Effects of sotalol on arrhythmias and electrophysiology during myocardial ischaemia and reperfusion.

Isolated, buffer perfused guinea pig hearts were used to study the effects of sotalol on arrhythmias and electrophysiology during 30 min of myocardial ischaemia, induced by reducing coronary flow to 10% of control, and subsequent reperfusion. Action potentials were recorded using the floating microelectrode technique and arrhythmias were noted and defined by extracellular electrical records. Sotalol 10(-4) mol X litre-1 reduced the incidence of ventricular arrhythmias during myocardial ischaemia and reperfusion. Prior to the onset of ischaemia sotalol reduced action potential amplitude and Vmax, and prolonged action potential duration, refractory period, and conduction time, and increased pacing threshold. During myocardial ischaemia the effect of sotalol on action potential duration disappeared, and that on refractory period was diminished. The effect of sotalol on action potential amplitude and Vmax was reduced during the early (2 to 12 min) part of ischaemia, but later, at the onset of arrhythmias, tended to reemerge, while the effect on QRS width was exaggerated. Thus the cellular electrophysiological effects of sotalol on normal myocardium provided a poor guide to the mechanism of its antiarrhythmic action in ischaemic tissue.

Effects of myocardial catecholamine depletion on cellular electrophysiology and arrhythmias during ischaemia and reperfusion.

The effect of myocardial catecholamine depletion on cellular electrophysiology and arrhythmias was assessed in Langendorff perfused guinea pig hearts during ischaemia and reperfusion. Myocardial noradrenaline was reduced to 0.17 +/- 0.04 microgram X g-1 by intracardiac injection of 6-hydroxydopamine (450 mg X kg-1 in six doses over 20 days) compared with 1.5 +/- 0.2 microgram X g-1 in vehicle injected controls. Myocardial catecholamine depletion significantly reduced the incidence of ventricular tachycardia and fibrillation during 30 min of global ischaemia and subsequent reperfusion. Myocardial catecholamine depletion prolonged action potential duration and refractory period during control perfusion and blunted ischaemia induced reduction in action potential amplitude, Vmax, and duration, but accentuated the prolongation in conduction time and QRS width. Catecholamine depletion abolished or attenuated reperfusion induced shortening of action potential duration and refractory period. Catecholamine depletion increased myocardial glycogen levels from 2.47 +/- 0.3 mg X g-1 wet weight to 4.39 +/- 0.3 mg X g-1; fasting animals for 48 h prior to study reversed this with no attenuation of the electrophysiological or antiarrhythmic action. These results provide further evidence that release of endogenous myocardial catecholamines contributes to the electrophysiological changes and arrhythmias associated with myocardial ischaemia and reperfusion.

Cardiac postjunctional supersensitivity to beta-agonists after chronic chemical sympathectomy with 6-hydroxydopamine.

The sensitivity to sympathomimetic amines of isolated atria removed from sham-injected and 6-hydroxydopamine-treated (6-OHDA) guinea-pigs was examined in the presence of an extraneuronal uptake blocker and an alpha-adrenoceptor antagonist. Three weeks of pretreatment with 6-OHDA resulted in leftwards shifts of the dose-response curves for the positive chronotropic and inotropic responses of right and left atria to isoprenaline. The responses to the partial agonist salbutamol were also potentiated after 6-OHDA pretreatment, revealed as an increase in the maximum response relative to isoprenaline. The supersensitivity was post-synaptic in origin and independent of changes in disposition or metabolism, since it was observed with agonists immune to neuronal uptake and O-methylation, and in the presence of extraneuronal uptake inhibition by metanephrine. It was also specific for the beta-adrenoceptor, no supersensitivity to histamine being found. In the right atria, the supersensitivity was partially masked by an opposing depressant effect after 6-OHDA pretreatment which was observed with histamine. Dissociation constants (KA) for the left atrial inotropic responses to orciprenaline were determined by use of the antagonist Ro 03-7894. Atria from 6-OHDA-pretreated animals were supersensitive to orciprenaline, but the KA value did not differ from that after sham injection. It could therefore be concluded that the increase in sensitivity was not due to an increase in affinity for the beta-adrenoceptor.

Polymorphous ventricular tachycardia due to alpha-blockade.

