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The goal of this prospective investigation was to study the course and the quality of patient-psychiatrist relationships during phase II / phase III clinical trials of antidepressant medication prescribed for depressive disorders. All patients who participated in the clinical trials (and subsequently in this survey) signed written informed consent statements and were subject to random double blind treatment assignment. Retrospective analysis of 118 investigations was carried out, and the patients involved were questioned concerning their experiences and impressions during and after the study. Data show that the outcome of clinical trials of antidepressant drugs are not a function of pre-existing good patient-psychiatrist relationships. On the other hand, no effects on the patient-psychiatrist relationship were found as a result of the experimental procedure, and it can be concluded that no detrimental effects on future patient-psychiatrist relationships were incurred.

Cisapride, a gastrointestinal prokinetic agent, has been associated with cases of Torsades de Pointes but its effects on the cardiac action potential have not been described. We investigated its electrophysiological effects on rabbit isolated Purkinje fibres. The results demonstrated that cisapride (0.01-10 microM) lengthened concentration-dependently the action potential duration without modifying other parameters and induced early after depolarizations and subsequent triggered activity. This typical class III antiarrhythmic effect, that showed "reverse" rate-dependence and was reduced by increasing external K concentration, can account for clinical arrhythmogenesis.

Tissues maintain O2 consumption (VO2) when blood flow and O2 delivery (DO2) are decreased by better matching of blood flow to meet local cellular O2 demand, a process that increases extraction of available O2. This study tested the hypothesis that ATP-sensitive K+ channels play a significant role in the response of pig hindlimb to ischemia. We pump perfused the vascularly isolated but innervated right hindlimb of 14 anesthetized pigs with normoxic blood while measuring hindlimb DO2, VO2, perfusion pressure, and cytochrome aa3 redox state. In one-half of the pigs, the pump-perfused hindlimb was also infused with 10 micrograms.min-1.kg-1 of glibenclamide, a potent blocker of ATP-sensitive K+ channels. Control animals were infused with 5% glucose solution alone. Blood flow was then progressively reduced in both groups in 10 steps at 10-min intervals. Glibenclamide had no effect on any preischemic hindlimb or systemic measurements. Hindlimb VO2 and cytochrome aa3 redox state began to decrease at a significantly higher DO2 in glibenclamide-treated compared with control pigs. At this critical DO2, the O2 extraction ratio (VO2/DO2) was 53 +/- 4% in the glibenclamide group and 73 +/- 5% in the control group (P < 0.05). Hindlimb vascular resistance increased significantly with ischemia in the glibenclamide group but did not change in the control group. We conclude that ATP-sensitive K+ channels may be importantly involved in the vascular recruitment response that tried to meet tissue O2 needs as blood flow was progressively reduced in the pig hindlimb.

Astemizole is a potent histamine H1-antagonist that has been associated with cases of life-threatening cardiac arrhythmias, including torsade de pointes and atrioventricular (AV) block. However, its effects on cardiac action potential (AP) has not been described. We examined the electrophysiological effects of astemizole on rabbit Purkinje fibers using conventional glass microelectrodes in parallel with the effects of the widely used histamine H2-antagonist cimetidine, selected because it has no known cardiac arrhythmic toxicity. Astemizole (0.01-3 microM) exerted a concentration-dependent prolonging effect on final repolarization that did not reach steady state after 3 h of exposure. This effect was more pronounced at low stimulation frequency and was less marked at high stimulation frequency. In addition, early afterdepolarizations (EADs) occurred in one third of the fibers. Increasing extracellular concentration of KCl (2.7-5.4 mM) or MgCl2 (1-5 mM) suppressed EADs and reversed the prolonging effect that was conversely exaggerated by decreasing KCl (4-2.7 mM) or MgCl2 (1-0.5 mM) concentration. At higher concentrations (3-30 microM), astemizole induced an increasing depressant effect on the maximal rate of depolarization (Vmax) that became more pronounced with high stimulation frequency. All parameters were strongly depressed at 10 microM astemizole, leading to cellular inexcitability in 5 of 12 fibers when exposed to 30 microM astemizole. In comparison, cimetidine induced minor changes on AP characteristics, i.e., a prolongation in plateau duration at high (30-100 microM) concentrations. These results provide evidence that astemizole exerts quinidine-like effects on cardiac APs that are compatible with the occurrence of the clinically observed arrhythmias.

