David McCall

Electrocardiographic changes and cardiac arrhythmias in patients receiving psychotropic drugs

Eight patients had cardiac manifestations that were life-threatening in five while taking psychotropic drugs, either phenothiazines or tricyclic antidepressants. Although most patients were receiving several drugs, Mellaril (thioridazine) appeared to be responsible for five cases of ventricular tachycardia, one of which was fatal in a 35 year old woman. Supraventricular tachycardia developed in one patient receiving Thorazine (chlorpromazine). Aventyl (nortriptyline) and Elavil (amitriptyline) each produced left bundle branch block in a 73 year old woman. Electrocardiographic T and U wave abnormalities were present in most patients. The ventricular arrhythmias responded to intravenous administration of lidocaine and to direct current electric shock; ventricular pacing was required in some instances and intravenous administration of propranolol combined with ventricular pacing in one. The tachyarrhythmias generally subsided within 48 hours after administration of the drugs was stopped. Five of the eight patients were 50 years of age or younger; only one clearly had antecedent heart disease. Major cardiac arrhythmias are a potential hazard in patients without heart disease who are receiving customary therapeutic doses of psychotropic drugs. A prospective clinical trial is suggested to quantify the risk of cardiac complications to patients receiving phenothiazines or tricyclic antidepressant drugs.

Kinetics of thallium exchange in cultured rat myocardial cells.

The kinetics of thallium exchange in cultured rat myocardial cells were studied and compared to those of potassium in the same tissue. Studies were carried out using low concentrations (10 nM to 5 μM) of thallium-204, approximating those likely to be encountered during clinical myocardial scintigraphy. Both thallium uptake and release could be described by a single exponential with a half-time of exchange which was approximately half that of potassium and which was largely independent of extracellular thallium concentration. Some 60% of thallium uptake occurred via an “active” or ouabain-inhibitable mechanism which, in the absence of extracellular potassium, could be activated by low concentrations (10 nM to 5 μM) of thallium. The apparent Km for thallium on this active transport mechanism was 2–7 μm. Increasing extracellular potassium from 0–10 mM caused significant, concentration-dependent decreases in both the total and the active component of the thallium influx. Similarly nonradioactive thallium (0.10 μM to 0.10 mM) caused a concentration-dependent decrease in active potassium influx. Analysis of these results by both Lineweaver-Burk plots and Dixon plots confirmed competitive inhibition, potassium on thallium influx and vice versa, for the active component of the fluxes, and noncompetitive in the remainder. These findings indicate that active transport accounts for the greater portion of the influx of thallium and potassium, and that this active transport occurs via a common mechanism. If, as the results suggest, the receptor for thallium and potassium is the same, then the analysis by Dixon plots would indicate that the affinity of the receptor for thallium is 260 to 900 times greater than for potassium. This would therefore explain the rapid accumulation of thallium-201 by the myocardium, in vivo, from the low circulating concentrations of the isotope.

Effect of atriopeptin II on Ca influx, contractile behavior and cyclic nucleotide content of cultured neonatal rat myocardial cells

The present study was carried out to evaluate the effects of biologically active atriopeptin II (APII) in synchronously contracting monolayer cultures of rat ventricular myocytes. The effects of 10 nM APII on Ca influx, contractile behavior and cyclic nucleotide content of the cells were measured. Applied acutely APII had no effect on Ca influx. There was however a time-dependent effect such that after 30 min Ca influx (pmol/cm2/s) had declined from a control (mean +/- S.E.M.) of 1.53 +/- 0.16 to 1.02 +/- 0.07 (P less than 0.001; n = 6). There was parallel decline in both the magnitude and velocity of cell edge motion which was maximal in 30 min at which time cell edge motion measured 65.3 +/- 4.4% of control. Treatment with APII for 30 min decreased cAMP (pmol/mg protein) from 5.35 +/- 0.17 to 2.86 +/- 0.24 (P less than 0.001; n = 5). At the same time cGMP (pmol/mg protein) increased from 0.86 +/- 0.21 to 2.14 +/- 0.33 (P less than 0.001; n = 5). Further studies elucidated the fact that the decline in Ca influx and contractile behavior was dependent on the decrease in cAMP rather than the increase in cGMP. Pre-treatment of the cells with 5 ng/ml of pertussis toxin to ADP-ribosylate the Gi protein abolished the effects of APII on cAMP, Ca influx and contractile behavior. The results indicate that in myocardial cells, as in other cells, APII stimulates guanylate cyclase and inhibits adenylate cyclase. The resultant fall in cAMP decreases Ca influx and negatively influences the contractile behavior of the cells.