We report a case of polymorphous ventricular tachycardia caused by treatment with the post-synaptic alpha-blocking agent indoramin. This has not been reported with indoramin previously, nor to our knowledge with any other alpha-blocker. This pro-arrhythmic effect appears to be related to its class 3 anti-arrhythmic properties (QT interval prolongation) which is dose dependent, occurring only at large doses.

A microcomputer system for real-time analysis of cardiac action potentials.

A system for performing real-time analysis of cardiac action potentials has been developed using a microcomputer based on the Motorola 6800 central processor. Transmembrane potentials obtained using standard microelectrodes were digitized to 8 bits at 80 ms intervals, stored in cyclic memory buffer from which they could be selected for analysis, converted back to analogue form and displayed on an oscilloscope in real time. For each action potential, amplitude, the maximum rate of change of potential and the action potential duration at 50% repolarization and 100% repolarization were measured. In addition, conduction time (taken as the interval between the stimulus artefact and the action potential) was measured. All data were stored in memory and later printed, together with the time at which the recording was made. The system was designed for analysis of action potentials recorded using floating microelectrodes. The computer was controlled by three remote switches and a potentiometer, positioned close to the muscle bath. The program was written in Motorola 6800 assembly language and stored in erasable programmable read-only memory.

A microcomputer system for analysis of coronary artery calibre and blood flow.

Measurement of myocardial blood flow and assessment of coronary calibre in man has important clinical and research value. An inexpensive microcomputer system has been developed to facilitate analysis of each of these. Coronary sinus and great cardiac vein blood flow are measured using the thermodilution technique. The output of the temperature measurement circuitry is digitized and used to calculate blood flows. For coronary artery calibre measurement, the outline of an arterial segment recorded during coronary arteriography is digitized manually. The microcomputer system provides a graphic display of the digitized artery and calculates diameters throughout its length. Excellent correlations were observed between computer and manual methods for both systems.

Electrophysiological effects of alpha-adrenoceptor stimulation in normal and ischemic myocardium.

To investigate the mechanism by which alpha-adrenoceptor blocking drugs prevent ventricular arrhythmias associated with myocardial ischaemia and reperfusion, we studied the effects of alpha blockade, alpha-adrenoceptor agonists, and myocardial catecholamine depletion on arrhythmias and cellular electrophysiology during ischaemia and reperfusion in isolated perfused guinea pig hearts. Perfusion with phentolamine or indoramin significantly reduced ventricular tachycardia (VT) and ventricular fibrillation (VF) during ischaemia and reperfusion, and phentolamine was equally effective during reperfusion when added at the end of ischaemia. Both drugs prolonged action-potential duration (APD) and refractory period during ischaemia and reperfusion, and studies with phentolamine, in catecholamine-depleted hearts, indicated that its action was related to the presence of catecholamines. Myocardial catecholamine depletion also significantly reduced VT and VF during ischaemia and reperfusion. Perfusion with an alpha 1-adrenoceptor agonist, however, significantly reversed this antiarrhythmic effect, increasing the incidence of VT and VF during ischaemia and reperfusion. This arrhythmogenic effect was associated with a reduction in APD and refractory period, i.e., a reversal of the electrophysiological effects of catecholamine depletion. These results indicate that alpha-adrenoceptor stimulation is arrhythmogenic during myocardial ischaemia and reperfusion, and that the antiarrhythmic action of alpha-adrenoceptor antagonists is mediated via adrenergic rather than direct myocardial effects.

It's not cricket! Myocardial infarction following non-penetrating blunt chest trauma.

While playing a game of cricket, a 42-year-old man was struck on the chest by the ball. The blunt trauma precipitated a myocardial infarct in the absence of other risk factors or evidence of pre-existing coronary artery disease. Probable pathophysiological mechanisms and potential problems of immediate treatment are discussed.

Cardiac tamponade after thrombolysis.

Thrombolysis has been very effective in reducing the morbidity and mortality from acute myocardial infarction. Serious adverse events are not uncommon, however. We describe a case in which a haemopericardium and tamponade developed in a patient with a history of recurrent idiopathic pericarditis and to whom streptokinase had been administered following a suspected myocardial infarction. The case highlights the need for caution in the administration of thrombolytics to patients with a documented history of pericarditis.

Ward based X-ray facilities can improve services.