Objectives: To determine the oxygen supply (DO2) and uptake (VO2) responses to a 60-min dobutamine infusion in critically ill septic patients without circulatory shock and with normal blood lactate concentrations. Also, to determine whether these responses would predict outcome., Design: Prospective, cohort study., Setting: Five intensive care units in university-affiliated, city hospitals., Patients: Fifty critically ill patients with sepsis syndrome were studied from April 1990 to August 1991., Interventions: Pulmonary artery catheterization; fluid loading if pulmonary artery occlusion pressure was < 10 mm Hg; and 10 micrograms/min/kg dobutamine infusion for 60 mins., Measurements and Main Results: Cardiac index, DO2, VO2, and oxygen extraction ratio were determined immediately before and 1 hr after the onset of the dobutamine test. Using receiver operating characteristic curves, responders to the dobutamine infusion were identified by a > 15% increase in VO2 from the time immediately before to 1 hr after the onset of the dobutamine test. We identified 23 responders and 27 nonresponders. Groups differed significantly in age (responders 46 yrs vs. nonresponders 55 yrs) and associated chronic disease (responders one cancer vs. nonresponders six cancers). Significant changes in responders were: a) cardiac index increased 42.9%; b) systemic vascular resistance decreased 20.7%; and c) DO2 increased 39.1% while VO2 increased 40.8%, with no changes in oxygen extraction or blood lactate concentration. Significant changes in nonresponders were: a) cardiac index increased 14.2%; b) DO2 increased 13.2% and c) oxygen extraction decreased from 0.26 to 0.22. Lactate concentration increased significantly by 25.1% in nonresponders. The mortality rate in responders (8.7%) was significantly less than that rate in nonresponders (44.4%)., Conclusions: Most of these septic patients without shock or hyperlactatemia responded to dobutamine infusion in one of two ways: with little increase in DO2 and no increase in VO2, or with significant increases in both DO2 and VO2. The latter response is typical of healthy volunteers given dobutamine. Because of the calorigenic effect of dobutamine, our results imply nothing about the presence or absence of oxygen supply limitation. Still, patients who had increases in DO2 and VO2 had a much higher survival rate than patients who did not. We speculate that the inability of some patients to respond to dobutamine and the associated higher mortality rate may be related to beta-adrenoreceptor dysfunction.

This study was designed to clarify discrepancies concerning the effects of droperidol on cardiac repolarization. Myocardial electrical activity was recorded by using microelectrode technique in rabbit Purkinje fibers and guinea pig ventricular muscle. In Purkinje fibers stimulated at 60 pulses/min, low concentrations (0.01-0.3 microM) of droperidol increased in a dose-dependent fashion action potential duration (APD) without altering the other parameters. At 1 and 3 microM, droperidol led to the reversal of the prolonging effect. The highest concentrations used (10 and 30 microM), produced shortening in APD at 50% repolarization concomitantly with a significant decrease in Vmax, action potential amplitude and resting membrane potential. Inexcitability occurred in 4 of 15 preparations exposed to 30 microM. In 8 of 15 Purkinje fibers, the prolonging effect induced by low concentrations was so important that APD exceeded the 1000-msec period of basal stimulation and early afterdepolarizations (EADs) and triggered activity developed. In guinea pig ventricular muscle, these effects were notably less pronounced. Prolongation of action potential showed a reverse use-dependence (i.e., much greater at the lowest stimulation frequencies), whereas Vmax depression was use-dependent. Decreasing extracellular K concentration from 4.0 to 2.7 mM enhanced the incidence of EADs in Purkinje fibers, whereas elevating the K concentration from 2.7 to 5.4 mM abolished them completely and shortened drastically APD. EADs were also eliminated by increasing magnesium concentration from 1 to 5 mM. Addition of isoproterenol favored EADs, whereas these were suppressed at plateau level by exposure to 0.3 microM nifedipine. The results indicate that in rabbit Purkinje fibers, droperidol exerts a dual effect on repolarization, prolongation with low concentrations with development of EADs and subsequent triggered activity. These abnormalities were suppressed at high concentrations concomitantly with a marked depression of other characteristics. These observations suggest multiple ionic channel activities and further studies are required to precise the underlying mechanisms at channel level.

Objective: Beta-blocking agents, particularly propranolol, are considered effective in the treatment of neuroleptic-induced akathisia, but considerable controversy exists about the involved receptor subtype(s). The authors conducted a randomized, controlled trial comparing the effects of propranolol and betaxolol to determine whether central beta 1-adrenoceptor blockade is sufficient to correct neuroleptic-induced akathisia., Method: The subjects were 19 patients whose neuroleptic-induced akathisia responded to 20 mg/day of propranolol and subsequently reemerged during a placebo washout period. They were randomly assigned to propranolol (20 or 40 mg/day) or betaxolol (10 or 20 mg/day) and, after another placebo period, were switched to the second beta blocker., Results: There was no significant difference in the antiakathisia effects of propranolol and betaxolol., Conclusions: The lack of difference between propranolol and betaxolol suggests that beta 1-adrenoceptor blockade is sufficient to improve neuroleptic-induced akathisia. The results of this explanatory study need therapeutic confirmation.

