibenclamide did not selectively reduce K+ loss without affecting lactate release, as would be expected for a selective K+ATP channel blocker. During a single 30 min period of ischaemia, a secondary release of K+ was observed corresponding to the onset of ventricular fibrillation, with no associated increase in lactate efflux, which appeared sensitive to glibenclamide. In conclusion, glibenclamide failed to reduce K+ loss in early ischaemia without reducing lactate release as would be expected for a selective K+ATP channel blocker. Caution should be exercised when using glibenclamide as a specific blocker of K+ATP channels in the absence of measurements of metabolic parameters.
Adenosine Triphosphate↗
K(+)-channel blockers and coronary vasoconstriction in guinea-pig perfused hearts in-vitro.
Glibenclamide, glipizide and phentolamine, three drugs which have been reported to block ATP-dependent potassium channels, increased the coronary perfusion pressure in guinea-pig isolated hearts perfused at constant flow. Blockers of other types of potassium channels, 4-aminopyridine and UK-66,914, did not significantly increase perfusion pressure. Exposing hearts to a single concentration of 3 microM glibenclamide caused a greater degree of vasoconstriction than when this was preceded by lower concentrations. The 3 microM glibenclamide-induced vasoconstriction was reduced by prazosin (1 microM), mepyramine (0.1 microM) and ranitidine (10 microM) but not by a combination of mepyramine and ranitidine or by ritanserin (0.01 microM). These results suggest that a component of the vasoconstriction induced by glibenclamide may result indirectly from the release of vasoactive mediators.
4-Aminopyridine↗
Effects of drugs on ventricular fibrillation and ischaemic K+ loss in a model of ischaemia in perfused guinea-pig hearts in vitro.
In a perfused guinea-pig heart model of myocardial ischaemia, reducing coronary flow by 95% for four successive 6 min periods caused a reproducible net loss of K+ into the coronary perfusate. This was reduced in a concentration-dependent manner by ATP dependent K+ channel blockers (glibenclamide and glipizide) and calcium channel blockers (verapamil and nifedipine). Other K+ channel blockers (UK-66,914, 4-aminopyridine, R56865 and phentolamine) and beta 1-adrenoceptor and beta 2-adrenoceptor antagonists (betaxolol and ICI118551) did not reduce this loss significantly. A single 30 min low-flow period reliably induced K+ release and ventricular fibrillation in control hearts. Glibenclamide, glipizide and phentolamine suppressed ventricular fibrillation but not ischaemic K+ loss in this model. R56865 and 4-aminopyridine and coadministration of betaxolol and ICI118551 yielded similar results while UK-66,914 suppressed neither. In our model, modulation of ischemic K+ loss and suppression of ventricular fibrillation were not closely associated and appeared to occur via separate mechanisms.
4-Aminopyridine↗
Electropharmacology of dofetilide, a new class III agent, in anaesthetised dogs.
In open chest anaesthetised dogs, dofetilide increased the ventricular effective refractory period over the dose range 1-100 micrograms/kg i.v. and the ventricular fibrillation threshold at doses between 3-100 micrograms/kg and was 80-1000 times more potent than sematilide, racemic sotalol, d-sotalol or quinidine. The maximal increases in ventricular fibrillation threshold induced by sematilide and quinidine were less than that induced by the other drugs. A change in the character of the induced arrhythmia from true ventricular fibrillation to a rapid ventricular flutter, with frequent spontaneous conversion, was observed following all drugs. No adverse haemodynamic effects of dofetilide, sematilide or d-sotalol were observed, but quinidine induced marked cardiac depression and racemic sotalol also impaired left ventricular contractility. All drugs reduced heart rate, though the effect of racemic sotalol was clearly greater than that of the other agents. Dofetilide is a potent class III antiarrhythmic agent with antifibrillatory properties and a favourable haemodynamic profile.
Action Potentials↗
Dofetilide, a new class III antiarrhythmic agent, reduces pacing induced heterogeneity of repolarisation in vivo.