Haemodynamics and myocardial function after sotalol.

may occur (Nakano and Kusakari, I966; Blinks, I967). Sotalol (M.J., i999)l has been reported to be a beta-adrenergic blocking agent devoid of significant myocardial depression (Lish, Weikel, and Dungan, 1965; Levy and Richards, I965). Though studies of sotalol in man have been reported (Brooks et al., 1970; Svedmyr, Malmberg, and Haggendal, I970), little is known of the effect of this drug on myocardial contractility in patients with heart disease. The purpose of the present study was to assess the cardiovascular effects of sotalol with particular reference to myocardial contractility.

Ethanol effects on active Na+ and K+ transport in cultured fetal rat hepatocytes☆

To define further the influence of ethanol on membranes, its effects on Na+ pump function were studied in monolayer cultures of fetal rat hepatocytes. The effects of ethanol (2 and 4 mg/ml) on total K+ influx, ouabain-sensitive K+ influx, Na+ pump density (from specific [3H]ouabain binding), pump turnover rates and intracellular Na+ were measured following exposure of the cells to ethanol for 1-24 hr. In parallel studies, the effects of ethanol (2 mg/ml) on cell water content and membrane fluidity were measured. Ethanol had no immediate effect on K+ influx, but after 1 hr ethanol in concentrations of 2 and 4 mg/ml decreased the total K+ influx (mumol/10(11) cells/sec) from a control of 8.5 +/- 0.64 to 4.46 +/- 0.50 and 4.09 +/- 0.26 respectively (N = 6 for each experiment; P less than 0.001). This represented the maximum effect of ethanol since after 6 and 24 hr of ethanol treatment the K+ influx had increased towards control levels but remained significantly (P less than 0.01 for 2 mg/ml and P less than 0.001 for 4 mg/ml) below that in control cells even at 24 hr. The decrease in K+ influx reflected a decrease in mean ouabain-sensitive K+ influx from a control of 5.87 to 3.24 and 2.70 (mumol/10(11) cells/sec) after a 1-hr treatment with 2 and 4 mg ethanol/ml medium respectively. Ethanol (2 mg/ml) treatment for 1-hr decreased Na+ pump density (x 10(5) molecules ouabain per cell) from a control of 2.80 +/- 0.30 to 1.70 +/- 0.11 (P less than 0.001). At 6 and 24 hr [3H]ouabain binding showed a pattern similar to that seen with the K+ influx, tending to return to pretreatment levels. There was no change in individual pump turnover rates in the presence of ethanol. Following exposure to ethanol, cellular Na+ content steadily increased over the first 6 hr and then returned to control levels. When corrected for parallel changes in cell volume, however, intracellular Na+ concentration increased by 17% (P less than 0.01) after 1 hr and thereafter remained at this higher level throughout the 24-hr period. Measurements of membrane fluidity showed that it was increased markedly by ethanol at a concentration of 2 mg/ml and that the effect bore a close temporal relationship to the changes in active K+ influx and Na+ pump density. We conclude that ethanol has a depressant effect on hepatic Na+ pump function, resulting in an increase in intracellular Na+ and an eventual gain in cell water.(ABSTRACT TRUNCATED AT 400 WORDS)

The effect of ethanol and acetaldehyde on Na pump function in cultured rat heart cells.