To evaluate whether the hydroxylated metabolites of quinidine (Q) and hydroquinidine (HQ): hydroxy-3S-quinidine (OH-Q) and hydroxy-3S-hydroquinidine (OH-HQ), exert electrophysiologic effects and participate in the therapeutic action of the parent drugs, we examined and compared the effects of the metabolites and the parent drugs on the electrical activity of guinea pig ventricular cells recorded by standard microelectrode technique. In addition, we investigated the potential arrhythmogenic properties of these compounds in rabbit Purkinje fibers in low K+ (2.7 mM) Tyrode's solution. The concentration [C]-, frequency-, and voltage-dependent effects of the drugs were investigated. Maximum upstroke velocity of phase 0 (Vmax) was [C]-dependently depressed by both OH-Q and OH-HQ but at a lesser degree than with Q and HQ, respectively: at the [C] of 50 microM, Vmax depression attained 26.7 +/- 2.6% with OH-Q versus 45.9 +/- 1.6% with Q and 32.3 +/- 1.9% with OH-HQ versus 54.6 +/- 1.4% with HQ. This effect was frequency and voltage dependent without significant differences between the four compounds. In the presence of equipotent [C], recovery kinetics of Vmax was significantly slower with metabolites than with respective parent drugs. In contrast, the effects of metabolites on action potential duration at 90% of repolarization (APD90) and effective refractory period (ERP) differed from those observed with parent drugs. With metabolites, APD90 and ERP were increased in a [C]-dependent manner, whereas the Q- and HQ-induced lengthening in APD90 and ERP was observed only at low concentration and low frequency. In addition, the OH-Q- and OH-HQ-induced APD90 lengthening was not altered by increasing pacing rate. In rabbit Purkinje fibers, increase in cycle length and prolonged exposure to either metabolites or parent drug caused early afterdepolarizations (EADs) and triggered activity. With all drugs tested, EADs arose more frequently at the plateau level than at the final repolarization of AP, but the incidence of EADs appeared to be much lower with metabolites than with parent drugs. The present results demonstrate that OH-Q and OH-HQ exert qualitatively similar but quantitatively less potent depressant effects on Vmax than Q and HQ, respectively, but differ in the lengthening effect on APD. We suggest that metabolites may participate in class I antiarrhythmic action of their respective parent drug and contribute to their arrhythmogenicity.

In 22 patients susceptible to and 34 patients not susceptible to malignant hyperthermia, we examined which muscle conditions may influence the degree of sensitivity of skeletal muscle to the in vitro caffeine contracture test: predrug resting membrane potential, predrug twitch tension, and maximum contracture induced by 32 mM caffeine in two caffeine tests performed respectively at 30 and 75 min after biopsy. No differences in the measured variables were observed between the first and the second caffeine tests in the 34 patients susceptible to malignant hyperthermia. The first caffeine test was found to be positive in all of the 22 patients susceptible to malignant hyperthermia. However, in eight patients, the second caffeine test was negative and the muscle fibers were found to be significantly depolarized. Resting membrane potential was -73.4 +/- 7.9 mV before the first caffeine test and -65.8 +/- 8.8 mV before the second test. We suggest that when time-induced partial depolarization of malignant hyperthermia-susceptible fibers occurs, fibers may become less sensitive to caffeine.

Formalin-fixed, paraffin-embedded tissue sections from 45 patients with mammary and extramammary Paget's disease were stained immunohistochemically with the use of a polyclonal antiserum directed against a 14-amino acid segment of the c-erbB-2 oncoprotein. Positive membrane staining, which correlates with gene amplification, was found in 15 of 19 cases (79%) of mammary Paget's disease, 4 of 13 cases (31%) of vulvar Paget's disease, none of 8 cases of scrotal Paget's disease, and none of 5 cases of perianal Paget's disease. Of the 19 patients with mammary Paget's disease, specimens of underlying breast tissue were available from 14; all contained a concurrent ductal adenocarcinoma. Concordance of c-erbB-2 antigen staining between the underlying breast carcinoma and the pagetoid component was observed in 12 cases. Of the 13 patients with vulvar Paget's disease, 2 had superficial stromal invasion, and 3 had underlying, deeply invasive adenocarcinomas. One superficially invasive case was positive for c-erbB-2 expression. One additional case of vulvar Paget's disease had an associated primary pagetoid endocervical adenocarcinoma that spread into the endometrium; both the endocervical and vulvar components stained positively for the c-erbB-2 antigen. The results of this study indicate that the c-erbB-2 oncoprotein may play a role in the pathogenesis of extramammary Paget's disease. These results also suggest that the c-erbB-2 oncoprotein may function in vivo to promote intraepithelial spread of adenocarcinoma cells.

In order to assess the utility of immunocytochemical staining of bile canaliculi with a polyclonal antiserum to carcinoembryonic antigen (pCEA) in the differentiation of primary hepatocellular carcinomas from metastatic malignancies, pCEA staining was performed on fine needle aspiration specimens from hepatic lesions in 60 patients. The original cytologic diagnoses were hepatocellular carcinoma in 22 patients, metastatic neoplasm or cholangiocarcinoma in 27 patients and benign hepatocytes in 11 cases. The cytologic diagnoses of malignancy were confirmed by surgical excision, autopsy or clinical investigations in 82% of the patients. Follow-up data, supported by pCEA staining, reversed the original cytologic diagnosis in three cases. Bile canalicular pCEA staining was identified in 18 of 22 cases of hepatocellular carcinoma and in all 11 benign hepatocellular aspirates. All 27 cases of metastatic malignancy or cholangiocarcinoma were negative for canalicular pCEA staining, although 11 cases exhibited cytoplasmic staining. Interpretation of pCEA staining was not affected by the intermingling of malignant cells and benign hepatocytes. Predictive values were 100% for a positive test and 87% for a negative test. These findings indicate that staining with pCEA antiserum is a useful adjunct in the differential cytologic diagnosis of malignant hepatic lesions.