OBJECTIVES: The aim was to determine whether dofetilide, a new class III antiarrhythmic agent, could reduce the heterogeneity of repolarisation produced by rapid cardiac pacing and to compare it with quinidine. Increased heterogeneity of repolarisation times may be causally linked to malignant cardiac re-entrant arrhythmias. METHODS: Studies were performed in open chest, artificially ventilated, pentobarbitone anaesthetised beagle dogs of 13 to 15 kg body weight. Myocardial electrocardiograms were simultaneously recorded from 31 electrodes located on the left and right ventricular surfaces of the in situ canine heart. Recordings were obtained over a single cardiac cycle during rapid ventricular pacing at the maximum following frequency. Computer assisted measurements of activation time, activation-repolarisation interval, and repolarisation time were performed and the heterogeneity of these measurements calculated. Measurements were performed before treatment and after each incremental intravenous dose of dofetilide (3, 10, 30, and 100 micrograms.kg-1), quinidine (1, 3, and 10 mg.kg-1), or saline vehicle. RESULTS: Dofetilide increased repolarisation time via a selective prolongation of activation-repolarisation interval, activation time being unchanged. It reduced the heterogeneity of repolarisation time and activation-repolarisation interval, heterogeneity of activation time being unchanged. Quinidine increased repolarisation time by a non-selective increase of both activation-repolarisation interval and activation time. It increased the heterogeneity of activation times which offset a decrease in heterogeneity of activation-repolarisation intervals to produce no change in heterogeneity of repolarisation times. CONCLUSIONS: Dofetilide, but not quinidine, reduces pacing induced asynchrony of repolarisation in the canine heart and this effect may contribute to its antiarrhythmic activity.
Animals↗
Electrophysiologic properties of UK-66,914, a novel class III antiarrhythmic agent.
A class III antiarrhythmic agent that preferentially increases the effective refractory period without altering conduction velocity holds considerable promise for the treatment of life-threatening cardiac arrhythmias dependent on a reentrant mechanism. In the present study, the cellular electrophysiologic effects of a novel class III antiarrhythmic agent, UK-66,914, were evaluated. UK-66,914 prolonged action potential duration and extended the effective refractory period in isolated canine ventricular muscle and Purkinje fibers in a concentration-dependent manner, beginning at a threshold concentration of 0.1 microM. Analogous effects were found in isolated rabbit atrium beginning at a threshold concentration of 2 microM. At concentrations of UK-66,914 up to 20 microM there was no effect on the maximum rate of phase 0 depolarization (Vmax) or the amplitude of the action potential. In guinea pig papillary muscles. UK-66,914 at concentrations from 0.1 to 20 microM increased the effective refractory period at stimulation frequencies of 1 or 5 Hz, but did not slow conduction velocity. Therefore, UK-66,914 exhibits high selectivity for a class III antiarrhythmic effect in normal tissue. To elucidate the mechanisms responsible for the increase in effective refractory period, voltage clamp procedures were used in guinea pig ventricular myocytes. UK-66,914 reduced the amplitude of outward tail currents following depolarizing clamp steps with little effect either on the background K+ current or calcium currents, indicating that UK-66,914 selectively blocked the time-dependent potassium current. In anesthetized dogs, UK-66,914 (10 micrograms/kg to 1 mg/kg i.v.) prolonged both atrial and ventricular effective refractory periods, but in contrast to the studies performed in vitro, the minimum effective doses required to increase the effective refractory period in atria and ventricle were the same. Therefore, UK-66,914 is a potent selective class III antiarrhythmic agent, which owes its electrophysiologic profile to blockade of the time-dependent potassium current.
Action Potentials↗
UK-68,798: a novel, potent and highly selective class III antiarrhythmic agent which blocks potassium channels in cardiac cells.
UK-68,798 increased the duration and effective refractory period of cardiac action potentials recorded in vitro from canine ventricular muscle and Purkinje fibers in a concentration dependent manner from 5 nM to 1 microM. The resting membrane potential, amplitude and maximum upstroke velocity of action potentials were unaffected by UK-68,798, indicating the selective class III antiarrhythmic properties of this agent. UK-68,798 (5 nM-1 microM) increased the effective refractory period of isolated guinea pig papillary muscles at stimulation frequencies of 1 Hz and 5 Hz without influencing the conduction velocity, further confirming that UK-68,798 is devoid of class I antiarrhythmic activity including block of the sodium channel. Studies using single voltage clamped guinea pig ventricular myocytes indicated that UK-68,798 at concentrations of 50 nM and 2 microM blocks a time-dependent K+ current, with no appreciable effects on the time-independent K+ current or the inward calcium current. UK-68,798 is therefore a highly selective K+ channel blocking agent with class III antiarrhythmic properties, a profile that holds considerable promise for the therapy of life-threatening cardiac arrhythmias.
