Effects Of Ranolazine Research Articles

Ranolazine improves oxidative stress and mitochondrial function in the atrium of acetylcholine-CaCl2 induced atrial fibrillation rats

AimsRanolazine, an antianginal agent used for chronic stable angina treatment, was demonstrated to be effective in atrial fibrillation (AF) treatment. The aim of this study was to explore the molecular mechanisms of its anti-AF effects. Main methodsAF rat model was established using acetylcholine (ACh)-CaCl2 injection for 7days followed by ACh infusion into the heart. Prior to ACh infusion, ranolazine at 10.7mg/kg/0.5ml was injected into vein and followed by 0.56mg/kg/min infusion. Blood pressure and electrocardiogram were monitored during the infusion. Histological changes of atrial tissue were observed after H&E staining. Activities and protein expression of NADPH oxidase-4, xanthine oxidase, glutathione peroxidase and superoxide dismutase were examined using commercial assay kits and Western botting, respectively. Mitochondrial functions were evaluated through membrane potential, ATP production, activities of complex I and III and reactive oxygen species production. Apoptosis was measured using TUNEL staining. Protein expression of apoptotic proteins Bcl-2, Bax and cleaved-caspase 3 and Akt/mTOR signaling proteins were detected using Western blotting. Key findingsResults demonstrated that ranolazine attenuated AF in ACh-CaCl2-exposed rats. In addition, ranolazine restored mitochondrial function, suppressed oxidative stress, and inhibited atrial cells apoptosis. Furthermore, the activated Akt/mTOR signaling pathway induced by AF was further activated by ranolazine. SignificanceThe present study confirms the effects of ranolazine on AF rats induced by ACh-CaCl2, and provides evidence that the anti-AF effects are associated with the restoration of mitochondrial function and activation of the Akt/mTOR signaling pathway in atrial tissue.

The combined effects of ranolazine and dronedarone on human atrial and ventricular electrophysiology

IntroductionPharmacological rhythm control of atrial fibrillation (AF) in patients with structural heart disease is limited. Ranolazine in combination with low dose dronedarone remarkably reduced AF-burden in the phase II HARMONY trial. We thus aimed to investigate the possible mechanisms underlying these results. Methods and resultsPatch clamp experiments revealed that ranolazine (5μM), low-dose dronedarone (0.3μM), and the combination significantly prolonged action potential duration (APD90) in atrial myocytes from patients in sinus rhythm (prolongation by 23.5±0.1%, 31.7±0.1% and 25.6±0.1% respectively). Most importantly, in atrial myocytes from patients with AF ranolazine alone, but more the combination with dronedarone, also prolonged the typically abbreviated APD90 (prolongation by 21.6±0.1% and 31.9±0.1% respectively). It was clearly observed that neither ranolazine, dronedarone nor the combination significantly changed the APD or contractility and twitch force in ventricular myocytes or trabeculae from patients with heart failure (HF). Interestingly ranolazine, and more so the combination, but not dronedarone alone, caused hyperpolarization of the resting membrane potential in cardiomyocytes from AF. As measured by confocal microscopy (Fluo-3), ranolazine, dronedarone and the combination significantly suppressed diastolic sarcoplasmic reticulum (SR) Ca2+ leak in myocytes from sinus rhythm (reduction by ranolazine: 89.0±30.7%, dronedarone: 75.6±27.4% and combination: 78.0±27.2%), in myocytes from AF (reduction by ranolazine: 67.6±33.7%, dronedarone: 86.5±31.7% and combination: 81.0±33.3%), as well as in myocytes from HF (reduction by ranolazine: 64.8±26.5% and dronedarone: 65.9±29.3%). ConclusionsElectrophysiological measurements during exposure to ranolazine alone or in combination with low-dose dronedarone showed APD prolongation, cellular hyperpolarization and reduced SR Ca2+ leak in human atrial myocytes. The combined inhibitory effects on various currents, in particular Na+ and K+ currents, may explain the anti-AF effects observed in the HARMONY trial. Therefore, the combination of ranolazine and dronedarone, but also ranolazine alone, may be promising new treatment options for AF, especially in patients with HF, and merit further clinical investigation.

Effects of Ranolazine on Astrocytes and Neurons in Primary Culture.