As with any therapeutic intervention, in the evaluation of medical treatment of chronic cardiac failure, methods of assessing the efficacy of the drug (for example, measuring haemodynamic parameters) have to be distinguished from those designed to show therapeutic benefit (for example, prolongation of survival, quantified improvement in performance without excess mortality or deterioration in the quality of life). Studies of survival are long and costly and, as yet, have been conducted only in advanced stages of the disease. They are difficult to set up before the drug has been approved for general use i.e. when the only indication is the treatment of cardiac failure. If a criterion of substitution is not validated, the evaluation of the effects of the drug on quantified performances remains essential in pilot studies and phase 3 trials despite their artificial appearances. These trials are difficult to coordinate as they are usually multicenter and relatively prolonged (at least 6 months) studies.

The effects of diltiazem (1 microM) and nifedipine (1 microM) were examined separately on the in vitro halothane tests for malignant hyperthermia (MH) susceptibility. Eighteen patients with MH susceptibility were diagnosed as MH-susceptible (MHS) according to the protocol of the European MH Group. In addition, halothane tests were carried out in the presence of either diltiazem (ten patients) or nifedipine (eight patients). These two calcium channel blockers significantly reduced the halothane contracture. Furthermore, in five of the ten MHS patients tested in the presence of diltiazem as well as in five of the eight MHS patients tested in the presence of nifedipine the halothane contracture test could be classified as negative. It is concluded that the presence of clinical concentrations of either diltiazem or nifedipine in the muscle bath affects the in vitro discrimination for MH susceptibility to halothane.

We examined the effects of verapamil on the in vitro caffeine and halothane tests for malignant hyperpyrexia (MH) susceptibility. Ten consecutive MH-susceptible patients were investigated according to the protocol of the European MH group. Additional tests were carried out in the presence of verapamil 10(-6) mol litre-1. In four of the 10 patients, the halothane contracture response following pretreatment with verapamil was classified as positive to halothane. In contrast, in nine of the 10 patients, contracture tests of muscle in the presence of verapamil were classified as negative to caffeine. It is advised that verapamil should be discontinued before performing a contracture test.

In anesthetized dogs, digoxin intoxication was performed after and before production of a definitive complete atrioventricular (A-V) block induced by formaldehyde injection in A-V node area, compared to intoxication in dogs in sinus or junctional rhythm. The results showed that digoxin toxicity was decreased in dogs with previous A-V block. This A-V block protective effect was abolished by resetting initial sinus-like frequency with ventricular pacing before digoxin administration. Ventricular arrhythmias were suppressed by production of complete A-V block. The A-V block protective effect can be explained by a lesser myocardial uptake of digoxin because of the low idioventricular frequency. However, ventricular arrhythmias in dogs with A-V block presented similarities both in occurrence and spreading with the development of oscillatory afterpotentials (OAPs) and rhythmical triggered activity demonstrated in isolated digitalis-poisoned Purkinje fibers and ventricular myocardium: the repetitive discharge of toxic foci masked normal idioventricular pacemakers and was interrupted by variable pauses followed by the resumption of either a very slow idioventricular rhythm or a toxic focus. It is suggested that because of the low idioventricular frequency, competition and/or superimposition of slow enhanced diastolic depolarization and OAPs can be electrocardiographically displayed. The terminal event was asystole in dogs with unpaced A-V block, and ventricular fibrillation in dogs with sinus, junctional and paced A-V block rhythms. The asystole (at least 30 seconds of electrical quiescence) may be explained partly as an intense depression of normal idioventricular pacemaker being overdriven by the discharge of toxic pacemakers, and partly as a consequence of the suppression of local autonomic influences in the A-V node area induced by the formaldehyde injection.

This study determines, with quantitative variables, if propranolol is detrimental in patients with documented coronary arterial spasm and if this drug can be used in combination with calcium antagonists. Eleven patients with documented coronary spasm were entered prospectively in a study with 4 phases of 2 days each: (1) control, (2) diltiazem or propranolol (mean 225 +/- 75 mg/day), (3) propranolol or diltiazem (360 mg/day), (4) propranolol and diltiazem. The effects of the drugs were assessed by the detection of ischemic electrocardiographic episodes (24-hour electrocardiographic monitoring) and provocative tests with ergonovine. During the period of treatment with propranolol, the number and the duration of attacks increased and provocative tests had positive results in all patients. Diltiazem completely abolished spontaneous episodes, but 6 of 11 patients remained sensitive to the administration of ergonovine. The association of the 2 drugs led to a disappearance of ischemic episodes. In conclusion, propranolol is ineffective in patients with coronary artery spasm. It can be used in combination with diltiazem, but without any advantage over diltiazem alone.

