Publications (11)21.71 Total impact
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Dataset: 1-s2.0-S0022282806007711-main(2)
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Article: A novel partial fatty acid oxidation inhibitor decreases myocardial oxygen consumption and improves cardiac efficiency in demand-induced ischemic heart.
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ABSTRACT: The benefits of inhibition of fatty acid oxidation (FOX) and stimulation of glucose oxidation (GOX) in ischemia are controversial. The objective of this study was to evaluate the effect of the FOX inhibitor CVT-4325 on the rates of FOX, GOX, myocardial oxygen consumption (MVO2), and cardiac efficiency in the absence and presence of palmitate during demand-induced ischemia of the rodent isolated hearts. Palmitate concentration-dependently increased FOX, decreased GOX, and increased MVO2. CVT-4325 inhibited FOX and increased GOX in the presence (but not the absence) of 1.2 mM palmitate, with EC50 values of 0.9 and 5.8 microM, respectively. The potency for CVT-4325 to inhibit FOX was 10-fold greater (0.9 versus 9.7 microM) in the presence of 1.2 mM compared with 0.4 mM palmitate. The increase in MVO2 caused by 1.2 mM palmitate was significantly reduced by 3 to 10 microM CVT-4325 in guinea pig hearts. In the presence of 1.2 mM palmitate, an increase in pacing rate of the guinea pig heart from 3.5 to 6.5 Hz caused a significant 50% increase in MVO2, a decrease in cardiac efficiency, and an increase in lactate concentration in the cardiac effluent from 0.04 +/- 0.01 to 0.10 +/- 0.02 mM (P < 0.01). CVT-4325 (3 microM) attenuated the increase (P < 0.05) in MVO2 while maintaining cardiac contractility, and decreased the lactate production to 0.05 +/- 0.01 mM (P < 0.01). Thus, the FOX inhibitor CVT-4325 decreased MVO2 and increased myocardial efficiency during demand-(pacing)-induced ischemia in the presence of palmitate in the rodent isolated hearts.Journal of Cardiovascular Pharmacology 04/2008; 51(4):372-9. · 2.29 Impact Factor -
Article: Ischemia-induced activation of AMPK does not increase glucose uptake in glycogen-replete isolated working rat hearts.
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ABSTRACT: Alterations in myocardial glucose metabolism are a key determinant of ischemia-induced depression of left ventricular mechanical function. Since myocardial glycogen is an important source of endogenous glucose, we compared the effects of ischemia on glucose uptake and utilization in isolated working rat hearts in which glycogen content was either replete (G replete, 114 micromol/g dry wt) or partially depleted (G depleted, 71 mumol/g dry wt). The effects of low-flow ischemia (LFI, 0.5 ml/min) on glucose uptake, glycogen turnover (glycogenolysis and glycogen synthesis), glycolysis, adenosine 5'-monophosphate-activated protein kinase (AMPK) activity, and GLUT4 translocation were measured. Relative to preischemic values, LFI caused a time-dependent reduction in glycogen content in both G-replete and G-depleted groups due to an acceleration of glycogenolysis (by 12-fold and 6-fold, respectively). In G-replete hearts, LFI (15 min) decreased glucose uptake (by 59%) and did not affect GLUT4 translocation. In G-depleted hearts, LFI also decreased initially glucose uptake (by 90%) and glycogen synthesis, but after 15 min, when glycogenolysis slowed due to exhaustion of glycogen content, glucose uptake increased (by 31%) in association with an increase in GLUT4 translocation. After 60 min of LFI, glucose uptake, glycogenolysis, and glycolysis recovered to near-preischemic values in both groups. LFI increased AMPK activity in a time-dependent manner in both groups (by 6-fold and 4-fold, respectively). Thus, when glycogen stores are replete before ischemia, ischemia-induced AMPK activation is not sufficient to increase glucose uptake. Under these conditions, an acceleration of glycogen degradation provides sufficient endogenous substrate for glycolysis during ischemia.AJP Heart and Circulatory Physiology 04/2008; 294(3):H1266-73. · 3.71 Impact Factor -
Article: A comparison between ranolazine and CVT-4325, a novel inhibitor of fatty acid oxidation, on cardiac metabolism and left ventricular function in rat isolated perfused heart during ischemia and reperfusion.