Ranolazine (Rn) is an antianginal agent used for the treatment of chronic angina pectoris when angina is not adequately controlled by other drugs. Rn also acts in the central nervous system and it has been proposed for the treatment of pain and epileptic disorders. Under the hypothesis that ranolazine could act as a neuroprotective drug, we studied its effects on astrocytes and neurons in primary culture. We incubated rat astrocytes and neurons in primary cultures for 24 hours with Rn (10−7, 10−6 and 10−5 M). Cell viability and proliferation were measured using trypan blue exclusion assay, MTT conversion assay and LDH release assay. Apoptosis was determined by Caspase 3 activity assay. The effects of Rn on pro-inflammatory mediators IL-β and TNF-α was determined by ELISA technique, and protein expression levels of Smac/Diablo, PPAR-γ, Mn-SOD and Cu/Zn-SOD by western blot technique. In cultured astrocytes, Rn significantly increased cell viability and proliferation at any concentration tested, and decreased LDH leakage, Smac/Diablo expression and Caspase 3 activity indicating less cell death. Rn also increased anti-inflammatory PPAR-γ protein expression and reduced pro-inflammatory proteins IL-1 β and TNFα levels. Furthermore, antioxidant proteins Cu/Zn-SOD and Mn-SOD significantly increased after Rn addition in cultured astrocytes. Conversely, Rn did not exert any effect on cultured neurons. In conclusion, Rn could act as a neuroprotective drug in the central nervous system by promoting astrocyte viability, preventing necrosis and apoptosis, inhibiting inflammatory phenomena and inducing anti-inflammatory and antioxidant agents.

Is the Pleotropic Effect of Ranolazine is Due to its Antioxidant Action

AbstractBACKGROUND: Ranolazine is indicated as antianginal drug. We observed that it has other pleotropic effects also. So, we want to study the effect of Ranolazine in improvement of left ventricular (LV) function in obstructive coronary artery (CAD) diseased patients along with ACC/AHA guidelines of treatment. And to see the mode of improvement in LV function is due to its antioxidant effect.MATERIALS AND METHODS: We recruited CAD patient between the age group 18-80 yrs with LV dysfunction in whom ischemic component was treated. Cases received ranolazine 500 mg two times a day and controls without the drug. Both groups received standard drug therapy according to ACC/AHA guidelines of treatment CAD. For all these patients at basal and at 6 months of follow up, all baseline and demographic parameters, clinical features and symptomatology with blood chemistry parameters were collected. In addition Two Dimensional echocardiography (EF, MAV), Treadmill test (METs) and plasma oxidative stress levels (MDA) will be performed at 0 day (day of recruitment) and at 6 months. MDA concentration was tested by using the method described by Draper and Hadley based on TBA reactivity. Normal Range of MDA is 3.60 ± 0.90 Nano mole/ml.RESULTS: 100 cases and 40 controls were recruited for this study. Male: Female ratio was 3.4:1 in cases and in controls. The mean age of cases was 56.8 ± 9.6 yrs in cases and 55.1 ± 12 yrs in controls. There was no difference in demographic features and risk factor profile in between the cases and controls expect smoking ( high in cases). Even in echo EF was comparable but MAV is more in cases than controls (9.5 ±2.1 vs 8.8±1.8) which are also not statistically significant.There is statistically significant improvement of EF either by dimension (48.3 ± 9.6 vs 43.8±8.4 %, p= 0.008) or volume (p=0.018) method of estimation and peak mitral annular velocity in cases (9.8±1,8 vs 8.7± 1.8 cm/sec, p= 0.001) who received additional ranolazine therapy than controls.MDA at 6 months in cases was decreases to 3.4±0.8 nano mole/dl where as in controls increased to 3.9±0.7 nano mole/dl. Out of 100 cases we could able to get Treadmill test done only for 89 patients with modified Bruce protocol and there was a statistically significant improvement in the number of metabolic equivalents at 6 months in cases comparison to basal exercise capacity (6.8± 2.4 vs 8.2 ± 8.1 METS, p= 0.05).ConclusionsRanolazine can act as not only an anti anginal drug but also it was shown to have positive effects on improving LV function (improvement in EF and mitral annular velocities) and improving the exercise capacity (increased METs by TMT). These effects may be due to reduction in the oxidative stress (decreased MDA levels).