Ten patients suffering from chronic premature ventricular complexes (greater than 60/h) were treated orally in a double-blind crossover study with encainide (50 mg three times a day) and disopyramide (200 mg three times a day), with five 7 day study periods: survey, placebo, encainide or disopyramide, washout placebo and disopyramide or encainide. At the end of each 7 day period, a 12 lead electrocardiogram, a 48 hour ambulatory electrocardiogram and a treadmill exercise test were performed. Blood levels of encainide and its metabolites and of disopyramide were measured at the end of each treatment (steady state). Drug efficacy was assessed by: 1) more than 80% reduction in the number of premature ventricular complexes per 24 hours, and 2) absence of ventricular tachycardia. Encainide was effective in four patients (complete suppression of premature ventricular complexes) and ineffective in five. One patient who showed a 92% reduction in the number of premature ventricular complexes developed sustained ventricular tachycardia after 24 hours of treatment. Disopyramide was effective in three patients (greater than 80% reduction in the number of premature ventricular complexes) and ineffective in seven patients. With encainide, the percent increase in PR, QRS and QT interval duration was, respectively: 32.7 (p less than 0.001), 30.8 (p less than 0.001) and 10.6% (p less than 0.01). With disopyramide this increase was not significant. Despite the variability of drug blood levels, a relation between blood levels and suppression of premature ventricular complexes on the 48 hour ambulatory electrocardiogram was found with encainide, but not with disopyramide.(ABSTRACT TRUNCATED AT 250 WORDS)

1. LND 623 and LND 796 are two aminosteroid derivatives which exert similar positive inotropic effects to digitalis. Their electrophysiological, toxic and inotropic effects were investigated in both normal and partially K+-depolarized ventricular muscle. 2. In guinea-pig myocardial fibres, LND 623 and LND 796 required tenfold higher concentrations than digoxin to induce the same signs of toxicity; e.g. triggered activities generated from delayed afterdepolarizations, leading to the marked depression of action potential characteristics and inexcitability. These abnormal rhythms and delayed afterdepolarizations were abolished by 1 mM caffeine. The toxic effects were reversed by washout, particularly in the case of LND 796. 3. In normal-K+ solution, LND 623 and LND 796 exhibited concentration-dependent positive inotropic effects on guinea-pig papillary muscle and increased concomitantly resting membrane potential and action potential amplitude. The range of active concentrations (0.1 to 1 microM) of LND 623 was larger than that of digoxin (0.3 to 1 microM). Like digoxin, LND 796 exerted negative inotropic effects at the lowest concentrations (0.01 to 0.03 microM) and positive inotropic effects at high concentrations (1 and 3 microM). 4. In partially K+-depolarized papillary muscle, in the presence of 2 microM histamine, LND 623 (3 and 10 microM) and LND 796 (10 and 30 microM) enhanced the two components P1 and P2 of the contraction and increased slow action potential amplitude, resting potential and maximal rate of depolarization. Low concentrations (0.03 to 0.3 microM) of LND 796 induced negative inotropic effects. beta-Adrenoceptor blockade with atenolol (1 microM) did not modify the activity of LND 623 but significantly enhanced the negative inotropic effect on P2 induced by 1 and 3 microM LND 796 and reduced the positive inotropic effect on P1 and P2 of the highest concentration (30 microM) studied. 5. In the presence of either caffeine (1 mM) or Ca2+-free, Sr2+-rich (3.6 mM) solution, LND 623 and LND 796 produced a positive inotropic effect which was stronger with LND 623. 6. It is suggested that two mechanisms are involved in the inotropic effects of these aminosteroids: (i) an enhanced Ca2 + entry via the slow calcium channels partially brought about by a local release of endogenous catecholamines in the case of LND 796, (ii) an inhibitory effect on Na+-K+ ATPase which, at the highest concentrations, lead to similar signs of cellular toxicity to those described for digitalis drugs. Because of their enlarged positive inotropic range, both aminosteroids may be of interest in the treatment of congestive heart failure.

The effects of prolonged exposure to combined mild hypoxia (Po2 230 +/- 20 mmHg) and acidosis (pH: 6.8 +/- 0.05) were studied in guinea-pig left ventricular myocardium superfused in vitro. Only Purkinje fibers were impaled by microelectrodes. Triggered activity developed in depolarized Purkinje fibers after 48 +/- 9 min of exposure to hypoxic and acid conditions and was initiated either by short periods of rapid electrical driving or by the background slow Purkinje automaticity. Triggered activity occurred when a delayed afterdepolarization attained its threshold potential and terminated after a subthreshold afterdepolarization. Interaction between triggered activity and slow background automaticity was observed until 90 to 180 min of exposure to hypoxic and acid conditions. These effects were reversed by replacement in standard conditions (Po2 510 +/- 20 mmHg; pH 7.35 +/- 0.05). Norepinephrine (1 X 10(-6)M) significantly accelerated the rate of discharge of triggered foci and led to a stable sustained triggered activity. Increasing extracellular Ca2+ concentration aggravated the effects of combined mild hypoxia and acidosis and led to the occurrence of early afterdepolarizations initiating triggered activity. In addition abnormal automaticity developed in quiescent fibers without any triggering action potential. Lidocaine and verapamil suppressed the triggered activity following a subthreshold afterdepolarization. Their effects were reversed on wash-out. It is concluded that prolonged exposure to combined mild hypoxia and acidosis induces triggered activity by a basic mechanism common to other situations leading to a calcium overload and showing such behaviour.