To further define the sarcolemmal effects of ethanol and acetaldehyde, their effects on Na pump function were studied in synchronously contracting monolayers of neonatal rat myocardial cells. The effects of ethanol (10 mg/dl to 1000 mg/dl: 2 X 10(-3) M-0.2 M) and acetaldehyde (10(-6) M to 10(-4) M) on total 42K influx, ouabain-sensitive 42K influx, Na pump density (from specific 3H-ouabain binding) and pump turnover rates were measured. Applied acutely ethanol had no effect on 42K influx but after 30 min of treatment 42K influx was decreased by 13%, 23% and 48% in 100 mg/dl, 300 mg/dl and 1000 mg/dl ethanol respectively. This primarily reflected a decrease in mean ouabain-sensitive K+ influx from a control of 12.54 to 9.90, 8.95 and 6.68 (p-mol/cm2/s) in 100, 300 and 1000 mg/dl (2 X 10(-2) M, 6 X 10(-2) M) ethanol. Acetaldehyde in the concentrations tested had no effect on K+ influx. Ethanol treatment produced a decrease in Na pump density, maximum within 30 min and dose-dependent, at concentrations of 100 mg/dl (22%), 300 mg/dl (37%) and 1000 mg/dl (55%). Acetaldehyde had no effect on Na pump density. In the presence of ethanol (300 mg/dl and 1000 mg/dl) intracellular Na+ increased significantly and the Na+ efflux declined in parallel with the K+ influx. From the ouabain-sensitive K+ and Na+ fluxes and the Na pump density individual pump turnover rates were calculated at 62.5/s in control cells and 66/s and 84/s in cells treated with 300 mg/dl (6 X 10(-2) M) and 1000 mg/dl (0.2 M) respectively. We conclude that ethanol, but not acetaldehyde has a depressant effect on sarcolemmal Na pump function. The results suggest this is due primarily to a decrease in the number of sarcolemmal Na pump sites.

Recognition and management of asymptomatic patients with left ventricular dysfunction

In recent years there have been encouraging developments in the therapy for congestive heart failure. Vasodilator therapy, as an adjunct to digitalis and diuretics, has made a major impact. Vasodilator therapy results in improved left ventricular (LV) ejection fraction, improved functional capacity, and enhanced quality of life. When an angiotensin-converting enzyme (ACE) inhibitor is used, several studies published since 1988 show that these improvements are accompanied by improved survival. Yet many questions remain. Principal among these is how to approach the patient who has significantly depressed LV function, but is asymptomatic or has only minimal symptoms. In these patients the prognosis cannot be based on New York Heart Association (NYHA) functional class, but must reflect objective measurements of ventricular function. Any intervention should be specifically designed to improve survival, since functional capacity and quality of life are apparently unimpaired. On the other hand, there are no data at present to suggest that intervention in these patients will improve survival. This article considers the evaluation of such asymptomatic patients and potential therapeutic approaches. These are the use of cardiac glycosides, the use of ACE inhibitors, or their combination. Circumstantial evidence supporting their use in this select patient population is considered. It is stressed that any decision to intervene therapeutically in the asymptomatic patient must be made by the physician on an individual basis.

Effect of quinidine and temperature on sodium uptake and contraction frequency of cultured rat myocardial cells.