Influences of rapid pacing-induced electrical remodeling on pharmacological manipulation of the atrial refractoriness in rabbits

Electrical remodeling plays a pivotal role in maintaining the reentry during atrial fibrillation. In this study, we assessed influence of electrical remodeling on pharmacological manipulation of the atrial refractoriness in rabbits. We used an atrial electrical remodeling model of the rabbit, subjected to rapid atrial pacing (RAP; 600 beats/min) for 2–4 weeks, leading to shortening of atrial effective refractory period (AERP). Intravenous administration of dl-sotalol (6 mg/kg), bepridil (1 mg/kg), amiodarone (10 mg/kg) or vernakalant (3 mg/kg) significantly prolonged the AERP both in the control and RAP rabbits. The extents in the RAP rabbits were similar to those in the control animals. On the other hand, prolonging effects of intravenously administered ranolazine (10 mg/kg) or tertiapin-Q (0.03 mg/kg) on the AERP in the RAP rabbits were more potent than those in the control animals. These results suggest that rapid pacing-induced electrical remodeling effectively modified the prolonging effects of ranolazine and tertiapin-Q on the AERP in contrast to those of clinically available antiarrhythmic drugs, dl-sotalol, bepridil amiodarone and vernakalant.

Ranolazine and Its Effects on Hemoglobin A1C.

To review the antihyperglycemic effect of ranolazine in type 2 diabetes mellitus (T2DM). An EMBASE search was conducted between January 1966 through December 2015 using the search termsranolazine, diabetes, andhemoglobin A1C(A1C). Additional references were identified from a review of literature citations. A search of clinicaltrials.gov was conducted to identify unpublished studies assessing ranolazine in diabetes. All English-language observational and randomized controlled trials assessing the effects of ranolazine on A1C were evaluated. Four published and 3 unpublished trials were identified. In all except 1 study, ranolazine 750 to 1000 mg twice daily was associated with a statistically significant decrease in A1C compared with placebo (placebo-corrected change in A1C: -0.28 to -0.7). In the trial in which a significant difference was not observed, patients assigned to ranolazine received a lower maintenance metformin dose compared with patients not assigned to ranolazine. A greater percentage of patients randomized to ranolazine achieved an A1C<7% compared with the placebo group (41.2%-59% vs 25.7%-49%). Ranolazine was not associated with an increase in the incidence of hypoglycemia and was well tolerated overall. The mechanism for lowering of A1C has not been determined. Ranolazine therapy may decrease A1C among patients with T2DM without an increase in hypoglycemia. For patients with T2DM and chronic stable angina, ranolazine may be of use given its utility in cardiovascular disease and benefit in A1C lowering.

Effect of late sodium current inhibition on MRI measured diastolic dysfunction in aortic stenosis: a pilot study

BackgroundRanolazine is a new anti-anginal drug that acts via late sodium current inhibition, and has been shown to improve diastolic dysfunction in isolated myocytes. Diastolic dysfuntion is common in patients with aortic stenosis (AS), and precedes symptom development and systolic dysfunction. The purpose of this study was to assess the effects of ranolazine on peak early diastolic strain rate (PEDSR) and exercise capacity in patients with AS.MethodsPatients with asymptomatic moderate to severe AS and diastolic dysfunction underwent trans-thoracic echocardiography, exercise testing and cardiac magnetic resonance (CMR) imaging at baseline, 6 weeks after commencing ranolazine and at 10 weeks (4 weeks after discontinuation). Diastolic function was assessed using PEDSR measured on tagged CMR images.ResultsFifteen patients (peak pressure gradient 48.8 ± 12.4 mmHg, mean pressure gradient 27.1 ± 7.5 mmHg, aortic valve area 1.26 ± 0.31 cm2) completed the week-6 visit and 13 completed the final visit. Global PEDSR did not significantly increase from baseline (0.79 ± 0.15) to week-6 (0.86 ± 0.18, p = 0.198). There was a borderline significant increase in total exercise duration from 10.47 ± 3.68 min to 11.60 ± 3.25 min (p = 0.06).ConclusionThis small pilot study did not show a significant improvement in diastolic function with the use of ranolazine in asymptomatic patients with moderate-severe AS. Further studies with a larger population may be indicated.EduraCT number 2011-000111-26Electronic supplementary materialThe online version of this article (doi:10.1186/s13104-016-1874-0) contains supplementary material, which is available to authorized users.

Effects of Ranolazine on Angina and Quality of Life After Percutaneous Coronary Intervention With Incomplete Revascularization: Results From the Ranolazine for Incomplete Vessel Revascularization (RIVER-PCI) Trial.