Action Potentials↗
Selective class III antiarrhythmic agents. 1 Bis(arylalkyl)amines.
A series of bis(arylalkyl)amines is described and their effects on prolonging effective refractory period in isolated cardiac tissue listed. Most compounds prolonged the cardiac action potential without significantly altering the maximum rate of depolarization and may be defined as selective class III antiarrhythmic agents. It was found that a particularly advantageous structural feature was to have a methanesulfonamido moiety on both of the aryl rings. Thus, compound 16 [1-(4-methanesulfonamidophenoxy)2-[N-(4-methanesulfonamidophene thyl)-N- methylamine]ethane] was selected for further investigations. The compound is highly potent and selective class III agent which acts by blockade of cardiac potassium channels.
Action Potentials↗
Comparative antifibrillatory effects of d- and dl-sotalol in normal and ischaemic ventricular muscle of the cat.
The aim of this study was to compare the effects of d- and dl-sotalol on the ventricular fibrillation threshold (VFT) and the effective refractory period (VERP) in anaesthetized cats subjected to coronary artery occlusion. Occlusion of the left anterior descending coronary artery caused a decrease in VFT (measured in mA) (1.40 +/- 0.1 to 0.6 +/- 0.1). dl-Sotalol (1 and 5 mg kg-1) increased VFT before the induction of ischaemia (1.7 +/- 0.1 to 33.8 +/- 1.0 and 38, respectively), and the higher dose prevented the ischaemia-induced fall in VFT. d-Sotalol (1 and 5 mg kg-1) caused only small increases in VFT in normal (1.9 +/- 0.3 to 2.3 +/- 0.3 and 2.6 +/- 0.3) and ischaemic (0.8 +/- 0.1 to 1.2 +/- 0.2 and 1.3 +/- 0.2) myocardium. Both d- and dl-sotalol increased VERP measured in normal myocardium. The % changes observed with 1 and 5 mg kg-1 of the racemate (17 +/- 1 and 57 +/- 4) were significantly greater than those with the d-isomer (8 +/- 3 and 16 +/- 2). dl-Sotalol, but not d-sotalol, prevented the haemodynamic responses to 50 ng kg-1 isoprenaline. These results suggest that VFT in anaesthetized cats is markedly increased by beta-adrenoceptor blockade and only marginally increased by the direct class III antiarrhythmic action of d-sotalol.
Adrenergic beta-Antagonists↗
High resolution on-line analysis of cardiac action potentials using a Motorola 68000 microcomputer.
We have developed a microcomputer system for the instantaneous on-line analysis of cardiac action potentials (APs) based on a Motorola 68000 microprocessor and 50 kHz A/D converter. This system can accurately analyze APs from all parts of the heart, including the extremely fast upstrokes of APs from Purkinje fibers. Facilities for tabulation of results, production of hard-copy plots of APs, pooling of experimental data, and statistical analyses are available off-line. The routine use of this system in our laboratory has greatly increased the accuracy and throughput of these time-consuming experiments.
Action Potentials↗
Action of antibodies directed against the acetylcholine receptor on channel function at mouse and rat motor end-plates.
1. The acute effects of antibodies (both polyclonal and monoclonal) raised against the acetylcholine receptor were studied at mouse and rat end-plates. Isolated muscles were incubated in solutions containing antibody for 2 1/4 to 3 1/2 h. Intracellular microelectrode techniques were then used to record miniature end-plate potentials (MEPPs) and voltage noise. 2. Most antibody preparations investigated did not reduce MEPP amplitudes as compared with controls. One monoclonal (C7) and one polyclonal (J) preparation irreversibly reduced MEPP amplitudes. Both preparations caused reductions in acetylcholine-induced depolarization and associated channel opening frequency (from voltage noise analysis). Single-channel depolarization was not altered by these antibodies. 3. On the basis of these and previous results, four antibody binding regions on the receptor surface were distinguished according to whether channel function and/or alpha-bungarotoxin binding were affected. Although most antibody preparations did not affect channel function, monoclonal antibody C7 appeared to alter function by acting on the channel itself so as to prevent channel opening.