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ABSTRACT: Inhibition of fatty acid oxidation has been reported to be cardioprotective against myocardial ischemic injury; however, recent studies have questioned whether the cardioprotection associated with putative fatty acid oxidation inhibitors, such as ranolazine and trimetazidine, are due to changes in substrate oxidation. Therefore, the goals of this study were to compare the effects of ranolazine with a new fatty acid oxidation inhibitor, CVT-4325 [(R)-1-(2-methylbenzo[d]thiazol-5-yloxy)-3-(4-((5-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-piperazin-1-yl)propan-2-ol], on carbohydrate and fatty acid oxidation and on left ventricular (LV) function in the response to ischemia/reperfusion in rat isolated perfused hearts. Metabolic fluxes were determined in hearts perfused in an isovolumic Langendorff mode using 13C nuclear magnetic resonance isotopomer analysis or in isolated working hearts using [14C]glucose and [3H]palmitate, with and without 10 microM ranolazine or 3 microM CVT-4325. Isovolumic perfused hearts were also subjected to 30 min of low-flow ischemia (0.3 ml/min) and 60 min of reperfusion, and working hearts were subjected to 15 min of zero-flow ischemia and 60 min of reperfusion. Regardless of the experimental protocol, ranolazine had no effect on carbohydrate or fatty acid oxidation, whereas CVT-4325 significantly reduced fatty acid oxidation up to approximately 7-fold with a concomitant increase in carbohydrate oxidation. At these same concentrations, although ranolazine significantly improved LV functional recovery following ischemia/reperfusion, CVT-4325 had no significant protective effect. These results demonstrate that at pharmacologically relevant concentrations, ischemic protection by ranolazine was not mediated by inhibition of fatty acid oxidation and conversely that inhibition of fatty acid oxidation with CVT-4325 was not associated with improved LV functional recovery.Journal of Pharmacology and Experimental Therapeutics 05/2007; 321(1):213-20. · 3.83 Impact Factor -
Article: Ranolazine decreases diastolic calcium accumulation caused by ATX-II or ischemia in rat hearts
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ABSTRACT: Cardiac pathologies are associated with increased late INa that contributes to the dysregulation of ion homeostasis and causes electrical and contractile dysfunction. This study was designed to test the hypothesis that an increased late sodium channel current (INa) leads to Ca2+ overload and left ventricular (LV) dysfunction, and thereby inhibition of late INa (e.g., by ranolazine) improves Ca2+ homeostasis and reduces LV dysfunction. Intracellular Ca2+ ([Ca2+]i) and LV function were measured simultaneously in rat isolated perfused hearts. Augmentation of late INa with sea anemone toxin-II (ATX-II, 12 nM) increased diastolic [Ca2+]i (d[Ca2+]i), and impaired LV mechanical function, but had no effect on [Ca2+]i transient amplitude. Although ranolazine (4 and 9 μM), an inhibitor of late INa, had no direct effects on d[Ca2+]i or LV function, it significantly reduced the deleterious effects of ATX-II. Global ischemia increased d[Ca2+]i and inhibited Ca2+ transient amplitude. During reperfusion, Ca2+ transient amplitude recovered fully, but d[Ca2+]i remained elevated and LV function was depressed, indicative of Ca2+ overload. Ranolazine (9 μM) reduced d[Ca2+]i accumulation during ischemia as well as reperfusion and improved recovery of LV function. These results show that augmentation of late INa with ATX-II or by ischemia is associated with diastolic Ca2+ overload and LV dysfunction. The beneficial effects of ranolazine in reducing Ca2+ overload and LV mechanical dysfunction during ischemia/reperfusion is consistent with the inhibition of late INa mechanism of action.Journal of Molecular and Cellular Cardiology 01/2007; · 5.17 Impact Factor -
Article: Electrophysiologic properties and antiarrhythmic actions of a novel antianginal agent.
