Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties.
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BACKGROUND: Ranolazine is a novel antianginal agent capable of producing antiischemic effects at plasma concentrations of 2 to 6 micromol/L without reducing heart rate or blood pressure. The present study examines its electrophysiological effects in isolated canine ventricular myocytes, tissues, and arterially perfused left ventricular wedge preparations. METHODS AND RESULTS: Transmembrane action potentials (APs) from epicardial and midmyocardial (M) regions and a pseudo-ECG were recorded simultaneously from wedge preparations. APs were also recorded from epicardial and M tissues. Whole-cell currents were recorded from epicardial and M myocytes. Ranolazine inhibited I(Kr) (IC50=11.5 micromol/L), late I(Na), late I(Ca), peak I(Ca), and I(Na-Ca) (IC50=5.9, 50, 296, and 91 micromol/L, respectively) and I(Ks) (17% at 30 micromol/L), but caused little or no inhibition of I(to) or I(K1). In tissues and wedge preparations, ranolazine produced a concentration-dependent prolongation of AP duration of epicardial but abbreviation of that of M cells, leading to reduction or no change in transmural dispersion of repolarization (TDR). At [K+]o=4 mmol/L, 10 micromol/L ranolazine prolonged QT interval by 20 ms but did not increase TDR. Extrasystolic activity and spontaneous torsade de pointes (TdP) were never observed, and stimulation-induced TdP could not be induced at any concentration of ranolazine, either in normal or low [K+]o. Ranolazine (5 to 20 micromol/L) suppressed early afterdepolarizations (EADs) and reduced the increase in TDR induced by the selective I(Kr) blocker d-sotalol. CONCLUSIONS: Ranolazine produces ion channel effects similar to those observed after chronic amiodarone (reduced I(Kr), I(Ks), late I(Na), and I(Ca)). The actions of ranolazine to suppress EADs and reduce TDR suggest that, in addition to its antianginal actions, the drug may possess antiarrhythmic activity. (+info)
Butachlor inhibits production and oxidation of methane in tropical rice soils under flooded condition.
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In laboratory incubation experiments, application of a commercial formulation of the herbicide butachlor (N-butoxymethyl-2-chloro-2',6'-diethyl acetanilide) to three tropical rice soils, widely differing in their physicochemical characteristics, under flooded condition inhibited methane (CH4) production. The inhibitory effect was concentration dependent and most remarkable in the alluvial soil. Thus, following application of butachlor at 5, 10, 50 and 100 microg g(-1) soil, respectively, cumulative CH4 production in the alluvial soil was inhibited by 15%, 31%, 91% and 98% over unamended control. Since CH4 production was less pronounced in the sandy loam and acid sulfate soil, the impact of amendment with butchalor, albeit inhibitory, was less extensive than the alluvial soil. Inhibition of CH4 production in butachlor-amended alluvial soil was related to the prevention in the drop in redox potential as well as low methanogenic bacterial population especially at high concentrations of butachlor. CH4 oxidation was also inhibited in butachlor-amended alluvial soil with the inhibitory effect being more prevalent under flooded condition. Inhibition in CH4 oxidation was related to a reduction in the population of soluble methane monooxygenase producing methanotrophs. Results demonstrate that butachlor, a commonly used herbicide in rice cultivation, even at very low concentrations can affect CH4 production and its oxidation, thereby influencing the biogeochemical cycle of CH4 in flooded rice soils. (+info)
Inhibition of human and rat CYP1A2 by TCDD and dioxin-like chemicals.
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Dioxins have been shown to bind and induce rodent CYP1A2, producing a dose-dependent hepatic sequestration in vivo. The induction of CYP1A2 activity has been used as a noninvasive biomarker for human exposure to dioxins; while there is a consistent relationship between exposure and hepatic CYP1A2 induction in rodents, this relationship has only been observed in some of the highest exposed human populations. This may be explained by inhibition of CYP1A2 activity by dioxins as some rodent studies demonstrate that rodent CYP1A2 activity can in fact be inhibited by dioxins in vitro. CYP1A2 activity was examined using a series of dioxins to inhibit human and rat CYP1A2 activity in species-specific CYP1A2 SUPERSOMES using three common CYP1A2 substrates. Methoxyresorufin was a more efficient substrate than acetanalide or caffeine in this in vitro system. Rat and human CYP1A2 enzymatic activity is inhibited by TCDD, PCDD, TCDF, 4-PeCDF, and PCBs 126, 169, 105, 118, and 156 in a concentration-dependent manner. These data demonstrate that the in vitro metabolism of prototype substrates is similar between the rat and human CYP1A2 SUPERSOME preparations and that dioxins inhibit CYP1A2 activity in both species. Because of the potential for inhibition of CYP1A2 activity by TCDD and other dioxins, studies examining CYP1A2 induction in dioxin-exposed populations using these substrates should be viewed cautiously. (+info)
Effects of ranolazine on exercise tolerance and HbA1c in patients with chronic angina and diabetes.
