Benoit Drolet

Block of the rapid component of the delayed rectifier potassium current by the prokinetic agent cisapride underlies drug-related lengthening of the QT interval.

BACKGROUND Lengthening of the QT interval and torsades de pointes resulting in cardiac arrests and deaths have been noticed during treatment with cisapride, a newly developed gastrointestinal prokinetic agent. The rapid (I[Kr]) and slow (I[Ks]) components of the delayed rectifier current (I[K]) are candidate ionic currents to explain cisapride-related toxicity because of their role in repolarization of cardiac ventricular myocytes. Our objectives were to (1) characterize effects of cisapride on two major time-dependent outward potassium currents involved in the repolarization of cardiac ventricular myocytes, I(Kr) and I(Ks), and (2) determine action potential-prolonging effects of cisapride on isolated hearts. METHODS AND RESULTS A first set of experiments was performed in isolated guinea pig ventricular myocytes with the whole-cell configuration of the patch-clamp technique. Cells were held at -40 mV while time-dependent outward currents were elicited by depolarizing pulses lasting either 250 ms (I[K250]) or 5000 ms (I[K5000]). Effects of cisapride on the I(Kr) component were assessed by measurement of time-dependent activating currents elicited by short pulses (250 ms; I[K250]) to low depolarizing potentials (-20, -10, and 0 mV). Time-dependent activating currents elicited by long pulses (5000 ms; I[K5000]) to positive potentials (>+30 mV) were recorded to assess effects of the drug on the I(Ks) component. A second set of experiments was conducted in isolated guinea pig hearts buffer-perfused in the Langendorff mode to assess effects of the drug on monophasic action potential duration measured at 90% repolarization (MAPD90). Hearts were exposed to cisapride 100 nmol/L at decremental pacing cycle lengths of 250, 225, 200, 175, and 150 ms to determine reverse frequency-dependent effects of the drug. Overall, 112 myocytes were exposed to seven concentrations of cisapride (10 nmol/L to 10 micromol/L). Cisapride inhibited I(Kr), the major time-dependent outward current elicited by short pulses (I[K250]) to low depolarizing potentials, in a concentration-dependent manner with an IC50 of 15 nmol/L (therapeutic levels, 50 to 200 nmol/L). Conversely, block of I(Ks) by the drug was less potent (estimated IC50 >10 micromol/L). In isolated hearts (n=9 experiments), cisapride 100 nmol/L increased MAPD90 by 23+/-3 (P<.05) at a basic cycle length of 250 ms but by only 7+/-1 ms (P<.05) at a basic cycle length of 150 ms. CONCLUSIONS Block of I(Kr) gives an explanation to lengthening of cardiac repolarization observed in isolated guinea pig hearts. Potent block of I(Kr) is also likely to underlie prolongation of the QT interval observed in patients receiving clinically recommended doses of cisapride as well as severe cardiac toxicity (torsades de pointes) observed in patients with increased plasma concentrations of the drug.

Droperidol lengthens cardiac repolarization due to block of the rapid component of the delayed rectifier potassium current

Droperidol Blocks Cardiac IKr. Introduction: Torsades de pointes have been observed during treatment with droperidol, a butyrophenone neuroleptic agent. Our objectives were (1) to characterize the effects of droperidol on cardiac repolarization and (2) to evaluate effects of droperidol on a major time‐dependent outward potassium current involved in cardiac repolarization (IKr).

Sildenafil (Viagra) Prolongs Cardiac Repolarization by Blocking the Rapid Component of the Delayed Rectifier Potassium Current