Ventricular strips of guinea-pig left myocardium were placed in a special tissue bath bisected by a thin membrane latex. One of the two compartments was flowed during 2 hours with modified Tyrode's solution in order to mimic the in vivo ischemia-induced effects. Replacement in standard conditions during 30 minutes was considered as representative of ischemic heart reperfusion. The second compartment was maintained in standard conditions throughout the experimental time course. Cellular electrical activity was recorded using standard microelectrode technique. Enzyme leakage was appreciated by creatine-kinase (CK) dosage in the effluent from each compartment. Ischemia induced well-known alterations in transmembrane action potentials and led fast-depressed action potentials and decremential responses to appear. Inexcitability occurred within 32 +/- 7 min of ischemia. CK leakage reached 80 +/- 10 I.U. per gram of myocardium dry weight (I.U./g dry) in ischemic chamber and 14 +/- 4 I.U./g dry in normal chamber. Three concentrations (1.10(-8) M, 1.10(-7) M, 1.10(-6) M) of nicardipine were studied. The two highest concentrations significantly decreased CK leakage and totally abolished decremential responses but did not modify the period while each stimulus elicited an action potential. During reperfusion, nicardipine did not significantly modify CK leakage but concentrations of 1.10(-7) M and 1.10(-6) M restored excitability in all preparations (versus 10 p. cent in control ischemia). Action potential characteristics but duration which remained inhomogeneously shortened, returned to almost normal values. The CK leakage decrease during ischemia and the recovery of excitability during reperfusion support a cardioprotective effect of nicardipine. A delay in ischemia-induced calcium overload via the voltage-operating channel is suggested as a possible mechanism for the beneficial effect of slow channel inhibitors.

We measured coronary sinus blood flow by continuous thermodilution technique and aortic pressure after administration of diltiazem to 23 patients with coronary artery disease. In one group of patients (n = 12) the drug was infused at a rate of 0.15 mg/kg during 2 min followed by an infusion of 0.05 mg/kg during 8 min. Heart rate was unchanged except at 5 min when it decreased slightly. Aortic pressure was significantly (p less than 0.01) decreased, while coronary sinus flow increased slightly and transiently. A second group of patients (n = 5) received an intracoronary injection of 0.15 mg/kg of diltiazem into the left coronary artery. In a third group of patients (n = 7) 0.05 mg/kg of diltiazem was injected into the left coronary artery. In both these two groups the drug induced a marked increase of coronary sinus flow and a decrease of aortic pressure, while myocardial oxygen consumption was unchanged. This effect was dose related, since the rise in coronary flow was 47% with an injection of 0.15 mg/kg but only 23% with a dose of 0.05 mg-kg. These changes were short-lasting with values returning to normal within 10 min after the injection. We conclude that diltiazem is a potent dilator of coronary arteries.

At the present time, there is no satisfactory pharmacological treatment for arrhythmia or conduction disorders induced by or aggravated by vagal hypertonia. The limited duration of action of the atropine derivatives currently available justifies the development of new compounds with expected longer acting duration. The aim of this study was to compare the effects of a single blind intravenous injection of ipratropium bromide to those of atropine sulfate in 22 patients. These patients were studied with continuous Holter recordings for three days. During the second and the third nights (patient sleeping), boluses of atropine (0.03 mg/kg) and of ipratropium bromide (0.03 mg/kg), respectively, were added to a continuous saline intravenous infusion. Accurate ECG analysis allowed determination of maximal heart rate peak, timing of maximal heart rate, variations in sinus cycle length, atrioventricular conduction, and durations of drug action. A nonsuggestive questionnaire was presented to patients to detect possible occurrence of side effects. The mean maximal heart rate rose significantly (p less than 0.001) for atropine (+46.2%) and for ipratropium bromide (+57.4%). The effects obtained with ipratropium bromide on the heart rate lasted nearly twice as long as those obtained with atropine (respectively, 120 +/- 38.4 min and 70 +/- 30 min- for the pharmacological half-life). Common minor muscarinic side effects (dryness of the mouth) were noted with the two drugs. In conclusion, this comparative intraindividual study confirmed the prolonged vagolytic effects of intravenous ipratropium bromide, which may be valuable in the treatment of patients with vagally mediated automaticity and conduction disturbances.