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ABSTRACT: Ranolazine is a novel antianginal agent capable of producing anti-ischemic effects at plasma concentrations of 2 to 6 microM without a significant reduction of heart rate or blood pressure. This review summarizes the electrophysiologic properties of ranolazine. Ranolazine significantly blocks I(Kr) (IC(50) = 12 microM), late I(Na), late I(Ca), peak I(Ca), I(Na-Ca) (IC(50) = 5.9, 50, 296, and 91 microM, respectively) and I(Ks) (17% at 30 microM), but causes little or no inhibition of I(to) or I(K1). In left ventricular tissue and wedge preparations, ranolazine produces a concentration-dependent prolongation of action potential duration (APD) in epicardium, but abbreviation of APD of M cells, leading to either no change or a reduction in transmural dispersion of repolarization (TDR). The result is a modest prolongation of the QT interval. Prolongation of APD and QT by ranolazine is fundamentally different from that of other drugs that block I(Kr) and induce torsade de pointes in that APD prolongation is rate-independent (ie, does not display reverse rate-dependent prolongation of APD) and is not associated with early after depolarizations, triggered activity, increased spatial dispersion of repolarization, or polymorphic ventricular tachycardia. Torsade de pointes arrhythmias were not observed spontaneously nor could they be induced with programmed electrical stimulation in the presence of ranolazine at concentrations as high as 100 microM. Indeed, ranolazine was found to possess significant antiarrhythmic activity, acting to suppress the arrhythmogenic effects of other QT-prolonging drugs. Ranolazine produces ion channel effects similar to those observed after chronic exposure to amiodarone (reduced late I(Na), I(Kr), I(Ks), and I(Ca)). Ranolazine's actions to reduce TDR and suppress early after depolarization suggest that in addition to its anti-anginal actions, the drug possesses antiarrhythmic activity.Journal of Cardiovascular Pharmacology and Therapeutics 10/2004; 9 Suppl 1:S65-83. · 1.75 Impact Factor -
Article: A mechanistic approach to assess the proarrhythmic risk of QT-prolonging drugs in preclinical pharmacologic studies.
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ABSTRACT: Drugs with diverse structures and from several therapeutic classes are reported to increase the risk that a patient will experience ventricular tachyarrhythmias (e.g., torsades de pointes [TdP]) during drug therapy. This review discusses the use of preclinical assays to assess the risk that a QT-prolonging drug will cause TdP. The mechanisms underlying the development of TdP and the factors that increase the risk of TdP are described and applied to the design of preclinical experimental models for detection of proarrhythmic drug actions. Recommended assays, conditions, and preparations for preclinical assessment of the drug-induced risk to TdP are given. No single preparation can simulate all conditions that cause TdP in patients. However, the assays described herein are capable of detecting the proarrhythmic effects of currently used drugs, even when these effects are reported to be extremely rare in clinical practice.Journal of Electrocardiology 02/2004; 37 Suppl:34-9. · 1.14 Impact Factor -
Article: … /persistent) sodium current: a potential drug target to reduce intracellular sodium-dependent calcium overload and its detrimental effects on cardiomyocyte function
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ABSTRACT: This article describes a potential target for therapeutic intervention in ischaemia and heart failure – inhibition of the late (sustained) sodium current to reduce the rise in intracellular sodium and calcium, and to reduce the electrical and mechanical abnormalities associated with these conditions. The new anti-anginal and anti-ischaemic drug ranolazine is a selective inhibitor of the late sodium current that is capable of reducing the electrical instability and mechanical dysfunction associated with conditions (e.g. ischaemia, heart failure) known to raise late I Na and [Na + ] i . Because the scope of the review is narrow, many relevant mechanisms involved in the regulation of intracellular sodium and calcium homeostasis are not discussed, and important individual contributions are not cited. Hence, the reader is referred to more comprehensive reviews of this subject. Intracellular sodium and calcium overload in the pathogenesis of ischaemia/reperfusion and heart failure Ischaemia/reperfusion and heart failure are associated with disruptions in cellular sodium and calcium home-ostasis 1–3 . Sodium overload may result from decreased efflux and increased influx during ischaemia, with greater intracellular accumulation of sodium as the duration of ischaemia increases 4 . This is followed by an increase in intracellular calcium through the Na + /Ca 2+ exchanger 4 . Failure to maintain the intracellular homeostasis of Na + and Ca 2+ leads to electrical instability (arrhythmias), mechanical dysfunction (reduced contrac- (L. Belardinelli).European Heart Journal Supplements. 01/2004; 6:3-7. -
Article: N-[3-(R)-tetrahydrofuranyl]-6-aminopurine riboside, an A1 adenosine receptor agonist, antagonizes catecholamine-induced lipolysis without cardiovascular effects in awake rats.