BACKGROUND-Several cases of unexpected death have been reported with sildenafil in patients predisposed to ischemic cardiac events. Although acute episodes of ischemia could account for some of these deaths, we hypothesized that sildenafil may have unsuspected electrophysiological effects predisposing some patients to proarrhythmia. METHODS AND RESULTS-Studies were undertaken in 10 isolated guinea pig hearts that demonstrated prolongation of cardiac repolarization in a reverse use-dependent manner by sildenafil 30 mcmol/L. Action potential duration increased 15% from baseline 117+/-3 to 134+/-2 ms with sildenafil during pacing at 250 ms cycle length, whereas a 6% increase from 99+/-2 to 105+/-2 ms was seen with pacing at 150 ms cycle length. Experiments in human ether-a-go-go-related gene (HERG)-transfected HEK293 cells (n=30) demonstrated concentration-dependent block of the rapid component (I(Kr)) of the delayed rectifier potassium current: activating current was 50% decreased at 100 mcmol/L. This effect was confirmed using HERG-transfected Chinese hamster ovary (CHO) cells, which exhibit no endogenous I(K)-like current. CONCLUSIONS-Sildenafil possesses direct cardiac electrophysiological effects similar to class III antiarrhythmic drugs. These effects are observed at concentrations that may be found in conditions of impaired drug elimination such as renal or hepatic insufficiency, during coadministration of another CYP3A substrate/inhibitor, or after drug overdose and offer a new potential explanation for sudden death during sildenafil treatment.

Risperidone Prolongs Cardiac Repolarization by Blocking the Rapid Component of the Delayed Rectifier Potassium Current

Cases of QT prolongation and sudden death have been reported with risperidone, a neuroleptic agent increasingly prescribed worldwide. Although hypokalemia was present in some of these events, we hypothesized that risperidone may have unsuspected electrophysiologic effects predisposing patients to proarrhythmia. In six isolated guinea pig hearts, risperidone elicited prolongation of cardiac repolarization: action potential duration increased from a baseline value of 128 ms ± 5 to 147 ms ± 5 (15%) with risperidone 1 &mgr;M during pacing at 250-ms cycle length, whereas the increase was only 10%, from 101 ms ± 2 to 111 ms ± 4, with pacing at a cycle length of 150 ms. In human ether-a-go-go (HERG)-transfected Chinese hamster ovary cells (n = 16), risperidone caused concentration-dependent block of the rapid component (IKr) of the delayed rectifier potassium current with an IC50 for tail block of 261 n M. Risperidone did not block IKs. Risperidone exerts cardiac electrophysiologic effects similar to those of Class III antiarrhythmic drugs. These effects are observed at clinically relevant concentrations. Because risperidone is metabolized primarily by CYP2D6, these actions likely enhance risk for risperidone-related QT prolongation and proarrhythmia in specific patient subsets (e.g., poor metabolizers and those taking interacting drugs).

Pimozide (Orap®) Prolongs Cardiac Repolarization by Blocking the Rapid Component of the Delayed Rectifier Potassium Current in Native Cardiac Myocytes

Background: Several cases of QT prolongation and ventricular tachyarrhythmia have been reported with pimozide, a potent neuroleptic useful in the management of motor and phonic tics associated with Tourette syndrome. To further elucidate the mechanism underlying these clinical observations, the effects of pimozide on monophasic action potential duration (MAPD9O) and on potassium currents involved in the repolarization of native isolated ventricular myocytes were examined. Methods and Results: Studies were undertaken in eight isolated guinea pig hearts that demonstrated reverse rate-dependent prolongation of cardiac repolarization by pimozide 100 nmol/L. Action potential duration increased 24% from baseline 115 ± 2 to 142 ± 4 msec with pimozide 100 nmol/L during pacing at 250 msec cycle length, while a 10% increase from 97 ± 2 to 107 ± 3 msec was seen with pacing at a cycle length of 150 msec. Experiments in native isolated ventricular myocytes (n = 20) demonstrated concentration-dependent block of the rapid component (I,) of the delayed rectifier potassium current: tail current was decreased by 50% at 15 nmol/L. Conclusions: Pimozide possesses cardiac electrophysiological effects similar to those of class III antiarrhythmic drugs. These effects are concentration-dependent and observed at recommended dosages of the drug. Since pimozide is strongly metabolized by CYP3A4, special care should be taken to avoid potential pharmacokinetic interactions leading to high plasma levels of pimozide and proarrhythmia.

Human cardiac potassium channel DNA polymorphism modulates access to drug-binding site and causes drug resistance.