Angina often persists or returns in populations following percutaneous coronary intervention (PCI). We hypothesized that ranolazine would be effective in reducing angina and improving quality of life (QOL) in incomplete revascularization (ICR) post-PCI patients. In RIVER-PCI, 2604 patients with a history of chronic angina who had ICR post-PCI were randomized 1:1 to oral ranolazine versus placebo; QOL analyses included 2389 randomized subjects. Angina and QOL questionnaires were collected at baseline and months 1, 6, and 12. Ranolazine patients were more likely than placebo to discontinue study drug by month 6 (20.4% versus 14.1%, P<0.001) and 12 (27.2% versus 21.3%, P<0.001). Following qualifying index PCI, the primary QOL outcome (Seattle Angina Questionnaire [SAQ] angina frequency score) improved markedly, but similarly, in the ranolazine and placebo groups, respectively, from baseline (67.3±24.5 versus 69.7±24.0, P=0.01) to month 1 (86.6±18.1 versus 85.8±18.5, P=0.27) and month 12 (88.4±17.8 versus 88.5±17.8, P=0.94). SAQ angina frequency repeated measures did not differ in adjusted analysis between groups post baseline (mean difference 1.0; 95% CI -0.2, 2.2; P=0.11). Improvement in SAQ angina frequency was observed with ranolazine at month 6 among diabetics (mean difference 3.3; 95% CI 0.6, 6.1; P=0.02) and those with more angina (baseline SAQ angina frequency ≤60; mean difference 3.4; 95% CI 0.6, 6.2; P=0.02), but was not maintained at month 12. Despite ICR following PCI, there was no incremental benefit in angina or QOL measures by adding ranolazine in this angiographically-identified population. These measures markedly improved within 1 month of PCI and persisted up to 1 year in both treatment arms. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01442038.

The Antianginal Agent Ranolazine Inhibits Mitochondrial β-Oxidation Pathway

Abstract Backgrounds: Ranolazine had two main functions: blocking cardiac late sodium channels and / or inhibition of 3- ketoacyl coenzyme A thiolase, an important enzyme in s-oxidation of fatty acids. Diabetic cardiomyopathy is a complication, defined as cardiac dysfunction without the involvement of epicardial vessels. In this study, the effect of ranolazine on fatty acid oxidation was investigated in diabetic rats induced by streptozotocin. Methods: After 8 weeks of diabetic induction, the effect of ranolazine on fatty acid oxidation rate was studied. Statistical data were analyzed using Mann-Whitney test. Results: The activity of s-oxidation enzymes were inhibited by ranolazine in the normal rat hearts significantly, while no significant inhibition was seen in diabetic ones. Conclusion: Our data suggest that the clinical efficacy of ranolazine in diabetic patients is associated with a mechanism other than inhibition of the s-oxidation pathway activity, although various hypotheses exist in the literature.

Antagonism of Nav channels and α1-adrenergic receptors contributes to vascular smooth muscle effects of ranolazine.

Ranolazine is a recently developed drug used for the treatment of patients with chronic stable angina. It is a selective inhibitor of the persistent cardiac Na+ current (INa), and is known to reduce the Na+-dependent Ca2+ overload that occurs in cardiomyocytes during ischemia. Vascular effects of ranolazine, such as vasorelaxation,have been reported and may involve multiple pathways. As voltage-gated Na+ channels (Nav) present in arteries play a role in contraction, we hypothesized that ranolazine could target these channels. We studied the effects of ranolazine in vitro on cultured aortic smooth muscle cells (SMC) and ex vivo on rat aortas in conditions known to specifically activate or promote INa. We observed that in the presence of the Nav channel agonist veratridine, ranolazine inhibited INa and intracellular Ca2+ calcium increase in SMC, and arterial vasoconstriction. In arterial SMC, ranolazine inhibited the activity of tetrodotoxin-sensitive voltage-gated Nav channels and thus antagonized contraction promoted by low KCl depolarization. Furthermore, the vasorelaxant effects of ranolazine, also observed in human arteries and independent of the endothelium, involved antagonization of the α1-adrenergic receptor. Combined α1-adrenergic antagonization and inhibition of SMCs Nav channels could be involved in the vascular effects of ranolazine.

