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Based on modulated receptor concepts, an agent with fast on-off sodium channel binding properties (e.g., lidocaine) may reverse the effects of a drug with slow on-off kinetics (e.g., cocaine) through competition for a single receptor site on the sodium channel. We compared the effects of two drugs with different sodium channel-binding kinetics with those of sodium bicarbonate, a known antidote, on cocaine-induced slowing of ventricular conduction. Electrocardiographic (ECG) intervals were recorded before and after the addition of cocaine 30 microM in 26 isolated, Tyrode-perfused guinea pig hearts. The effects of the three potential antidotes were then analyzed: equimolar lidocaine (8 hearts), equimolar quinidine (6), and sodium bicarbonate (8). Cocaine significantly increased all ECG intervals. The addition of lidocaine to cocaine-containing perfusate decreased QRS duration from 42 +/- 3 to 29 +/- 3 msec (p < 0.01), a 60% reversal. Addition of sodium bicarbonate to increase the pH of the perfusate from 7.37 +/- 0.09 to 7.52 +/- 0.08 (p < 0.01) decreased the QRS duration from 38 +/- 4 to 30 +/- 6 msec (p < 0.01), a 47% reversal. Addition of quinidine 30 microM augmented the effects of cocaine: QRS increased from 40 +/- 6 msec to 54 +/- 9 msec (p < 0.01). Consistent with modulated receptor concepts, lidocaine reverses slowed ventricular conduction due to cocaine. The magnitude of this reversal is similar to that due to sodium bicarbonate. The potential of fast on-off agents to serve as antidotes for cocaine-induced arrhythmias requires further study.

Ventricular arrhythmias due to cocaine may be related to its ability to slow ventricular conduction or prolong repolarization. We previously showed that lidocaine reversed QRS prolongation due to cocaine. The purposes of these experiments were to characterize cocaine's concentration-effect relationship on both ventricular conduction and repolarization, and to determine the effects of lidocaine on these relationships. The effects of lidocaine on cocaine-induced electrocardiographic changes were studied in 20 isolated, Tyrode-perfused guinea pig hearts. Variables at cocaine concentrations ranging from 3-195 microM were measured and repeated in the presence of a fixed concentration of lidocaine 30 microM. Using nonlinear regression analysis, the sigmoid Emax and simple Emax models were fit to cocaine concentration versus percentage change in QRS plots. Measures of best fit indicated that this relationship was best described by the sigmoid Emax model. Compared with cocaine alone, the curve for cocaine with lidocaine showed a greater EC50 (concentration at 50% of maximum effect) (59 vs 100 microM) but similar Emax (371 vs 367%), consistent with competition. Similar values were obtained from the linear transformation of the data. Cocaine concentration versus percentage change in the JTc interval showed a biphasic effect: concentrations below 65 microM prolonged JTc, but those above 65 microM had no effect or decreased JTc. In contrast to changes in QRS, addition of lidocaine increased the effects of cocaine on JTc: area under the concentration-effect curve for cocaine alone was 720 versus 859 microM% for cocaine with lidocaine. Lidocaine reverses cocaine-induced slowed ventricular conduction through competition for binding, but it appeared to increase cocaine-induced prolongation of repolarization.(ABSTRACT TRUNCATED AT 250 WORDS)

Using a dog model, a sublingual form of the free base of verapamil (SLV) was developed with the intent of avoiding stereoselective first-pass metabolism and the necessity of intravenous administration. Intravenous verapamil (IVV) 5 mg and SLV 40 mg or 60 mg were sequentially administered to seven healthy human volunteers. Electrocardiograms and serum concentrations were obtained before and periodically from 5 to 480 minutes after each dose. The time to peak serum concentration (mean +/- SD) was 77.6 +/- 38.1 minutes after SLV. Bioavailability of SLV was 58.2 +/- 36.9% compared to IVV. Verapamil half-lives after IVV and SLV were 2.83 +/- 0.93 and 2.28 +/- 0.45 hours (NS), respectively. In one subject, the time to peak effect was delayed and overall change in PR interval was minimum. In the remaining six subjects, the maximum percentage increases in PR interval after IVV and SLV were 20.6 +/- 6.4% and 14.8 +/- 5.5% (p less than 0.05), respectively. Times to peak increase in PR interval were 28.3 +/- 15.7 and 57.0 +/- 17.5 minutes after IVV and SLV (p less than 0.05), respectively. Analysis of plots of percentage change in PR interval versus serum concentration revealed a shift to the right and therefore, lesser effect of SLV than of IVV in six subjects. All seven subjects complained of oral numbness and bitter taste. In conclusion, SLV is inferior to IVV in terms of rate and extent of absorption and pharmacologic effect in delaying atrioventricular nodal conduction. Probably SLV has little clinical utility because of its slow onset and poor tolerance.