Animals↗
Calcium channel blocking properties of amlodipine in vascular smooth muscle and cardiac muscle in vitro: evidence for voltage modulation of vascular dihydropyridine receptors.
Amlodipine was twice as potent as nifedipine at inhibiting Ca2+-induced contractions in depolarised rat aorta (IC50 1.9 nM vs. 4.1 nM) but, unlike nifedipine, displayed a very slow onset of action. Contractions induced by depolarising steps with 45 mM K+ were much less potently blocked by amlodipine (IC50 19.4 nM), whereas the potency of nifedipine was little changed (IC50 7.1 nM). This difference may be explained by a modulated receptor hypothesis, similar to that described for cardiac muscle, in which block of vascular calcium channels by dihydropyridines is enhanced at depolarized membrane potentials, such voltage-dependence only being apparent with a slow-acting drug such as amlodipine. Recovery from amlodipine block of K+-responses in rat portal vein after drug washout was also very slow. Amlodipine and nifedipine blocked phenylephrine-induced contractions of the rat aorta with potencies similar to those against depolarisation-induced responses. Negative inotropic potencies of amlodipine and nifedipine in perfused guinea pig hearts were approximately one-tenth those against Ca2+-induced contractions in rat aorta. Amlodipine caused complete block of guinea pig papillary muscle single-cell slow action potentials at a concentration (5 microM) that had no effect on upstroke velocity of normal, fast potentials but reduced the duration of the plateau phase.
Action Potentials↗
The effect of chronic neostigmine treatment on channel properties at the rat skeletal neuromuscular junction.
We have studied the effects of chronic neostigmine treatment on single channel properties at the rat skeletal neuromuscular junction. Rats received 0.86 mg kg-1 neostigmine (s.c.) daily for 9-11 days. Microelectrode recordings were then made from the extensor digitorum longus muscle. The amplitude of miniature endplate potentials was significantly reduced in muscles from neostigmine-treated rats as compared with controls. Acetylcholine (2-5 microM) applied in the bath produced a depolarization and associated channel opening frequency (from voltage noise analysis) which were significantly reduced in neostigmine-treated muscles with respect to controls. The depolarization resulting from the opening of a single channel (from voltage noise analysis) and single channel open time and conductance (from current noise analysis) were not significantly changed by chronic neostigmine treatment. It is concluded that chronic neostigmine treatment causes an adaptive reduction in the number of functional acetylcholine receptors at the endplate without otherwise affecting single channel properties themselves.
Animals↗
Lambert-Eaton myasthenic syndrome: electrophysiological evidence for a humoral factor.
Noncarcinomatous Lambert-Eaton myasthenic syndrome (LEMS) often associates with autoimmune disorders. A course of plasma exchange in both carcinomatous and noncarcinomatous LEMS induced clinical and significant electromyographic improvement which reached its peak 10 to 20 days after the last exchange. Prednisolone and azathioprine treatment was associated with striking clinical and electromyographic improvement in the 3 noncarcinomatous patients. The IgG fraction of LEMS plasma, and to a lesser extent plasma itself, injected daily intraperitoneally into mice induced similar electrophysiological changes to human LEMS, the reduction in the quantal content of the end-plate potential (epp) in diaphragm being highly significant. A train of stimuli at 40 Hz produced early facilitation or a less marked decline in epp amplitudes than occurred in mice injected with control IgG. The results indicate that the electrophysiological abnormalities in both forms of LEMS arise from an IgG autoantibody that binds to nerve terminal determinants which are concerned with the quantal release of transmitter.
Adult↗
Effects of action potential prolongation via different cellular mechanisms on the electrophysiological properties of rat and guinea-pig ventricular myocardium.
The effects of d-sotalol and the sea anemone toxin ATXII on the electrophysiological properties of rat and guinea-pig ventricular myocardium in vitro and on arrhythmias following coronary artery ligation in rat hearts in vivo were studied. ATXII (1-5 nM) prolonged the cardiac action potential of isolated papillary muscles and the effective refractory period of perfused hearts from both rats and guinea-pigs. In rat hearts, ATXII induced gross action potential prolongation and early afterdepolarizations at concentrations above 1 nM. In contrast, d-sotalol prolonged the action potential and effective refractory period of guinea-pig, but not of rat myocardium. Neither drug prevented arrhythmias in anaesthetized rats following coronary ligation.
Action Potentials↗