Influence of trimetazidine and ranolazine on endothelial function in patients with ischemic heart disease.

Endothelial dysfunction is an independent predictor of atherosclerosis progression and cardiovascular events in patients with ischemic heart disease. Ranolazine and trimetazidine are novel drugs that reduce angina symptoms in the above-mentioned patients. The aim of this study was to compare the effects of ranolazine and trimetazidine on flow-mediated (FMD) and nitroglycerine-induced (GTN) dilation of the brachial artery. In a prospective, double-blind study, 56 men between 32 and 65 years of age with chronic ischemic heart disease were randomized and subjected to 12 weeks of treatment with either trimetazidine (35 mg twice daily) or ranolazine. Ranolazine was administered at a dose of 375 mg twice daily for 4 weeks and was increased to 500 mg twice daily for the rest of the study. FMD and GTN were measured using high-resolution ultrasound before and after treatment. FMD increased from 3.5±7.4 to 13.8±9.4% (P<0.013; 294%) in the trimetazidine group and from 2.4±4.3 to 9.5±7.7% (P<0.037; 296%) in the ranolazine group, with no difference between the groups (P=0.444). GTN increased from 16.1±9.2 to 21.2±19.3% (P<0.022; 32%) in the trimetazidine group and from 13.8±9.6 to 21.7±13.7% (P<0.006; 57%) in the ranolazine group, with no difference between the groups (P=0.309). Both trimetazidine and ranolazine led to an improvement in FMD and GTN of the brachial artery in patients with ischemic heart disease, with no statistically significant difference between the groups.

Abstract 13387: Effect of Ranolazine on the Incidence of Atrial Fibrillation Following Cardiac Surgery

Introduction: Atrial fibrillation (AF) is common following cardiac surgery. Reduction of postoperative AF would decrease average length of stay and improve patient outcomes. Ranolazine has been shown to prevent AF by increasing postrepolarization refractoriness in atrial tissue. This study evaluates prophylactic ranolazine on postoperative AF in cardiac surgery. Hypothesis: To assess the effect of ranolazine as a selective atrial sodium channel blocker on prevention of AF following cardiac surgery. Methods: This double blinded, randomized trial assessed primary prevention of postoperative AF with ranolazine in patients undergoing coronary artery bypass grafting (CABG) and/or aortic valve replacement (AVR) from 2012-13. Mitral valve surgery was an exclusion criterion. Fifty-four patients were randomly allocated to twice daily ranolazine 1000 mg (n=27) or placebo (n=27) 48 hours prior to surgical intervention and postoperatively for 14 days. Cardiac monitoring for arrhythmias was continued for 2 weeks post discharge using Holter monitor. The primary endpoint was AF up to postoperative day 14. Secondary endpoints included 30 day readmission, complications, and length of stay. (ClinicalTrials.gov: NCT01590979). Results: Fifty-one patients completed the study to 30 days postoperatively. Cohort mean age was 64.3±11.4 years, females were 10(19%), mean ejection fraction was 46.4±14.6%, hypertension 48(89%), dyslipidemia 32(59%) and diabetes 22 (41%), with no difference between the groups. Patients underwent isolated CABG (44, 81%), AVR (4, 7%) and combined AVR/CABG (3, 6%). The incidence of AF was 24%, control 8 (30%) and treated 5 (19%) groups, a 38% reduction, not statistically significant (p=0.530). QT duration was longer in the ranolazine group (p=0.014). The length of stay of patients who developed AF was significantly longer (8.3±5.0 vs. 5.4±2.7, p=0.009), with no drug related adverse events. Conclusion: This study illustrates the prevalence of AF following cardiac surgery. Ranolazine is an antianginal medication that can be used safely in patients to reduce postoperative AF. In conclusion, this study showed a reduction in the incidence of AF by 38%. Although not statistically significant, this indicates a trend towards our hypothesis.

