Cellular mechanism underlying the efficacy of the sotalol-quinidine combination.

The combination of quinidine and sotalol is very effective in prevention of recurrent sustained ventricular tachycardia (SVT). The cellular mechanisms underlying this efficacy were examined in guinea pig papillary muscle, using standard microelectrode techniques and stimulation frequencies of 1, 2, and 3 Hz. Action potential duration (APD) and effective refractory period (ERP) were measured under control conditions, after 30-min perfusion with quinidine (5 microM) or sotalol (6 microM), and after an additional 30 min of quinidine + sotalol (5 and 6 microM, respectively). Quinidine, sotalol, and quinidine + sotalol all prolonged APD at 90% repolarization (APD90) by 9 +/- 1, 13 +/- 1, and 15 +/- 2%, respectively (at 3 Hz; p = NS, comparison of the three drugs; p < 0.05 for each drug as compared with control). Quinidine + sotalol prolonged ERP (at 3 Hz) by 27 +/- 2% as compared with 11 +/- 2% after sotalol and 18 +/- 2% after quinidine alone (p < 0.05). As a result, the ERP/APD ratio was increased by the combination to 0.87 +/- 0.2 (p < 0.05) as compared with 0.78 +/- 0.2 for control 0.79 +/- 0.1 for sotalol, and 82 +/- 0.1 for quinidine (at 3 Hz). Although sotalol alone decreased the maximum rate of depolarization of phase 0 of the AP (Vmax) by only 3 +/- 2% (p = NS), sotalol attenuated Vmax decrease of quinidine (at 3 Hz) from 40 +/- 4 to 16 +/- 3% (p < 0.05). Effects at 1 and 2 Hz were similar.(ABSTRACT TRUNCATED AT 250 WORDS)

The cellular electropharmacology of mexiletine in papillary muscles of guinea pigs chronically treated with amiodarone.

OBJECTIVE: The combination of mexiletine and amiodarone has proved useful in the control of serious ventricular arrhythmias, but the electrophysiological basis for their effectiveness in combination is unknown. The objective of this study was to compare the effects of mexiletine on action potential parameters of papillary muscles taken from guinea pigs chronically treated with amiodarone, with tissue taken from a control group. DESIGN: The effects of 12.5 to 200 microM mexiletine on action potential parameters of papillary muscles taken from guinea pigs chronically treated with amiodarone were compared with tissue taken from a control group, at frequencies of 1.0, 1.5 and 3.0 Hz, using standard microelectrode techniques. Onset of use-dependent block was assessed by 30 beat trains, and recovery from block by extrastimuli at diastolic intervals ranging from 200 to 5000 ms at both 1.5 and 3.0 Hz. ANIMALS: Eighteen four-week-old guinea pigs were randomly divided into two groups. One group received amiodarone in a loading dose of 20 mg/kg/day by intraperitoneal injection for one week, followed by 10 mg/kg/day for 15 weeks. The control animals were given equivalent volumes of dextrose intraperitoneally for 16 weeks. MAIN RESULTS: Mexiletine depressed the maximum rate of depolarization of phase 0 of the action potential (Vmax) in a concentration- and use-dependent fashion. Whereas chronic amiodarone treatment did not alter steady-state Vmax values, the extent of tonic Vmax depression induced by mexiletine was decreased, while use-dependent depression was increased. Mexiletine combined with amiodarone increased effective refractory period prolongation from 306.7 +/- 27.2 to 348.8 +/- 37.2 ms, while action potential duration shortening of mexiletine was moderated from 134.0 +/- 19.8 to 151.0 +/- 8.3 ms (to 90% repolarization at 3 Hz in the presence of 200 microM mexiletine).

The cellular electropharmacology of mexiletine combined with sotalol in porcine papillary muscle and Purkinje fibre. I. Alteration of mexiletine-induced Vmax depression.