A number of different in vitro or in vivo experimental tests or models are now available for the demonstration of antiarrhythmic properties. In vitro electrophysiological studies on cells or healthy tissues usually establish the properties of antiarrhythmic agents, rather than their actual antiarrhythmic properties. New information has recently been provided by studies on abnormal tissues or tissues which have been made abnormal experimentally. The methods used to cause this dysfunction are discussed to determine their possible clinical relevance. There are over 50 in vivo arrhythmia models but only 2 or 3 are in common usage: aconitine or digitalis intoxication and experimental myocardial infarction (Harris' method and variants). The study of thresholds to ventricular fibrillation is more a study of an electrophysiological parameter than a study of an arrhythmia. Statistical studies require the uniformity of an experimental model and its stability (or relative stability) over a sufficiently long period from one animal or preparation to another. These conditions widen the gap between some experimental models and clinical reality. Present experimental models are essentially models of acute arrhythmias as experimental animals with chronic degenerative heart disease are not usually available (the problem of cardiomyopathic hamsters and Japanese woodcocks is discussed). The failure to appreciate the differences between species, the direct action of the drug under study (particularly on the autonomic nervous system), the hemodynamic changes induced by the experimental conditions, and the pharmacokinetics of the drug, often make extrapolations to clinical practice very difficult. Although the recent advances in our understanding of the mechanisms of arrhythmias derived from these models have not lead to any significant changes in the clinicians' attitude to the choice of antiarrhythmic therapy or to the introduction of new criteria of antiarrhythmic efficacity, none of the active antiarrhythmic agents used in clinical practice have been submitted to these antiarrhythmic screening tests. These models even provide an "honourable" classification of the relative efficacity of antiarrhythmic drugs.

Antiarrhythmic and cardioprotective effects of propranolol and sotalol were examined by studying their action on cellular electrical activity (recorded using standard microelectrode techniques) and creatine-kinase leakage (measured in the effluent from the experimental bath chamber) in the in vitro guinea-pig left ventricular myocardium exposed to conditions mimicking severe or moderate ischemia. Returning the tissue to the normal conditions was considered as equivalent to ischemic-heart reperfusion. Propranolol (2 X 4 mg/kg) was intraperitoneally administered to guinea-pigs, daily for 21 days. It was perfused in vitro (1.10(-6) M) during the whole experiments. Propranolol decreased action potential duration in control conditions (p less than 0,05), precipitated the occurrence of inexcitability during severe ischemia (p less than 0,01) and improved the recovery of cellular excitability during reperfusion. Propranolol did not significantly affect the creatine-kinase leakage during ischemia and reperfusion.

Arrhythmogenic effects of digoxin were studied in guinea pig ventricular myocardium driven at a low frequency, using microelectrode technique. Prolonged exposure to digoxin made two distinct phases of arrhythmias to appear: the first phase early occurred without apparent alteration in membrane diastolic potential of the impaled ventricular cells, the second phase was later initiated from oscillatory afterpotentials in diastolic potential. It is proposed that phase 1 of arrhythmias is initiated from oscillatory afterpotentials generated in Purkinje fibers more sensitive to digoxin-induced arrhythmogenic effects than myocardial cells. Phase 2 of arrhythmias would be originated in ventricular muscle fibers. Caffeine abolished oscillatory afterpotentials and suppressed sustained rhythmical activities of phases 1 and 2. The results indirectly confirm the important role of calcium movements between the myoplasm and sarcoplasmic reticulum in the origin of digoxin-induced arrhythmias triggered by oscillatory afterpotentials.

1. The electrophysiological effects of hypoxia alone or combined with subtherapeutic concentrations of procainamide superfusion were investigated in guinea-pig ventricular muscle fibres in order to elucidate the procainamide activity on suffering myocardial cells. 2. A first 30 minute-long hypoxia depressed action potential characteristics but never induced cellular inexcitability. These alterations were entirely reversible. A second consecutive hypoxia period similarly affected cellular activity. 3. After a control hypoxia period, procainamide 0.15 microM and 1.5 microM further depressed or abolished the hypoxia-altered transmembrane potentials. 4. In procainamide 0.15 microM and 1.5 microM pretreated cells, hypoxia more extensively depressed or abolished the myocardial cell activity than in unpretreated cells. 5. It has been demonstrated that antiarrhythmic drugs only slowly and incompletely reached the ischaemic myocardium. The present results suggest that in clinical situations, such weak concentrations may be efficient for inducing pronounced modifications in ischaemic areas and rapid antiarrhythmic effects.

Biphasic contractions were obtained in guinea-pig papillary muscle by inducing partial depolarization in K+-rich solution (17 mM) in the presence of 0.3 microM isoproterenol. Mn2+ ions inhibited the two components of contraction in a similar way. Nifedipine and particularly Cd2+ ions specifically inhibited the second component of contraction. Isoproterenol and BAY K 8644 markedly increased the amplitude of the second component (P2) of contraction. Nevertheless, a moderate positive inotropic effect of isoproterenol was found on the first component (P1) of contraction when excitability was restored by 0.2 mM Ba instead of isoproterenol. Acetylcholine and hypoxia decreased the amplitude of the second component of contraction to a greater extent. In the presence of digoxin or Na+-free solution, P1 was strongly increased. When sarcoplasmic reticular function was hindered by 1mM caffeine or in the presence of Ca2+-free Sr2+ solution, digoxin always induced a negative inotropic effect on P2. Inversely in these conditions the transient positive inotropic effect of Na+-free solution was strongly reduced. These results are consistent with the hypothesis that the late component of contraction is triggered by the slow inward Ca2+ current and that the early component is due to Ca2+ release from the sarcoplasmic reticulum.