Abstract 17401: Ranolazine: A Novel Anti-ischemic Drug in Preventing Post-operative Af in Patients Undergoing Coronary Artery Bypasses Grafting: Meta-analysis

Introduction: Atrial fibrillation (AF) is common after coronary artery bypass grafting (CABG). Ranolazine is a novel drug used in the treatment of angina, which also has antiarrhythmic properties. Recent studies demonstrated the benefit of ranolazine in preventing post-operative AF (POAF) in patients undergoing CABG. Hypothesis: To assess the role of ranolazine in preventing POAF in patients undergoing CABG surgery. Methods: We performed comprehensive search of PubMed, MEDLINE, and Cochrane library database on the study assessing the effectiveness of ranolazine in preventing POAF by comparing it with standard therapy. Meta-analysis was performed by fixed effect model by entering POAF events and the total population from each study. Data are expressed as Odds ratio (OR) with 95% confidence interval (CI). Results: A total of three studies with 628 patients (259 pts in ranolazine group, 369 pts in standard therapy group) were included in the meta-analysis. In pooled analysis, ranolazine was associated with 54% reduction in post-operative AF events compared to standard therapy [odds ratio = 0.46 (0.31, 0.70), P&lt;0.001]. The number needed to be treated was 7.14. In one of the study, more patients in ranolazine group (52.2%) had symptomatic hypotension three days after the surgery. Conclusions: Ranolazine may prove beneficial in the prevention of POAF following CABG. However, because of small number of studies further research with large randomized clinical trial is warranted to determine specific dose and duration of ranolazine therapy.

Effects of ranolazine on exercise capacity, right ventricular indices, and hemodynamic characteristics in pulmonary arterial hypertension: a pilot study.

Ranolazine, a late inward sodium current and fatty acid oxidation inhibitor, may improve right ventricular (RV) function in pulmonary arterial hypertension (PAH); however, the safety and efficacy of ranolazine in humans with PAH is unknown. Therefore, we sought to (1) determine whether ranolazine is safe and well tolerated in PAH and (2) explore ranolazine's effect on symptoms, exercise capacity, RV structure and function, and hemodynamic characteristics. We therefore conducted a 3-month, prospective, open-label pilot study involving patients with symptomatic PAH (n = 11) and echocardiographic evidence of RV dysfunction. We evaluated the safety and tolerability of ranolazine and compared symptoms, exercise capacity, exercise bicycle echocardiographic parameters, and invasive hemodynamic parameters between baseline and 3 months of ranolazine therapy using paired t tests. Of the 11 patients enrolled, one discontinued ranolazine therapy due to a drug-drug interaction after 3 days of therapy. All 10 of the remaining patients continued therapy for 3 months, and 8 (80%) of 10 completed all study tests. After 3 months, ranolazine administration was safe and associated with improvement in functional class (P = 0.0013), reduction in RV size (P = 0.015), improved RV function (improvement in RV strain during exercise at 3 months; P = 0.037), and a trend toward improved exercise time and exercise watts on bicycle echocardiography (P = 0.06 and 0.01, respectively). Ranolazine was not associated with improvement in invasive hemodynamic parameters. In conclusion, in a pilot study involving PAH, ranolazine therapy was safe and well tolerated, and it resulted in improvement in symptoms and echocardiographic parameters of RV structure and function but did not alter invasive hemodynamic parameters. ClinicalTrials.gov Identifier: NCT01174173.

Ranolazine and its Antiarrhythmic Actions.

Ranolazine, a newly introduced, FDA-approved antianginal agent, has more recently been shown to have additional beneficial antiarrhythmic actions attributed to its inhibitory effect on both peak and late sodium current. The first clinical evidence of ranolazine's antiarrhythmic efficacy has been provided by the MERLIN-TIMI 36 trial, which showed that ranolazine may suppress both supraventricular and ventricular arrhythmias in patients with non-ST-segment elevation acute coronary syndrome. An interesting observation of available studies is that ranolazine seems to be more effective in pathological conditions, such as heart failure, ischemia, tachyarrhythmias or long QT3 syndrome, and has little effect on normal myocytes. Importantly, the drug may have an antiarrhythmic effect without causing proarrhythmia. The mechanisms involved in the antiarrhythmic action of ranolazine, experimental and clinical data for its antiarrhythmic efficacy in suppressing atrial fibrillation and ventricular tachyarrhythmias, are herein reviewed. Current data from small randomized trials indicate that further larger randomized controlled trials are needed that will examine the antiarrhythmic effects of ranolazine and its potential use in patients with arrhythmias.

