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Domperidone possesses cardiac electrophysiological effects similar to those of cisapride and class III antiarrhythmic drugs. These effects are observed at clinically relevant concentrations of the drug. Therefore, domperidone should not be considered a no-risk alternative to cisapride, a drug that was recently withdrawn from the US market.

Background. Left ventricular endocardial reentry is the conventional concept underlying surgery for ventricular tachycardia (VT). We assessed the incidences of patterns showing complete reentry circuits at either the subendocardial or subepicardial level and of patterns in which left ventricular endocardial mapping could only in part account for a reentrant mechanism.Methods and Results. We retrospectively analyzed epicardial and left ventricular endocardial isochronal maps of 47 VTs induced in 28 patients with chronic myocardial infarction (inferior, 14 patients; anteroseptal, 14 patients). Electrograms were recorded intraoperatively from 128 sites with epicardial sock and transatrial left ventricular endocardial balloon electrode arrays. Given the methodology used in this study, the mapping characteristics of the tachycardias suggested five types of activation patterns: 1) complete (90% or more ofVT cycle length) subendocardial reentry circuits in seven VTs (15%) and seven patients (25%), 2) complete subepicardial reentry circuits in four VTs (9%o) and four patients (14%), 3) incompletely mapped circuits with a left ventricular endocardial breakthrough preceding the epicardial breakthrough in 25 VTs (53%) and 21 patients (75%), 4) incompletely mapped circuits with a left ventricular epicardial breakthrough preceding the endocardial breakthrough in three VTs (6%) and three patients (11%), and 5) a right ventricular epicardial breakthrough preceding the left ventricular endocardial breakthrough in eight VTs (17%) and seven patients (25%). After surgery, one type 3 VT and three type 5 VTs were reinducible. Thus, left ventricular endocardial reentry substrates (types 1 and 3) accounted for 68% of VTs, but substrates involving subepicardial (types 2 and 4) and deep septal layers (type 5) accounted for 32%

Abstract-We have previously shown that oxytocin receptors are present in the heart and that perfusion of isolated rat hearts with oxytocin results in decreased cardiac flow rate and bradycardia. The mechanisms involved in the negative inotropic and chronotropic effects of oxytocin were investigated in isolated dog right atria in the absence of central mechanisms. Perfusion of atria through the sinus node artery with 10 Ϫ6 mol/L oxytocin over 5 minutes (8 mL/min) significantly decreased both beating rate (Ϫ14.7Ϯ4.9% of basal levels, nϭ5, PϽ0.004) and force of contraction (Ϫ52.4Ϯ9.1% of basal levels, nϭ5, PϽ0.001). Co-perfusion with 10 Ϫ6 mol/L oxytocin receptor antagonist (nϭ3) completely inhibited the effects of oxytocin on frequency (PϽ0.04) and force of contraction (PϽ0.004), indicating receptor specificity. The effects of oxytocin were also totally inhibited by co-perfusion with 5ϫ10Ϫ8 mol/L tetrodotoxin (PϽ0.02) or 10 Ϫ6 mol/L atropine (PϽ0.03) but not by 10 Ϫ6 mol/L hexamethonium, which implies that these effects are neurally mediated, primarily by intrinsic parasympathetic postganglionic neurons. Co-perfusion with 10 Ϫ6 mol/L NO synthase inhibitor (L-NAME) significantly inhibited oxytocin effects on both beating rate (Ϫ1.85Ϯ1.27% versus Ϫ14.7Ϯ4.9% in oxytocin alone, PϽ0.05) and force of contraction (Ϫ24.9Ϯ4.4% versus Ϫ52.4Ϯ9.1% in oxytocin alone, nϭ4, PϽ0.04). The effect of oxytocin on contractility was further inhibited by L-NAME at 10 Ϫ4 mol/L (Ϫ8.1Ϯ1.8%, PϽ0.01). These studies imply that the negative inotropic and chronotropic effects of oxytocin are mediated by cardiac oxytocin receptors and that intrinsic cardiac cholinergic neurons and NO are involved in these actions. (Hypertension. 2001;38:292-296.) Key Words: receptors Ⅲ neurons Ⅲ heart rate Ⅲ contractility Ⅲ nervous system, parasympathetic Ⅲ nitric oxide O xytocin, 1 of 2 major posterior pituitary hormones (oxytocin and vasopressin), is a neuropeptide synthesized primarily in magnocellular neurons in the paraventricular and supraoptic nuclei of the hypothalamus, which project to posterior pituitary, median eminence, and several brain regions. Oxytocin is also produced in peripheral tissues, 1 including the heart. We have recently shown that the heart is an important source of oxytocin production and synthesis. 2 In addition to its well-known effects on reproductive functions, such as uterine contraction, milk-ejection reflex, and induction of maternal behavior, 3,4 oxytocin was recently shown to be involved in endocrine and neuroendocrine regulation through receptor-mediated actions exerted on the heart, vasculature, and kidneys. [5][6][7][8][9] In humans, intravenous oxytocin injections cause biphasic dose-dependent changes in mean arterial pressure that consist of an initial pressor response accompanied by bradycardia and a decrease in cardiac output, followed by a prolonged fall in mean arterial pressure accompanied by increased cardiac output. 10 Oxytocin administration at the rat upper spinal cord 11 or into acutely decentralized canine stel...

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Ardell JL, Cardinal R, Vermeulen M, Armour JA. Dorsal spinal cord stimulation obtunds the capacity of intrathoracic extracardiac neurons to transduce myocardial ischemia.

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.

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