Midalcipran is a new antidepressant drug inhibiting both noradrenaline and serotonin uptake without any postsynaptic and anticholinergic activities. Its cardiac effects were compared with those of imipramine, a tricyclic antidepressant drug. In anaesthetised guinea-pigs intravenous perfusion of imipramine and midalcipran (1 ml/min from a solution at 0.66 mg/ml) brought about ventricular arrhythmias, respectively at 16.5 and 26.4 mg/kg and cardiac arrest at 58 and 97 mg/kg. The safety index (ratio of i.v. lethal dose and ED50 evaluated by the yohimbine test) is 22 times wider for midalcipran than imipramine. In in vitro studies on guinea-pig ventricular myocardium, imipramine exerted a greater class 1 antiarrhythmic effect than midalcipran. The reduction of Vmax was significant at 3 X 10(-6) M for imipramine and 1 X 10(-5) M for midalcipran in normal (4 mM K+) and hyperpolarizing (2.7 mM K+) conditions. At the concentration of 1 X 10(-5) M midalcipran significantly lengthened, whereas imipramine non significantly shortened the action potential durations (APD50, APD90). The results provide confirmation of a lesser depression in sodium conductance with midalcipran as compared to imipramine. Therefore it is proposed that less adverse cardiac effects may be observed at therapeutic doses.

The neuroleptic malignant syndrome (NMS) is an uncommon but dangerous complication of treatment with neuroleptic drugs. A primary defect in skeletal muscle has been suggested in view of similarities in the clinical presentations of NMS and anaesthetic-induced malignant hyperthermia (MH). The in vitro halothane-caffeine contracture tests are the most reliable method of identifying individuals susceptible to MH. The aim of this study was to define if a relationship exists between NMS and MH susceptibility. Hence, the in vitro halothane and caffeine contracture tests were performed on muscle tissue obtained from eight NMS, ten MH-susceptible and ten control patients. The results, which are expressed in accordance with the criteria of the European MH Group, defined the eight NMS subjects as MH non-susceptible. The response to halothane and caffeine exposure of skeletal muscle from NMS and control subjects was the same and significantly different from that of muscle from patients susceptible to MH. Furthermore, muscle from subjects in NMS and control group responded similarly to increasing concentrations of chlorpromazine. These results do not point towards an association between NMS and MH.

Propafenone (Pf) is a class I antiarrhythmic drug that can be given both orally and intravenously. In order to examine whether its two major metabolites [5-hydroxypropafenone (5-OH-Pf) and N-depropylpropafenone (N-DP-Pf)] possess pharmacodynamical properties, we compared their electrophysiological effects to those of the parent drug on papillary muscle fibers from guinea pig ventricular myocardium. After baseline action potential and refractory period characteristics were measured at different pacing rates, the tissue preparations were superfused with either Pf, 5-OH-Pf, or N-DP-Pf at five different concentrations and electrophysiological characteristics were studied again. The maximal rate of depolarization (Vmax) was depressed by the three compounds only at the highest concentration, although the effect of N-DP-Pf was slightly less than the other two. Refractory periods were altered only by the highest concentration of 5-OH-Pf. Propafenone and N-DP-Pf exhibited equally slow on-set/off-set kinetics of the sodium channel block, whereas those of 5-OH-Pf were twice as long, which seems to suggest a slower rate of dissociation of the latter from the inactivated sodium channels. Thus, 5-OH-Pf and N-DP-Pf comply with the definition of the class IC antiarrhythmic drugs. The cumulative in vivo effects of the two metabolites and of the parent drug could have far reaching clinical implications, especially in the genetically predisposed extensive metabolizing subject.

Biphasic contractions have been obtained in guinea-pig papillary muscle by inducing partial depolarization in K+-rich solution (17 mM) containing 0.3 microM isoproterenol; whereas in guinea-pig atria, the same conditions led to monophasic contractions corresponding to the first component of contraction in papillary muscle. The relationships between the amplitude of the two components of the biphasic contraction and the resting membrane potential were sigmoidal curves. The first component of contraction was inactivated for membrane potentials less positive than those for the second component. In Na+-low solution (25 mM), biphasic contraction became monophasic subsequent to the loss of the second component, but tetraethylammonium unmasked the second component of contraction. The relationship between the amplitude of the first component of contraction and the logarithm of extracellular Ca2+ concentration was complex, whereas for the second component it was linear. When Ca2+ ions were replaced by Sr2+ ions, only the second component of contraction was observed. It is suggested that the first component of contraction may be triggered by a Ca2+ release from sarcoplasmic reticulum, induced by the fast inward Ca2+ current and (or) by the depolarization. The second component of contraction may be due to a direct activation of contractile proteins by Ca2+ entering the cell along with the slow inward Ca2+ current and diffusing through the sarcoplasm. These results do not exclude the existence of a third "tonic" component, which could possibly be mixed with the second component of contraction.