Using standard microelectrode techniques, the authors compared the effects of 15 to 125 microM concentrations of mexiletine, 31 to 500 microM concentrations of sotalol and 15 to 125 microM of mexiletine combined with 125 microM sotalol, on the beat-to-beat maximum rate of depolarization of phase 0 of the action potential (Vmax) of porcine papillary muscles and Purkinje fibres stimulated by 30 beat trains at a frequency of 1 Hz. Sotalol alone had no effect on Vmax. Mexiletine caused both tonic and use-dependent depression of Vmax in papillary muscle. In the presence of sotalol, tonic Vmax depression was exaggerated, while use-dependent depression was attenuated. In Purkinje fibres, mexiletine exposure resulted in tonic Vmax depression, but no use-dependence could be demonstrated at this frequency. These results are best explained in the context of the modulated receptor hypothesis with the added consideration of two receptors--one within and one external to the sodium channel.

The cellular electropharmacology of mexiletine combined with sotalol in porcine papillary muscle and Purkinje fibre. II. Effects on action potential duration and refractoriness.

Using standard microelectrode techniques, the authors compared the effects of 15 to 125 microM concentrations of mexiletine, 31 to 500 microM concentrations of sotalol and 15 to 125 microM of mexiletine combined with 125 microM sotalol, on the beat-to-beat action potential duration and refractoriness of porcine papillary muscles and Purkinje fibres stimulated by 30 beat trains at a frequency of 1 Hz. Sotalol alone prolonged action potential duration and effective refractory period without altering their ratio. Mexiletine shortened action potential duration while prolonging refractoriness. When the two drugs were combined, action potential duration was shortened to the same extent as with mexiletine alone, but refractoriness, particularly in papillary muscle, was further prolonged. These changes suggest additive inhibition of the sodium window current by both drugs. Purkinje action potential duration was longest in the first beat of the train, while in papillary muscle, this beat was shortest. Exposure to either or both drugs eliminated the prolongation of duration of the first beat of the train in Purkinje fibre. Thus, the phenomenon of restitution, which prolongs the duration of the first beat after a long diastolic interval, appears also to be related to the sodium window current.

A comparison of the cellular electrophysiology of mexiletine and sotalol, singly and combined, in canine Purkinje fibers.

To determine if combinations of mexiletine and sotalol retain Class I and III electrophysiologic actions, using standard microelectrode techniques, we examined the electrophysiologic effects on canine Purkinje fibers of solutions of mexiletine (3.1-100 microM), sotalol (3.1-400 microM), and combinations of the two drugs, at stimulation frequencies of 1.5 and 2.0 Hz. The combinations consisted of 12.5 microM of one drug combined with 3.1, 12.5, and 50 microM of the other. Mexiletine caused a concentration dependent depression of Vmax, the degree of depression always being greater at the more rapid frequency. At concentrations above 50 microM, sotalol depressed Vmax slightly. Increasing the stimulation frequency did not result in further Vmax depression. The addition of sotalol did not alter the Vmax depression produced by mexiletine but prior exposure to sotalol attenuated the effect of subsequent mexiletine. Both drugs reduced action potential amplitude and in combination their effects on this parameter were additive. Sotalol prolonged and mexiletine shortened action potential duration. Low concentrations of mexiletine reversed the prolongation caused by sotalol, whereas the addition of sotalol did not alter the effect of mexiletine. Mexiletine shortened the effective refractory period at low concentrations and prolonged it at high concentrations. Sotalol prolonged the effective refractory period at all concentrations. Exposure to a low concentration of sotalol did not alter the effects on the effective refractory period of subsequent exposure to mexiletine but a low concentration of mexiletine reduced the prolongation from subsequent sotalol. Thus, the combination of mexiletine and sotalol may add a Class II action to the Class I effects of mexiletine but the mexiletine prevents the Class III effects of sotalol.

A simple BASIC program for constructing three-dimensional graphs.