As part of a wider experiment, a satellite X-ray facility, run by 2 part-time radiographers (1 whole time equivalent), was established to provide all plain radiographs on inpatients in a patient focused unit of 114 beds created from 4 medical wards of a 370-bed district general hospital providing acute services to a local population of about 200,000. Fewer staff were needed to provide an X-ray and report on the ward, the number of steps was reduced from 54 to 42 and the time taken from 104 to 62 minutes. Radiographers spent a smaller proportion of their time on professional duties but freed up substantial time for other members of staff. The reactions of all involved, staff and patients, were favourable. With present technology, the patient focused approach brings net benefits and possibly decreases costs, but the balance may swing back to centralisation when picture archiving and communication systems (PACS) become more widely available.

The patient focused approach: a better way to run a hospital?

It can take 2 hours of hospital staff time to obtain a routine chest X-ray, up to 47 clinical staff may be involved with a patient during a 5-day stay, and only a quarter of total costs may be for direct patient care, so some hospitals are experimenting with patient focused care by relocating services such as X-ray to the bedside, training ward staff in a wider range of skills, and managing care itself by using multidisciplinary protocols. Potential benefits can be measured in terms of reduced process times and faster turn-round, but duplication of, for example, high-tech pathology and radiology equipment is expensive, as is releasing staff for training. Proponents say that higher quality patient care will result without increased cost, and theoretical analyses suggest that advantages should outweigh disadvantages. The more established patient focused units in the UK are now over a year old; practical analyses of their quality and cost are under way.

Clozapine associated dilated cardiomyopathy.

A 31-year-old white man was referred for investigation of a persistent sinus tachycardia. His only significant past medical history was of chronic schizophrenia for which he had been taking clozapine for six years. An electrocardiogram demonstrated sinus tachycardia, voltage criteria for left ventricular hypertrophy, and a prolonged QTc. Echocardiographic findings were consistent with a dilated cardiomyopathy. Serious cardiac complications of clozapine use are rare but have been reported previously. It is important to note that sinus tachycardia may be the only obvious clinical sign, and that complications can manifest months or even years (as in this case) after starting the drug. Patients on clozapine should be informed of potential cardiac symptoms and doctors should maintain a high degree of clinical suspicion throughout the duration of treatment.

Acute haemodynamic effects of felodipine during beta blockade in patients with coronary artery disease.

The acute effects of felodipine on left ventricular function and haemodynamics were studied in 11 patients with coronary artery disease. To block reflex sympathetic activation due to peripheral vasodilatation and to avoid effects secondary to changes in heart rate all patients received a standard regimen of beta adrenoceptor blockade and all measurements were made during sinus rhythm and right atrial pacing. At 30 minutes after an oral dose (0.075 mg/kg in solution) felodipine plasma concentration were 16.4 (3.5) nmol/l. A significant fall in systemic vascular resistance (30%) and increase in cardiac index (30%) occurred, whereas pulmonary vascular resistance was unchanged. Felodipine increased left ventricular ejection fraction and mean velocity of circumferential fibre shortening but had no effect on derivates of left ventricular pressure (dP/dt or dP/dt P-1) during sinus rhythm or pacing. Thus at the dosage used felodipine was a potent dilator of systemic arterioles but had no direct effect on left ventricular function.

What the SHO saw.

As discussions about junior doctors' training and duty hours continue, we have looked at the actual 'on take' case load and case mix of a medical senior house officer (SHO) in a district general hospital (DGH) over a six-month period. In our DGH, on a one in four rota, exposure to a few common conditions is high and exceeds the minimum requirements for a post to be approved for general professional training. Limited but useful experience may also be gained in the management of many other conditions. The benefits in terms of structured training and lifestyle resulting from the implementation of the Calman report and the junior doctors' hours initiative need to be set against a possible reduction in patient exposure and in the associated opportunities to learn that may occur with a decrease in SHOs' 'front line' exposure.

Antianginal and haemodynamic effects of alpha 1-adrenoceptor blockade.