Glucose-Lowering Medications and Angina Burden in Patients with Stable Coronary Disease: Results from the Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina (TERISA) Trial

Different classes of glucose-lowering medications have been associated with varying risks of myocardial infarction and cardiovascular death, but their effect on angina is unknown. Therefore, we sought to determine the association of different glucose-lowering medication classes with angina frequency and nitroglycerin (NTG) use. We performed a secondary, observational analysis of the TERISA multinational trial, which evaluated the antianginal effect of ranolazine versus placebo in patients with type 2 diabetes mellitus, documented coronary disease, and a 3-month history of stable angina. Patients recorded angina and NTG use in a daily dairy for 3 weeks prior to randomization, to establish their baseline angina burden for the trial. We then examined the association of different glucose-lowering medication classes with baseline angina and NTG use using multivariable linear regression. Among 952 patients enrolled, 494 were taking metformin, 504 taking a sulfonylurea, 186 taking insulin, 29 taking DPP-4 inhibitors, 22 taking other glucose-lowering medications, and 68 were diet-controlled only. After adjustment for demographic and clinical factors, patients taking versus not taking sulfonylureas had 1.02 more episodes of angina and used 0.93 more doses of NTG per week (P = .002 and .011, respectively). The weekly angina burden or NTG use was not different for those taking versus not taking metformin (P > .7 for both). Patients taking versus not taking insulin had 0.83 more episodes of angina and used 1.40 more NTG doses per week, increases evident only in those taking insulin without concomitant metformin (Pinteraction < .05 for both). Different classes of glucose-lowering medications were associated with varying angina burden in patients with type 2 diabetes mellitus and stable coronary disease. Patients taking sulfonylureas or insulin had more angina and used more NTG, while metformin was not associated with angina burden. Given the increasing prevalence of glucose abnormalities in patients with coronary disease, a better understanding of the relationship between glucose-lowering medications and angina is needed.

Ranolazine inhibits voltage-gated mechanosensitive sodium channels in human colon circular smooth muscle cells.

Human jejunum smooth muscle cells (SMCs) and interstitial cells of Cajal (ICCs) express the SCN5A-encoded voltage-gated, mechanosensitive sodium channel NaV1.5. NaV1.5 contributes to small bowel excitability, and NaV1.5 inhibitor ranolazine produces constipation by an unknown mechanism. We aimed to determine the presence and molecular identity of Na(+) current in the human colon smooth muscle and to examine the effects of ranolazine on Na(+) current, mechanosensitivity, and smooth muscle contractility. Inward currents were recorded by whole cell voltage clamp from freshly dissociated human colon SMCs at rest and with shear stress. SCN5A mRNA and NaV1.5 protein were examined by RT-PCR and Western blots, respectively. Ascending human colon strip contractility was examined in a muscle bath preparation. SCN5A mRNA and NaV1.5 protein were identified in human colon circular muscle. Freshly dissociated human colon SMCs had Na(+) currents (-1.36 ± 0.36 pA/pF), shear stress increased Na(+) peaks by 17.8 ± 1.8% and accelerated the time to peak activation by 0.7 ± 0.3 ms. Ranolazine (50 μM) blocked peak Na(+) current by 43.2 ± 9.3% and inhibited shear sensitivity by 25.2 ± 3.2%. In human ascending colon strips, ranolazine decreased resting tension (31%), reduced the frequency of spontaneous events (68%), and decreased the response to smooth muscle electrical field stimulation (61%). In conclusion, SCN5A-encoded NaV1.5 is found in human colonic circular smooth muscle. Ranolazine blocks both peak amplitude and mechanosensitivity of Na(+) current in human colon SMCs and decreases contractility of human colon muscle strips. Our data provide a likely mechanistic explanation for constipation induced by ranolazine.

Cardioprotective Effect of Ranolazine in the Process of Ischemia-reperfusion in Adult Rat Cardiomyocytes

Introduction and objectivesRanolazine is used as a complementary treatment for angina in symptomatic patients who are inadequately controlled with first-line antianginal therapies. Ranolazine inhibits sodium voltage-dependent channels, suggesting their possible involvement in the reperfusion process by preventing the sodium and calcium overload that occurs during ischemia. In this study, we characterized the effect of ranolazine on calcium homeostasis in isolated adult cardiac myocytes from rats subjected to a simulated ischemia and reperfusion protocol. MethodsThe effects of ranolazine on changes in intracellular calcium concentration were evaluated at different times using field electrostimulation. The study of intracellular calcium was performed using microfluorimetry with the fluorescent indicator, Fura-2, and by confocal microscopy with the indicator, Fluo-3. ResultsWe found that cardiomyocytes subjected to ischemia-reperfusion showed an increase in the diastolic calcium concentration and a decrease in the amplitude of intracellular calcium transients. The application of ranolazine during ischemia significantly improved intracellular calcium handling, preventing intracellular calcium overload, decreasing the diastolic calcium concentration, increasing the sarcoplasmic reticulum calcium load, and preserving the amplitude of the intracellular calcium transient, which was reflected by successful recovery in the process of excitation-contraction coupling during reperfusion. However, these effects of ranolazine did not occur when it was applied during reperfusion or when applied in both ischemia and reperfusion. ConclusionsRanolazine shows beneficial effects in cardiomyocytes exposed to ischemia/reperfusion but only when applied during ischemia. This effect is achieved through its improvement of calcium handling during ischemia.