This report describes a simple program for plotting three-dimensional curves and thus allowing a visual representation of the simultaneous interaction of three variables. Graphs can be displayed on the screen or printed using a graphics printer. The original data can be stored, printed, recalled and edited, as can the graph parameters. Completed graphs can also be stored for later review or printing. The program as outlined can accommodate up to 10 curves of up to 50 points each, but these limits can be easily increased. The program is written in BASIC, thus allowing it to be readily modified. As listed, the complete source code has 357 lines and occupies about 12 kilobytes when saved in compressed binary format.

The cellular electropharmacology of the simultaneous administration of propranolol and mexiletine: a class I and II antiarrhythmic drug combination.

The addition of propranolol to mexiletine may reduce the adverse effects of mexiletine and possibly increase its efficacy. We compared the cellular electrophysiologic effects of this combination with mexiletine and propranolol alone, over concentration ranges of 3.2 to 100 microM mexiletine and 0.80 to 25.0 microM propranolol, using standard microelectrode techniques and a stimulation frequency of 1.5 Hz. Mexiletine and propranolol both depressed the rate of rise of phase 0 (Vmax) with concentration-response curves of similar slope and a relative potency of 8:1, propranolol to mexiletine. Thus, combinations of 8:1 molar ratios of mexiletine to propranolol were assessed. The combination depressed Vmax to the same extent as mexiletine or propranolol alone. Mexiletine, propranolol and the combination all shortened action potential duration (APD) to the same extent. At low concentration mexiletine, propranolol and the combination shortened effective refractory period (ERP). At 25 microM mexiletine, this effect reversed and ERP began lengthening. The effect of the combination paralleled mexiletine while with propranolol alone the reversal did not occur until the highest concentration was reached. Mexiletine prolonged ERP relative to APD, an effect not shared by propranolol and attenuated with the combination (P less than 0.05). We conclude that combining propranolol with mexiletine does not alter any of the cellular electrophysiologic effects of mexiletine except the prolongation of ERP relative to APD. Although this may be an important antiarrhythmic effect, the extent by which in vivo concentrations of propranolol may reduce the clinical antiarrhythmic efficacy of mexiletine is likely to be negligible.

Persistence of the electrophysiologic effects of mexiletine in canine Purkinje fibers alters the response to subsequent hypoxia.

The persistence of cellular electropharmacologic effects of mexiletine on canine Purkinje fibers was studied utilizing standard microelectrode techniques and two different protocols. In the first, the tissue was exposed to hypoxic perfusion before and 30 min after perfusion with one of the following: mexiletine hydrochloride 6.25 microM solution, mexiletine hydrochloride 12.5 microM solution, or drug-free Tyrode's solution. With the higher concentration of mexiletine, depression of the maximal upstroke velocity (Vmax) persisted 30 min after drug washout and subsequent exposure to hypoxia did not result in the anticipated shortening of action potential duration but did prevent the restoration of normal Vmax. After perfusion with the lower concentration of mexiletine, Vmax was not depressed and hypoxic action potential duration shortening was not prevented. In the second protocol, Purkinje fibers were perfused with 12.5 microM mexiletine hydrochloride solution and then exposed to hypoxia after 15, 30, 45, or 60 min of perfusion with drug-free solution. Depression of maximal upstroke velocity and shortening of action potential duration persisted during washout, returning to control values by 45 min, although mexiletine was not detectable in the tissue bath after 10 min of washout. Hypoxia initiated at 15 or 30 min of washout failed to produce the anticipated shortening of action potential duration. At 45 and 60 min, action potential duration was shortened by hypoxia. We concluded that mexiletine depression of Vmax and shortening of action potential duration may persist in the absence of drug. Further shortening of action potential duration in response to hypoxia is prevented during this period. The persistence of Vmax depression is prolonged by hypoxia.

Apparent pacemaker malfunction due to ventricular blanking.