Expression of voltage-gated K channel, shaker-related subfamily, member 5 (KCNA5) underlies the human atrial ultra-rapid delayed rectifier K current (I(Kur)). The KCNA5 polymorphism resulting in P532L in the C terminus generates I(Kur) that is indistinguishable from wild type at baseline but strikingly resistant to drug block. In the present study, truncating the C terminus of KCNA5 generated a channel with wild-type drug sensitivity, which indicated that P532 is not a drug-binding site. Secondary structure prediction algorithms identified a probable alpha-helix in P532L that is absent in wild-type channels. We therefore assessed drug sensitivity of I(Kur) generated in vitro in CHO and HEK cells by channels predicted to exhibit or lack this C-terminal alpha-helix. All constructs displayed near-identical I(Kur) in the absence of drug challenge. However, those predicted to lack the C-terminal alpha-helix generated quinidine-sensitive currents (43-51% block by 10 microM quinidine), while the currents generated by those constructs predicted to generate a C-terminal alpha-helix were inhibited less than 12%. Circular dichroism spectroscopy revealed an alpha-helical signature with peptides derived from drug-resistant channels and no organized structure in those associated with wild-type drug sensitivity. In conclusion, we found that this secondary structure in the KCNA5 C terminus, absent in wild-type channels but generated by a naturally occurring DNA polymorphism, does not alter baseline currents but renders the channel drug resistant. Our data support a model in which this structure impairs access of the drug to a pore-binding site.

Impact of weight-loss medications on the cardiovascular system: focus on current and future anti-obesity drugs.

Overweight and obesity have been rising dramatically worldwide and are associated with numerous comorbidities such as cardiovascular disease (CVD), type 2 diabetes mellitus, hypertension, certain cancers, and sleep apnea. In fact, obesity is an independent risk factor for CVD and CVD risks have also been documented in obese children. The majority of overweight and obese patients who achieve a significant short-term weight loss do not maintain their lower bodyweight in the long term. This may be due to a lack of intensive counseling and support from a facilitating environment including dedicated healthcare professionals such as nutritionists, kinesiologists, and behavior specialists. As a result, there has been a considerable focus on the role of adjunctive therapy such as pharmacotherapy for long-term weight loss and weight maintenance. Beyond an unfavorable risk factor profile, overweight and obesity also impact upon heart structure and function. Since the beginning, the quest for weight loss drugs has encountered warnings from regulatory agencies and the withdrawal from the market of efficient but unsafe medications. Fenfluramine was withdrawn from the market because of unacceptable pulmonary and cardiac adverse effects.Nevertheless, there is extensive research directed at the development of new anti-obesity compounds. The effect of these molecules on CVD risk factors has been studied and reported but information regarding their impact on the cardiovascular system is sparse. Thus, instead of looking at the benefit of weight loss on metabolism and risk factor management, this article discusses the impact of weight loss medications on the cardiovascular system. The potential interaction of available and potential new weight loss drugs with heart function and structure is reviewed.

Prolongation of cardiac ventricular repolarization under paliperidone: how and how much?

Introduction: Paliperidone (9-hydroxyrisperidone) is a second-generation antipsychotic. As observed with risperidone, QT interval prolongation was reported with paliperidone. Objective: The aim was to evaluate the effects of paliperidone on cardiac ventricular repolarization. Methods: (1) Patch-clamp experiments: Human ether-a-go-go-related gene (HERG)- or KCNQ1 + KCNE1-transfected cells were exposed to 0.1-100 μmol/L paliperidone (N = 39 cells, total) to assess the drug effect on HERG and KCNQ1 + KCNE1 currents. (2) Langendorff perfusion experiments: Hearts isolated from male Hartley guinea pigs (N = 9) were exposed to 0.1 μmol/L paliperidone to assess drug-induced prolongation of monophasic action potential duration measured at 90% repolarization. (3) In vivo cardiac telemetry experiments: Guinea pigs (N = 8) implanted with transmitters were injected a single intraperitoneal dose of 1 mg/kg of paliperidone, and 24-hour electrocardiogram recordings were made. Results: (1) The estimated concentration at which 50% of the maximal inhibitory effect is observed (IC50) for paliperidone on HERG current was 0.5276 μmol/L. In contrast, 1 μmol/L paliperidone had hardly any effect on KCNQ1 + KCNE1 current (4.0 ± 1.6% inhibition, N = 5 cells). (2) While pacing the hearts at cycle lengths of 150, 200, or 250 milliseconds, 0.1 μmol/L paliperidone prolonged monophasic action potential duration measured at 90% repolarization by, respectively, 6.1 ± 3.1, 9.8 ± 2.7, and 12.8 ± 2.7 milliseconds. (3) Paliperidone (1 mg/kg) intraperitoneal caused a maximal 15.7 ± 5.3-millisecond prolongation of QTc. Conclusions: Paliperidone prolongs the QT interval by blocking HERG current at clinically relevant concentrations and is potentially unsafe.