Efecto cardioprotector de la ranolazina en el proceso de isquemia-reperfusión en cardiomiocitos de rata adultos

Introduction and objectivesRanolazine is used as a complementary treatment for angina in symptomatic patients who are inadequately controlled with first-line antianginal therapies. Ranolazine inhibits sodium voltage-dependent channels, suggesting their possible involvement in the reperfusion process by preventing the sodium and calcium overload that occurs during ischemia. In this study, we characterized the effect of ranolazine on calcium homeostasis in isolated adult cardiac myocytes from rats subjected to a simulated ischemia and reperfusion protocol. MethodsThe effects of ranolazine on changes in intracellular calcium concentration were evaluated at different times using field electrostimulation. The study of intracellular calcium was performed using microfluorimetry with the fluorescent indicator, Fura-2, and by confocal microscopy with the indicator, Fluo-3. ResultsWe found that cardiomyocytes subjected to ischemia-reperfusion showed an increase in the diastolic calcium concentration and a decrease in the amplitude of intracellular calcium transients. The application of ranolazine during ischemia significantly improved intracellular calcium handling, preventing intracellular calcium overload, decreasing the diastolic calcium concentration, increasing the sarcoplasmic reticulum calcium load, and preserving the amplitude of the intracellular calcium transient, which was reflected by successful recovery in the process of excitation-contraction coupling during reperfusion. However, these effects of ranolazine did not occur when it was applied during reperfusion or when applied in both ischemia and reperfusion. ConclusionsRanolazine shows beneficial effects in cardiomyocytes exposed to ischemia/reperfusion but only when applied during ischemia. This effect is achieved through its improvement of calcium handling during ischemia.Full English text available from:www.revespcardiol.org/en

Effects of Ranolazine in Patients With Chronic Angina in Patients With and Without Percutaneous Coronary Intervention for Acute Coronary Syndrome: Observations From the MERLIN-TIMI 36 Trial.

Ranolazine, a piperazine derivative with anti-ischemic effects, reduces the frequency of angina and improves exercise performance in patients with chronic angina. The effects of ranolazine in patients with established ischemic heart disease and chronic angina undergoing percutaneous coronary intervention (PCI) for acute coronary syndromes (ACS) is not well described. We hypothesized that ranolazine would reduce ischemic events, regardless of revascularization. We examined the 1-year incidence of recurrent cardiovascular (CV) events in the subgroup of patients with prior chronic angina (n = 3565) enrolled in the randomized, double-blind, placebo-controlled Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-Elevation ACS (MERLIN)-Thrombolysis In Myocardial Infarction (TIMI) 36 trial who did or did not have a PCI within 30 days of the index event. Ranolazine reduced the risk of recurrent ischemia following admission regardless of whether patients had (hazard ratio [HR], 0.69; 95% confidence interval [CI] 0.51-0.92] or did not have PCI (HR, 0.81; 95% CI, 0.66-0.99; P interaction = 0.39). CV death, myocardial infarction, and recurrent ischemia were similarly lower with ranolazine in the PCI group (HR, 0.71; 95% CI, 0.55-0.91) vs the non-PCI group (HR, 0.91; 95% CI, 0.78-1.06; P interaction = 0.10), with a nominally significant decrease in CV death (HR, 0.39; 95% CI, 0.16-0.93) in the PCI group vs no difference in the non-PCI group (HR, 1.19; 95% CI, 0.89-1.59; P interaction = 0.02). In patients with chronic angina, ranolazine reduced recurrent ischemic events, regardless of whether patients did or did not receive PCI within 30 days of a non-ST-segment ACS.