We studied the effects of alpha 1-adrenoceptor blockade with indoramin on exercise tolerance in 15 patients with chronic stable angina using a double-blind crossover protocol. Thirteen patients had been receiving beta-adrenoceptor blocking drugs and nitrates. The therapy of these patients was continued unchanged throughout the study. Indoramin, in a dose of 25 mg three times daily, prolonged exercise duration by 17% (p less than 0.01) and increased oxygen consumption during exercise by 21% (p less than 0.01), while the maximal double product was unchanged. This increase in exercise capacity was associated with significant attenuation in ST segment depression during exercise. To investigate the mechanism of this antianginal effect, we studied the effects of indoramin (0.2 mg/kg i.v.) on coronary and systemic haemodynamics in a further 11 male patients with chronic stable angina who were receiving beta-adrenoceptor blocking drugs. Measurements were obtained during sinus rhythm and during atrial pacing from 100 beats/min, incremented by 20 beats/min at intervals of 3 min until the onset of angina. Indoramin had no effect on resting heart rate (64 +/- 2 vs. 67 +/- 2 beats/min), but did prolong pacing time to angina (7.4 +/- 0.7 vs. 5.4 +/- 0.5 min; p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Electrophysiological disturbances associated with acute myocardial infarction.

By the time most patients reach hospital with acute myocardial infarction the risk of developing ventricular fibrillation (VF) is receding and Q wave evolution is complete. While these changes are the culmination of a single irreversible ischaemic insult, this may follow several reversible episodes of ischaemia associated with marked ECG changes during the preceding hours or days and further ischaemic episodes may follow the development of Q waves. Cellular electrophysiological changes associated with experimental myocardial ischaemia in an isolated guinea pig preparation were a reduction in refractory period and action potential amplitude, Vmax and duration while conduction time and QRS width were prolonged. Spontaneous recovery in action potential amplitude and Vmax was observed after 12 min of ischaemia and depended on the presence of residual coronary flow. Electrophysiological recovery commenced rapidly on reperfusion but with further shortening of action potential duration. Reperfusion VF was most likely to occur when the associated ischaemic insult was 20-30 min in duration. Myocardial catecholamine depletion significantly reduced these arrhythmias and this antiarrhythmic action was associated with marked attenuation of the electrophysiological effects of ischaemia and reperfusion.

Changes in the haemodynamic responses to exercise, posture and nitrates after treatment of congestive heart failure with an arteriolar vasodilator.

1. Haemodynamic responses to exercise, posture and nitrates were measured before and after 8 weeks of therapy with an arteriolar smooth muscle specific calcium antagonist, nicardipine, in eight patients with congestive heart failure (New York Heart Association class II or III). 2. The acute haemodynamic effects of intravenous nicardipine before and after 8 weeks of oral therapy confirmed its vasodilating properties, with similar end-points to the initial response after the 8 week period. 3. After 8 weeks of oral therapy all patients improved by one New York Heart Association class and treadmill exercise duration was significantly increased. In contrast, sitting bicycle exercise duration was not prolonged, although, at the same peak workload, changes in cardiac output, stroke volume and systemic vascular resistance were significantly improved after 8 weeks of therapy. 4. Sublingual glyceryl trinitrate predominantly affected pulmonary vascular resistance before and after chronic therapy with nicardipine, although the effects were less marked after 8 weeks. In contrast, the systemic vascular effects of glyceryl trinitrate were significantly increased after 8 weeks of therapy with nicardipine. 5. Increased vasodilator responses to sublingual glyceryl trinitrate and exercise after chronic treatment with nicardipine, in the absence of significant residual vasodilatation at rest, suggests that indirect changes in systemic arterioles may accompany and possibly contribute to the clinical improvement in heart failure.

Arrhythmogenic and electrophysiological effects of alpha adrenoceptor stimulation during myocardial ischaemia and reperfusion.

To examine possible arrhythmogenic effects of alpha adrenoceptor stimulation, we studied the effects of methoxamine 10(-6) M on arrhythmias and cellular electrophysiology during global myocardial ischaemia and reperfusion in isolated Langendorff perfused guinea-pig hearts. To avoid interference from release of endogenous catecholamines during ischaemia or reperfusion, experiments were performed using catecholamine depleted hearts (myocardial noradrenaline = 11% of control). Catecholamine depletion markedly reduced the incidence of VT and VF during ischaemia and reperfusion and perfusion with methoxamine significantly reversed this. This arrhythmogenic effect of methoxamine was only observed during ischaemia or reperfusion, was independent of beta adrenoceptor blockade and H2 receptor blockade but was abolished by alpha adrenoceptor blockade with phentolamine. Catecholamine depletion blunted the ischaemia induced fall in action potential amplitude and Vmax and prolonged action potential duration and refractory period. Perfusion with methoxamine either partially or completely reversed these effects. Thus, alpha adrenoceptor stimulation has little effect on normally perfused myocardium, but may induce VT or VF during ischaemia or reperfusion.