Decreased CYP3A expression and activity in guinea pig models of diet-induced metabolic syndrome: is fatty liver infiltration involved?

Background: In humans, CYP3A drug-metabolizing enzyme subfamily is the most important. Numerous pathophysiological factors, such as diabetes and obesity, were shown to affect CYP3A activity. Often considered a precursor state for type II diabetes, metabolic syndrome exerts a modulating role on CYP3A, in our hypothesis. Objective: To evaluate the effect of metabolic syndrome on CYP3A drug-metabolizing activity/expression in guinea pigs. Methods: Hepatic microsomes were prepared from male Hartley guinea pigs fed with a control, a high-fat high sucrose (HFHS) or a high-fat high fructose diet (HFHF). Domperidone was selected as a probe substrate of CYP3A and formation of four of its metabolites was evaluated using high-performance liquid chromatography. CYP3A protein and mRNA expression were assessed by Western blot and reverse-transcription quantitative polymerase chain reaction, respectively. Hepatic fatty infiltration was evaluated using standard Oil Red O staining. Triglyceride and free fatty acid liver content were also quantified. Results: Microsomal CYP3A activity was significantly decreased in both HFHS and HFHF diet groups versus the control diet group. Significant decreases of CYP3A mRNA and protein expression were observed in both HFHS and HFHF diet groups. Oil Red O staining showed a massive liver fatty infiltration in the HFHS and HFHF diet groups, which was not observed in the control diet group. Both triglyceride and free fatty acid liver content were significantly increased in the HFHS and HFHF diet groups. Conclusion: Diet-induced metabolic syndrome decreases CYP3A expression/activity in guinea pigs. This may ultimately lead to variability in drug response, ranging from lack of effect to life-threatening toxicity.

QRS widening and QT prolongation under bupropion: a unique cardiac electrophysiological profile

QRS widening and QT prolongation are associated with bupropion. The objectives were to elucidate its cardiac electrophysiological properties. Patch‐clamp technique was used to assess the IKr‐, IKs‐, and INa‐blocking effects of bupropion. Langendorff retroperfusion technique on isolated guinea‐pig hearts was used to evaluate the MAPD90‐, MAP amplitude‐, phase 0 dV/dt‐, and ECG‐modulating effects of bupropion and of two gap junction intercellular communication inhibitors: glycyrrhetinic acid and heptanol. To evaluate their effects on cardiac intercellular communication, fluorescence recovery after photobleaching (FRAP) technique was used. Bupropion is an IKr blocker. IC50 was estimated at 34 μm. In contrast, bupropion had hardly any effect on IKs and INa. Bupropion had no significant MAPD90‐modulating effect. However, as glycyrrhetinic acid and heptanol, bupropion caused important reductions in MAP amplitude and phase 0 dV/dt. A modest but significant QRS‐widening effect of bupropion was also observed. FRAP experiments confirmed that bupropion inhibits gap junctional intercellular communication. QT prolongation during bupropion overdosage is due to its IKr‐blocking effect. QRS widening with bupropion is not related to cardiac sodium channel block. Bupropion rather mimics the QRS‐widening, MAP amplitude‐ and phase 0 dV/dt ‐reducing effect of glycyrrhetinic acid and heptanol. Unlike class I anti‐arrhythmics, bupropion causes cardiac conduction disturbances by reducing cardiac intercellular coupling.