To evaluate the effects of calcium pretreatment on the disposition and electrocardiographic effects of verapamil, 8 healthy male volunteers received treatment in each of 3 phases in a randomized, double-blind, crossover manner. Phase I denoted 10 ml of 0.9% intravenous sodium chloride followed by 10 mg of intravenous verapamil; phase II denoted 10 ml of 10% intravenous calcium chloride followed by 4 ml of 0.9% intravenous sodium chloride; and phase III denoted 10 ml of 10% intravenous calcium chloride followed by 10 mg of intravenous verapamil. Blood samples for the determination of verapamil concentrations were drawn at 5, 10, 15, 20, 30, 45, 60 and 90 minutes, and at 2, 4, 6, 10 and 24 hours. Blood pressure, heart rate and PR intervals were also measured at these times. Pretreatment of verapamil with intravenous calcium did not alter the disposition of intravenous verapamil. Blood pressure was not significantly altered in any treatment phase, although calcium tended to increase mean arterial pressure and verapamil abolished this effect. Calcium had no significant affect on verapamil-induced PR prolongation (maximum percent change in PR interval: phase I = 19 +/- 11%, phase III = 18 +/- 7%; time to maximal prolongation: phase I = 0.38 +/- 0.21 hours, phase III = 0.37 +/- 0.26 hours; and area under the percent change in PR vs time curve: phase I = 15.5 +/- 10, phase III = 21 +/- 9). Verapamil caused a reflex increase in heart rate of similar magnitude in both phases I and III (24 +/- 10% and 21 +/- 7%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

A method for recording electrical activity of the sinoatrial (S-A) node and automatic atrial foci in human subjects is described. To record S-A nodal electrograms, an electrode catheter was inserted percutaneously into the femoral vein and advanced under fluoroscopic control to the superior vena caval-right atrial junction. The distal terminal of the catheter was placed in the area of the S-A node and the proximal terminal on the free right atrial wall or in the right atrial lumen. Polarity was reversed from the conventional electrocardiographic recording; high amplification (about 100 microV/cm) and selective filters (0.1 to 20 hertz) were used. S-A nodal electrograms recorded with this method in human subjects were similar to electrograms obtained previously from the dog and rabbit and revealed negatively directed diastolic and upstroke slopes preceding the P wave of the electrocardiogram. Sinoatrial conduction time measured from the S-A nodal electrograms in 15 cases was 34.9 +/- 2.1 ms(mean +/- standard error of the mean) for a sinus cycle length of 736.4 +/- 38.6 ms. The coronary sinus electrograms in a patient with coronary sinus rhythm were recorded by the same technique except that the distal terminal of the catheter was placed at the coronary sinus ostium. A negatively directed diastolic slope preceding the P wave was consistently recorded. This method for recording electrograms of the S-A node and ectopic automatic atrial foci should prove useful in (1) assessment of both normal and abnormal S-A nodal function, (2) direct determination of conduction time from the S-A nodal pacemaker to the atrium, and (3) localization of automatic atrial foci.

Recent reports have shown that it is possible to record extracellular electrograms from the rabbit and dog sinoatrial (SA) node. We applied similar techniques to record SA nodal activity in 23 patients who underwent cardiac surgery for various forms of heart disease. Both a bipolar technique, using pairs of electrodes at various interelectrode distances, and a unipolar technique, using an exploring and an indifferent electrode, were used. To record SA nodal electrograms, polarity was reversed from the conventional electrocardiographic recording; high amplification (100 microV/cm) and low-pass filters (0.15-20 Hz) were used. SA nodal electrograms were recorded from eight of 12 patients using the bipolar method and from nine of 11 patients using the unipolar method. There were no significant differences in the success rate or quality of the recording between the two methods. However, the unipolar method allowed a more accurate localization of the SA node. Human SA nodal electrograms resembled those of the dog and rabbit and showed two distinct slopes: a diastolic slope and an upstroke slope preceding the P wave of the ECG, SA conduction times were 32.4 +/- 2.8 msec (mean +/- SEM) at sinus (PP) cycle lengths of 587.6 +/- 35.6 msec for the bipolar method, and 38.2 +/- 3.2 msec at sinus (PP) cycle lengths of 712.2 +/- 50.7 msec for the unipolar method. These methods for recording of extracellular SA nodal electrograms in man may prove useful in 1) localization of the SA node during open heart surgery and 2) assessment of SA nodal function in health and disease.

We have identified extracell potential changes associated with the electrical activity of the canine sinoatrial pacemaker. Small nonpolarizable electrodes and low frequency high gain amplification were used to record unipolar electrograms from both the epicardial and the endocardial surfaces of the canine sinus node. Initially in vitro studies were performed so that transmembrane action potential changes could be recorded simultaneously with the extracell potentials. The sinus nodal electrogram showed two characteristic potentials when the electrode was in immediate proximity to pacemaking cells: (1) During phase 4 there was a steady slope of about -30 to -100 muv/sec, and (2) during the transition from phase 4 to phase 0 of the transmembrane action potential the slope of the electrogram increased smoothly to approximately -400 to -1,000 muv/sec. These potentials were followed by high frequency deflections as cells in the surrounding atrium depolarized. Tetrodotoxin (5 mg/liter) rendered the atrial muscle inexcitable and delayed and then abolished the high frequency activity in the sinus electrogram, which then appeared as a continuous smooth tracing similar to the sinus pacemaker action potential but reversed in polarity. We then recorded these small localized potentials from the in situ canine heart. Sinus nodal electrograms could be obtained from beating hearts with hand held probes on the epicardial surface and with conventional recording catheters on the endocardial surface. The results demonstrate that the canine sinus node gives rise to detectable and characteristic changes in extracell potential and suggest that similar potentials can be recorded from man to evaluate sinus nodal function.