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AIMS: The anti-anginal efficacy and safety of ranolazine in diabetic and non-diabetic patients included in the Combination Assessment of Ranolazine In Stable Angina (CARISA) trial (JAMA 2004;291:309) were studied. Glycaemic control was also assessed in CARISA and its long-term open-label extension study. METHODS AND RESULTS: Patients with chronic angina enrolled in CARISA (189 with diabetes, 634 without diabetes) on background atenolol, diltiazem, or amlodipine therapy were randomized to placebo, ranolazine 750 or 1000 mg twice daily for 12 weeks, during which exercise tolerance, angina frequency, nitroglycerin usage, glucose, HbA(1c), and lipids were measured. Patients completing the randomized study could enroll in an ongoing open-label extension study and were evaluated every 3 months. Ranolazine produced similar improvements in exercise parameters, nitroglycerin use, and angina frequency in diabetic and non-diabetic patients. Adverse events were similar between groups. Fasting glucose and lipids remained unaltered in diabetic patients after 12 weeks of therapy. In a post hoc analysis, ranolazine 750 and 1000 mg reduced HbA(1c) vs. placebo by 0.48+/-0.18% (P=0.008) and 0.70+/-0.18% (P=0.0002), respectively; the HbA(1c) levels appeared to remain unchanged over time during long-term therapy. CONCLUSION: Anti-anginal efficacy and safety of ranolazine for angina were similar between diabetic and non-diabetic patients. Ranolazine significantly improved glycaemic control in diabetic patients. (+info)
Ranolazine and late cardiac sodium current--a therapeutic target for angina, arrhythmia and more?
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Ranolazine is a new antianginal drug approved for clinical use in the United States in January 2006. A study published in this same issue of the British Journal of Pharmacology characterizes ranolazine block of late sodium current caused by the long QT syndrome 3 mutations. This commentary discusses the implications of that study and the background and implications for block of late cardiac sodium current in general. (+info)
Molecular basis of ranolazine block of LQT-3 mutant sodium channels: evidence for site of action.
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1 We studied the effects of ranolazine, an antianginal agent with promise as an antiarrhythmic drug, on wild-type (WT) and long QT syndrome variant 3 (LQT-3) mutant Na(+) channels expressed in human embryonic kidney (HEK) 293 cells and knock-in mouse cardiomyocytes and used site-directed mutagenesis to probe the site of action of the drug. 2 We find preferential ranolazine block of sustained vs peak Na(+) channel current for LQT-3 mutant (DeltaKPQ and Y1795C) channels (IC(50)=15 vs 135 microM) with similar results obtained in HEK 293 cells and knock-in myocytes. 3 Ranolazine block of both peak and sustained Na(+) channel current is significantly reduced by mutation (F1760A) of a single residue previously shown to contribute critically to the binding site for local anesthetic (LA) molecules in the Na(+) channel. 4 Ranolazine significantly decreases action potential duration (APD) at 50 and 90% repolarization by 23+/-5 and 27+/-3%, respectively, in DeltaKPQ mouse ventricular myocytes but has little effect on APD of WT myocytes. 5 Computational modeling of human cardiac myocyte electrical activity that incorporates our voltage-clamp data predicts marked ranolazine-induced APD shortening in cells expressing LQT-3 mutant channels. 6 Our results demonstrate for the first time the utility of ranolazine as a blocker of sustained Na(+) channel activity induced by inherited mutations that cause human disease and further, that these effects are very likely due to interactions of ranolazine with the receptor site for LA molecules in the sodium channel. (+info)
Improved left ventricular function and reduced necrosis after myocardial ischemia/reperfusion in rabbits treated with ranolazine, an inhibitor of the late sodium channel.