Electrocardiographic interpretation in patients with dual chamber pacemakers requires an intimate understanding of their manner of functioning. This report describes a patient whose pacemaker was suspected of malfunction because of failure to sense premature beats. This sense-failure resulted from the fortuitous concurrence of the sensed portion of the premature beat with the ventricular blanking period and was resolved by reducing the low rate limit of the pacemaker. Three principles must be recognized in interpreting suspected failure of sensing: 1. The channel of origin of the pacing artifact must be identified. 2. The surface QRS morphology does not necessarily correspond to the signal detected by the pacemaker. 3. Failure to sense does not necessarily equal pacemaker malfunction.

Effects of simultaneous administration of mexiletine and quinidine on the electrophysiologic parameters of canine Purkinje fibers.

The electropharmacologic effects of an equimolar combination of mexiletine and quinidine on canine Purkinje action potential parameters were compared with the effects of either drug alone in concentrations ranging from 0.31 to 5.0 X 10(-5) M. Six separate experiments were performed with mexiletine alone, quinidine alone, and the combination. At low concentrations, all three shortened action potential duration (APD) and effective refractory period (ERP) to the same degree; however, the combination depressed Vmax to the same extent as did solutions containing twice the concentration of quinidine alone even though mexiletine alone, in these concentrations, had no effect on the maximum rate of depolarization of phase 0 of the action potential Vmax. In higher concentrations, the combination depressed Vmax and prolonged the ERP to values midway between that achieved by the two drugs separately. Although increasing concentrations of mexiletine alone progressively shortened APD, the combination prolonged this parameter to values similar to those seen with twice the concentration of quinidine alone. The electropharmacologic effects of mexiletine and quinidine in combination are not simply additive and cannot be entirely predicted on the basis of a knowledge of their effects in isolation.

Comparative electropharmacology of mexiletine, lidocaine and quinidine in a canine Purkinje fiber model.

Although said to be lidocaine-like, there is evidence that mexiletine has some properties similar to those of quinidine. To evaluate the relationship between the effects of these three drugs we analyzed their effects on action potentials of Purkinje fibers from canine false tendons. Experiments with each drug were done on single preparations from each of six dogs over the concentration range 0.31 to 10.0 X 10(-5) M. Lidocaine shortened action potential duration and effective refractory period with a log concentration-response relationship. The maximum velocity of phase "0" (Vmax) was unaffected at low concentrations and only slightly depressed at high concentrations. Quinidine also shortened action potential duration and effective refractory period but the effect levelled off at midrange and was reversed at higher concentrations. Quinidine depressed Vmax throughout the concentration range studied. Mexiletine shortened action potential duration with a log concentration response relationship. Effective refractory period was shortened at low concentrations but the effect levelled off and then reversed at higher concentrations of the drug. Mexiletine had no effect on Vmax at the lower end of the concentration curve but did suppress this parameter at higher concentrations. Mexiletine resembled lidocaine in its effect on Vmax and action potential duration whereas the effects of quinidine on these two parameters were distinct. On the other hand, the effects of mexiletine on effective refractory period were more akin to quinidine than lidocaine.

Antiarrhythmic therapy in the elderly: pacemakers and drugs.

Investigations of syncope often fail to demonstrate any abnormality. However, in view of the ease of permanent pacemaker implantation and the potential dangers of recurrent syncope, patients with this symptom should receive pacemaker therapy. In general, acute therapy of any tachyarrhythmia associated with hemodynamic collapse consists of DC cardioversion, but skillful use of drug therapy and, occasionally, pacemaking are also highly important in preventing recurrences.

Differential electrophysiologic effects of mexiletine on normal and hypoxic canine Purkinje fibers.

We studied the effects of increasing concentrations of mexiletine on the active membrane characteristics of canine Purkinje fibers under normal and hypoxic conditions. Under normal conditions, there was a progressive shortening of action potential duration and a small decrease in maximum diastolic potential and overshoot potential. Effective refractory period was shortened by low concentrations but lengthened by higher concentrations. Only at the higher concentrations was Vmax decreased. When the tissue was rendered hypoxic, the shortening effect on action potential duration was attenuated. Low concentrations of mexiletine had a more pronounced effect on maximum diastolic potential and overshoot potential. The reversal of the effect on refractory period occurred at lower concentrations. The effect on Vmax was exaggerated. Hypoxia sensitizes Purkinje fibers to some of the electrophysiologic effects of mexiletine, but other effects are, in fact, attenuated in the presence of hypoxia.