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ABSTRACT: Elevated serum nonesterified free fatty acid (NEFA) concentrations are detrimental to both the mechanical and electrical function of the heart. A(1) adenosine receptor agonists are potent and efficacious inhibitors of lipolysis; however, their cardiovascular effects have limited their use to lower serum NEFA. Our objective was to determine whether the antilipolytic effect of N-[3-(R)-tetrahydrofuranyl]-6-aminopurine riboside (CVT-510), an A(1) agonist, could be distinguished from its bradycardia effect and demonstrated in rats with normal or elevated serum NEFA. Rats were instrumented with telemetry transmitters for continuous recording of heart rate, and catheterized, for delivery of drugs and blood sampling. CVT-510 caused a rapid and sustained dose-dependent decrease in NEFA at doses that did not cause bradycardia (2, 5, and 20 micro g/kg). Significant bradycardia was observed at 50 micro g/kg. Norepinephrine (NE) increased NEFA from 0.5 +/- 0.01 to 0.9 +/- 0.2 mM and this effect lasted for 2 h. CVT-510 (10 micro g/kg) given at 40 min postinjection of NE reversed the rise in NEFA (69% reduction). When CVT-510 (20 micro g/kg) was given 15 min before a 30-min long infusion of NE, the lipolytic response to NE was prevented. To mimic the antilipolytic effect of CVT-510 in awake rats, hearts were perfused with palmitate at concentrations similar to those observed in the in vivo studies (0.8 and 0.2 mM), which decreased myocardial oxygen consumption (MVO(2)) by 11%. Thus, CVT-510 at doses > or =5-fold lower than those that slow heart rate caused a marked and sustained lowering of normal or elevated NEFA, that when mimicked in vitro decreased MVO(2) and would be expected to improve cardiac efficiency.Journal of Pharmacology and Experimental Therapeutics 05/2003; 305(1):225-31. · 3.83 Impact Factor -
Article: Activation of Ca2+-independent nitric oxide synthase by 17{beta}-estradiol in post-ischemic rat heart
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ABSTRACT: Background: Nitric oxide (NO) donors or facilitation of endogenous NO production is cardioprotective. This study sought to determine whether enhanced myocardial NO production might contribute to estrogen-induced cardioprotection. Methods: Ca2+-dependent and Ca2+-independent NOS activities (pmol min−1 mg−1 protein), NOS protein expression (quantitative immunoblot), cGMP content (pmol mg−1 protein) and LV work (Joules) were measured in hearts isolated from ovariectomized rats that were either untreated or treated chronically with 17β-estradiol (0.25 mg, 21 day release formulation). Results: After 14 days, serum levels of 17β-estradiol were 6±1 and 135±16 pg ml−1 in untreated and 17β-estradiol-treated animals, respectively. After 60 min aerobic working mode perfusion, Ca2+-dependent NOS (untreated, 1.47±0 36; 17β-estradiol 1.13±0.25) and Ca2+-independent NOS (untreated, 0.45±0.24; 17β-estradiol, 0.41±0.21) activities, eNOS and iNOS proteins and cGMP content (untreated, 0.64±0.08; 17β-estradiol, 0.76±0.12) were not different in the two groups. After 60 min low-flow (0.5 ml min−1) ischemia and 30 min reperfusion, Ca2+-dependent NOS activities were again similar (untreated, 1.25±0.23; 17β-estradiol, 0.78±0.27). However, after reperfusion, Ca2+-independent NOS activity (untreated, 0.39±0.10; 17β-estradiol, 1.36±0.36) was 3.5-fold higher ( P =0.008) and cGMP content (untreated, 0.30±0.03; 17β-estradiol, 0.49±0.07) was 1.6-fold higher ( P =0.017) in hearts from 17β-estradiol-treated animals. Although pre-ischemic function was similar, recovery of post-ischemic LV work was 2-fold greater ( P =0.024) in the 17β-estradiol group. Conclusion: The ability of ischemia and reperfusion in combination with chronic 17β-estradiol to increase Ca2+-independent NOS activity and cGMP content supports a role for enhanced myocardial NO signaling in 17β-estradiol-induced cardioprotection. -
Article: The mechanism of ranolazine action to reduce ischemia-induced diastolic dysfunction
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ABSTRACT: Ischaemia of myocardium is associated with increases in the late sodium current ( I Na ), intracellular sodium and calcium concentrations, calcium overload, and impairment of contractile relaxation (i.e. increased diastolic wall tension). An increase in diastolic wall tension compresses the vasculature and reduces nutritive blood flow, creating a positive feedback system that further impairs myocardial oxygenation and contractile function. Ranolazine reduces the late I Na and, is expected to decrease sodium entry into ischaemic myocardial cells. As a consequence, ranolazine is proposed to reduce calcium uptake indirectly via the sodium/calcium exchanger and to preserve ionic homeostasis and reverse ischaemia-induced contractile dysfunction.
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2007–2008
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University of Alberta
- Department of Pharmacology
Edmonton, Alberta, Canada
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