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Ranolazine is an inhibitor of the late sodium current and, via this mechanism, decreases sodium-dependent intracellular calcium overload during ischemia and reperfusion. Ranolazine reduces angina, but there is little information on its effects in acute myocardial infarction. The aim of this study was to test the effects of ranolazine on left ventricular (LV) function and myocardial infarct size after ischemia/reperfusion in rabbits. Ten minutes before coronary artery occlusion (CAO), anesthetized rabbits were assigned to vehicle (n=15) or ranolazine (2 mg/kg i.v. bolus plus 60 microg/kg/min i.v. infusion; n=15). Hearts received 60 min of CAO and 3 h of reperfusion. CAO caused LV dysfunction associated with necrosis. However, at the end of reperfusion, rabbits treated with ranolazine had better global LV ejection fraction (0.42+/-0.02 versus 0.33+/-0.02; p<0.007) and stroke volume (1.05+/-0.08 versus 0.78+/-0.07 ml; p<0.01) compared with vehicle. The fraction of the LV wall that was akinetic or dyskinetic was significantly less in the ranolazine group at 0.23+/-0.03 versus 0.34+/-0.03 in vehicle-treated group; p<0.02. The ischemic risk region was similar in both groups; however, infarct size was significantly smaller in the treated group (44+/-5 versus 57+/-4% vehicle; p<0.04). There were no significant differences among groups in heart rate, arterial pressure, LV end-diastolic pressure, or maximum-positive or -negative first time derivative of LV pressure (dP/dt). In conclusion, the results of this study show that ranolazine provides protection during acute myocardial infarction in this rabbit model of ischemia/reperfusion. Ranolazine treatment led to better ejection fraction, stroke volume and less wall motion abnormality after reperfusion, and less myocardial necrosis. (+info)
Ranolazine improves abnormal repolarization and contraction in left ventricular myocytes of dogs with heart failure by inhibiting late sodium current.
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BACKGROUND: Ventricular repolarization and contractile function are frequently abnormal in ventricular myocytes from human failing hearts as well as canine hearts with experimentally induced heart failure (HF). These abnormalities have been attributed to dysfunction involving various steps of the excitation-contraction coupling process, leading to impaired intracellular sodium and calcium homeostasis. We previously reported that the slow inactivating component of the Na(+) current (late I(Na)) is augmented in myocytes from failing hearts, and this appears to play a significant role in abnormal ventricular myocytes repolarization and function. We tested the effect of ranolazine, a novel drug being developed to treat angina, on (1) action potential duration (APD), (2) peak transient and late I(Na) (I(NaT) and I(NaL), respectively), (3) early afterdepolarizations (EADs), and (4) twitch contraction (TC), including after contractions and contracture. METHODS: Myocytes were isolated from the left ventricle of normal dogs and of dogs with chronic HF caused by multiple sequential intracoronary micro-embolizations. I(NaT) and I(NaL) were recorded using conventional whole-cell patch-clamp techniques. APs were recorded using the beta-escin perforated patch-clamp configuration at frequencies of 0.25 and 0.5 Hz. TCs were recorded using an edge movement detector at stimulation frequencies ranging from 0.5 to 2.0 Hz. RESULTS: Ranolazine significantly (P<0.05) and reversibly shortened the APD of myocytes stimulated at either 0.5 or 0.25 Hz in a concentration-dependent manner. At a stimulation frequency of 0.5 Hz, 5, 10, and 20 microM ranolazine shortened the APD(90) (APD measured at 90% repolarization) from 516+/-51 to 304+/-22, 212+/-34 and 160+/-11 ms, respectively, and markedly decreased beat-to-beat variability of APD(90), EADs, and dispersion of APDs. Ranolazine preferentially blocked I(NaL) relative to I(NaT) in a state-dependent manner, with a approximately 38-fold greater potency against I(NaL) to produce tonic block (IC(50)=6.5 microM) than I(NaT) (IC(50)=294 microM). When we evaluated inactivated state blockade of I(NaL) from the steady-state inactivation mid-potential shift using a theoretical model, ranolazine was found to bind more tightly to the inactivated state than the resting state of the sodium channel underlying I(NaL), with apparent dissociation constants K(dr)=7.47 microM and K(di)=1.71 microM, respectively. TCs of myocytes stimulated at 0.5 Hz were characterized by an initial spike followed by a dome-like after contraction, which was observed in 75% of myocytes from failing hearts and coincided with the long AP plateau and EADs. Ranolazine at 5 and 10 microM reversibly shortened the duration of TCs and abolished the after contraction. When the rate of myocyte stimulation was increased from 1.0 to 2.0 Hz, there was a progressive increase in diastolic "tension," that is, contracture. Ranolazine at 5 and 10 microM reversibly prevented this frequency-dependent contracture. (+info)