The elderly patient in the coronary care unit: III. Factors affecting long-term prognosis.

Patients aged 70 years and older who were admitted to a coronary care unit in 1976 with documented acute myocardial infarction were followed to April 30, 1982. At that time, of the 46 patients who had survived initial hospitalization, 28 had died, 16 were still living, and two were lost to follow up. The actuarial survival rates were 71 per cent, 60 per cent, and 44 per cent for one, three, and five years, respectively. Only two of the variables available by history, physical examination, and clinical course of the patient in the coronary care unit had prognostic significance--complex ventricular premature beats and congestive heart failure of any degree of severity. Patients who suffered congestive heart failure during their hospitalization had a five-year survival rate of less than 25 per cent, compared with about 60 per cent for those who had neither heart failure nor complex ventricular premature beats. All five patients who had complex ventricular premature beats died within three years.

Pacemaker therapy in the seventies: interaction of patient age, time of implant, and indications for pacing.

In the 1970s, 707 patients received a primary pacemaker implant in our hospital. An analysis of the indications for pacemaker therapy revealed that one-third had third degree heart block, one-third had sick sinus syndrome and one-third had other indications. The distribution of indications was identical in all age groups. Furthermore, this distribution did not change from the first half of the decade to the second.

Interactions between a rapid atrial stimulator and a multiprogrammable ventricular demand pacemaker.

A patient with drug-resistant supraventricular tachycardia was well controlled for 8 years with a patient-activated rapid atrial pacemaker until she developed symptomatic bradycardic episodes. A multiprogrammable ventricular pacemaker was implanted. Assessment of the interactions between the two pacemakers demonstrated inhibition of VVI pacing by the atrial stimulator initially. Two months after implant no interaction was seen. At no time was VVT pacing affected by the atrial stimulator. Thus, interactions between these two units can occur and a multiprogrammable pacemaker should be used in this situation as it offers the flexibility to minimize any interaction that might be present.

Acute and chronic clinical performance comparison of a porous and a solid electrode design.

The long-term performance of porous and solid ring-tipped electrodes was compared in clinical use over a one-year period. Each of the two electrode designs was implanted in 22 patients in conjunction with an output-programmable pacemaker. Implant evaluation included impedance, height of sensed R wave, and a strength-duration curve. Threshold determination by pulse-width programming was performed at the time of implant and at one week, two weeks, two months, six months, and one year. There were no dislodgements with either electrode. No significant differences were noted in the acute parameters or in chronic thresholds.

Long-term results following coronary bypass operation. Importance of preoperative actors and complete revascularization.

The initial 102 patients who underwent aorta-coronary bypass grafting between 1969 and 1971 were followed for a mean of 96 months (minimum follow-up 7 years). Preoperative variables predictive of survival at 5 years were stability of angina, previous heart failure, and left ventricular function. Stability of angina, previous heart failure, previous myocardial infarction, and smoking were important predictors of symptomatic status at 5 years. At operation, 62 patients had anatomic or technically complete revascularization, whereas 40 had incomplete revascularization. There was a significantly improved survival rate in those patients who were completely revascularized. The 5 year survival rate was 84% for completely revascularized patients compared to 96% for incompletely revascularized patient (p less than 0.02). This improvement in survival was continued to 9 years. There was also a significant improvement in asymptomatic status of the completely revascularized patients compared to the incompletely revascularized patients. At 2 years, 75% of the completely revascularized subjects were asymptomatic compared to 45% of the incompletely revascularized patients. However, this difference disappeared after 5 years. Thus complete myocardial revascularization is superior to incomplete revascularization in terms of survival and asymptomatic state. Preoperative variables may be useful in predicting postoperative results.