Paolo-Emilio Puddu

Cicletanide Improves Outcome After Left Circumflex Coronary Artery Occlusion-Reperfusion in the Dog

Summary: The possible antifibrillatory effect of cicletanide, a new diuretic antihypertensive drug, was investigated at random in 50 anesthetized dogs subjected to left circumflex coronary artery ligation for 60 min and later reperfused. In this model, standard electrocardiographic leads 2 and 3 were continuously registered to measure ΔR wave percent changes, to count the number of ventricular premature beats, and to document the onset of ventricular fibrillation; aortic pressure was recorded; 6-keto PGF1α and TXB2 plasma levels were determined. Cicletanide significantly reduced early (Phase 1a) postischemic ventricular fibrillation (5 of 25 vs. 12 of 25, p = 0.036) but failed to reduce the incidence of global ischemia-induced ventricular fibrillation. On the other hand, the incidence of postreperfusion ventricular fibrillation was lower in the cicletanide group (1 of 14 vs. 5 of 9, p = 0.04). In addition, the total survival rate was improved in cicletanide treated dogs (p = 0.0257). While the rate-pressure product was lowered by the drug independent of the presence of ischemia, ΔR% changes after occlusion were less in treated dogs than in controls. Moreover, the drug reduced significantly the number of ventricular premature beats in the early (Phase 1a) postischemic period. Finally, the drug increased (mean twofold) the plasma levels of 6-keto PGF1α as compared with controls; however, this increase was less than that achieved (mean 20-fold) after 100 ng/kg/min epoprostenol (prostacyclin) given in a further series of animals. Thus, improved outcome follows 10 mg/kg i.v. cicletanide administration in this model.

Molsidomine prevents post-ischaemic ventricular fibrillation in dogs.

1 Forty anaesthetized dogs were subjected to left circumflex coronary artery ligation followed by reperfusion. Molsidomine was randomly administered to 20 dogs (50 μg kg−1 as an i.v. bolus −15 min prior to coronary occlusion – followed by an infusion of 0.05 μg kg−1 min−1). Standard electrocardiographic leads 2 and 3 were continuously recorded to measure ST segment and ΔR% changes and to document both the number of ventricular premature beats and the onset of ventricular fibrillation; aortic pressure and cardiac output were measured; thromboxane B2 plasma levels, platelet aggregation produced by ADP, and molsidomine plasma levels were determined before and at 10, 30 and 75 min after the start of the drug protocol. 2 Molsidomine protected the treated animals from early (10 min) post‐ischaemic ventricular fibrillation (0 of 20 vs 6 of 20, P = 0.0202), reduced the incidence of overall post‐occlusion ventricular fibrillation (3 of 20 vs 10 of 20, P = 0.0407) and improved the total survival rate (P = 0.0067). 3 In molsidomine treated dogs: mean aortic pressure and the rate‐pressure product were lowered 10 min after the start of the drug; immediate post‐occlusion (3 min) ST segment changes (0.82 ± 0.52 vs 1.52 ± 0.78 mV, P < 0.025) and ΔR% changes (37 ± 50 vs 90 ± 84%, P < 0.025) were less marked; the number of ventricular premature beats was lowered and finally, a progressive decline of platelet aggregation produced by ADP was achieved after 75 min of drug infusion. 4 These results were obtained in the presence of mean plasma levels of molsidomine ranging from 20 to 28 ng ml−1. 5 The time‐action curve of the antifibrillatory effect of molsidomine parallels those at the level of post‐ischaemic electrocardiographic changes.

Proarrhythmic effects of aldosterone during myocardial ischemia-reperfusion: implication of the sarcolemmal-KATP channels.