The effects of quinidine and temperature on Na influx and contraction frequency of synchronously contracting rat myocardial cells in mooolayer cultures were studied. Quinidine (10-6 M to 10-2 m) produced a prompt reduction in Na influx, maximum after 30 seconds of exposure, and dose-dependent along a sigmoid log dose-response curve. At 37°C, Na influx (&mgr;mol/1011cells per sec) decreased from 30.19 to 24.70 (p < 0.001)and 10.49(P < 0.001)on exposure to quinidine, 10-6 and 10-1 M, respectively. Simultaneously the contraction frequency decreased from a control of 120/min to 105/min and 48/min with 10-6 m and 5 × 10-4 M quinidine. At higher concentrations spontaneous contractions ceased. The effects on Na influx and contraction were reversible by washing the cells free of the drug (30 seconds). A temperature-dependent decrease in the Na influx between 37° C and 22° C also induced a decrease in contraction frequency. Between 25°C and 35°C the Q10 values for Na influx and contraction frequency were 2.41 and 2.44, respectively. Under all conditions tested there was a constant linear relationship (r = 0.98) between Na influx and contraction frequency for all values of Na influx greater than 11.82 &mgr;mol/1011 cells per sec. Na influx and contraction frequency were insensitive to tetrodotoxin (10-5 g/ml) but very sensitive to verapamil and to changes in extracellular Na. Quinidine affected only the verapamQ-sensitive Na influx. The results indicate a close relationship between rerapamil-sensitive inward Na movement and automaticity in these cells and demonstrate that the quinidine-induced changes in automaticity are closely linked to the effect on Na influx.

The effects of histamine on contraction frequency, sodium influx, and cyclic AMP in cultured rat heart cells.

Histamine has been shown to have both positive inotropic and chronotropic effects. To evaluate the chronotropic effects, spontaneously contracting monolayers of cultured rat myocardial cells were treated with histamine, 10−7 M-10−4 M. This resulted in a dose-dependent increase in contraction frequency reaching a maximum in 10−5 M histamine. Contraction frequency (mean ± SEM) increased from a control of 121 ± 5 contractions per minute to 153 ± 4.5,181 ± 9, 212 ± 4, and 216 ± 1 in 10−7 M, 10−6 M, 10−5 M, and 10−4 M histamine, respectively (for each n = 10, p < 0.001). The effect was time-dependent, taking 30 minutes to develop fully. Changes in contraction frequency were accompanied by parallel dose- and time-dependent increases in the verapamil-sensitive sodium influx. Verapamil-sensitive sodium influx (pmol/cm2/sec) increased from a control of 10.45 ± 1.44 (mean ± SEM) to 24.34 ± 2.41 and 32.57 ± 2.35 at 10- and 30-minute treatment with 10−6 M histamine (n = 5, p < 0.001). These data fit the previously described relation between verapamil-sensitive sodium influx and contraction frequency in these cells. Cimetidine (10−4 M) but not diphenhydramine (10−4M) abolished both the contraction frequency and sodium influx response to histamine. Subsequent studies showed a dose- and time-dependent elevation of cyclic adenosine monophosphate (cAMP) with histamine treatment. Cell cAMP (control = 5.25 pmol/mg protein) increased by 30%, 57%, 94%, and 224% in 10−7 M, 10−6 M, 10−5 M, and 10−4 M histamine, respectively, the changes between 10−7 M and 10−5 M closely paralleled the changes in beating rate and sodium influx. The histamine effect on cAMP was competitively inhibited by cimetidine. The results suggest histamine increases beating rate by increasing verapamil-sensitive sodium influx and that the effects are mediated by H2 receptors coupled to adenylate cyclase.

Precordial counting: evaluation and comparison of iodine-131 labelled albumin and technetium-99m in detection of left-to-right shunts.

Methods of precordial counting of radio-active isotopes in the detection of left-to-right intracardiac shunts are presented. Both iodine-131 labelled albumin and technetium-99m were used but the latter is preferred, especially for children, since it has a short physical half-life and emits a single gamma ray. Investigations were done to establish normal values and those in patients who had either rheumatic or congenital heart disease. All left-to-right shunts were confirmed at cardiac catheterization. False negative results were rare but false positive results can occur in the presence of congestive cardiac failure. It is possible to detect left-to-right shunts with a pulmonary to systemic flow ratio as low as 1·2:1 and an estimate of this ratio can be made from the precordial curve. The main value of the method is as a preliminary investigation in the detection of intracardiac shunts.