Objective: To assess the electrophysiological impact of aldosterone during myocardial ischemia–reperfusion. Methods: We used an in vitro model of “border zone” using rabbit right ventricle and standard microelectrodes. Results: Aldosterone (10 and 100 nmol/L) shortened ischemic action potential [action potential duration at 90% of repolarization (APD90), from 55 ± 3 to 39 ± 1 ms and 36 ± 3 ms, respectively, P < 0.05] and induced resting membrane potential (RMP) hyperpolarization in the nonischemic zone (from −83 ± 1 to −93 ± 7 mV and −94 ± 3 mV, respectively, P < 0.05) and in the ischemic zone during reperfusion (from −81 ± 2 to −88 ± 2 mV and −91 ± 2 mV, respectively, P < 0.05). Bimakalim, an ATP-sensitive potassium (KATP) channel opener, also induced RMP hyperpolarization and APD90 shortening. Aldosterone (10 and 100 nmol/L) increased APD90 dispersion between ischemic and nonischemic zones (from 96 ± 3 to 117 ± 5 ms and 131 ± 6 ms, respectively, P < 0.05) and reperfusion-induced severe premature ventricular contraction occurrence (from 18% to 67% and 75%, respectively, P < 0.05). Adding glibenclamide, a nonspecific KATP antagonist, to aldosterone superfusion abolished these effects different to sodium 5-hydroxydecanoate, a mitochondrial-KATP antagonist. Conclusions: In this in vitro rabbit model of border zone, aldosterone induced RMP hyperpolarization and decreased ischemic APD90 evoking the modulation of K+ currents. Glibenclamide prevented these effects different to 5-hydroxydecanoate, suggesting that sarcolemmal-KATP channels may be involved in this context.

Dronedarone versus amiodarone in preventing premature ventricular contractions in an in vitro model of "border zone".

Objective: To compare the acute ability of amiodarone and dronedarone (a noniodinated benzofuran derivative with a pharmacologic profile similar to amiodarone) to prevent premature ventricular contractions (PVCs) occurrence. Methods: We used an in vitro model of rabbit right ventricle mimicking the “border zone” existing between normal and ischemic/reperfused regions to test acute electrophysiological effects of dronedarone and amiodarone both at 1 and 10 &mgr;mol/L. Results: Similar to amiodarone, dronedarone affected action potential parameters with multichannel blocking properties. Dronedarone at both concentrations was equivalent to amiodarone regarding PVCs occurrence, except regarding extrasystoles occurrence during the reperfusion period (dronedarone, 10 &mgr;mol/L, was superior to amiodarone with extrasystoles incidence at 33% and 50%, respectively vs. 92% in controls, P < 0.05). Both dronedarone and amiodarone systematically induced conduction blocks during simulated ischemia (in 100% of preparations vs. 42% in controls, P < 0.05) and a marked decrease of Vmax (to 24 and 23 V/s at 10 minutes of ischemia with 1 and 10 &mgr;mol/L dronedarone versus 65 V/s in controls, P < 0.05), thus indicating class 1 antiarrhythmic effects. Both dronedarone and amiodarone at 10 &mgr;mol/L induced an increase of APD90 dispersion between normal and ischemic regions, without pro-arrhythmic effects. Conclusions: Dronedarone and amiodarone have very similar electrophysiological effects in this in vitro model of border zone and were both efficient in preventing PVCs occurrence particularly through a class 1 antiarrhythmic effect.

Aldosterone and testosterone: two steroid hormones structurally related but with opposite electrophysiological properties during myocardial ischemia–reperfusion

Steroid hormones appear to be a key factor in the gender differences in the rates and severity of cardiovascular diseases. Aldosterone and testosterone have typical steroid ring structure, but despite this, they demonstrate very different properties. During acute myocardial ischemia–reperfusion, the deleterious impact of aldosterone is now well established. Conversely, the electrophysiological impact of testosterone in this context remained unknown. We used female rabbit in vitro models and standard microelectrode technique including right ventricle mimicking the ‘border zone’ existing between normal and ischemic/reperfused areas and isolated right ventricle experiments to assess the acute electrophysiological impact of both aldosterone and testosterone. During ischemia–reperfusion, acute superfusion of 10 and 100 nmol/L testosterone decreased normoxic and reperfused action potential duration at 90% (APD90), systematically induced conduction blocks, and decreased APD90 dispersion between ischemic and nonischemic areas (from 98 ± 4 to 57 ± 7 ms and 66 ± 3 ms, for, respectively, testosterone 10 and 100 nmol/L, P < 0.05). Testosterone 10 and 100 nmol/L concomitantly decreased sustained premature ventricular contraction (PVC) occurrence (from 55 to 0%, P < 0.05). Conversely, aldosterone 10 and 100 nmol/L increased normoxic and reperfused APD90, APD90 dispersion, and reperfusion‐induced PVCs. Furthermore, testosterone demonstrated cycle length‐dependent effects on APD90 for high heart rate, whereas aldosterone did not exhibit any significant effect compared with controls. During acute myocardial ischemia–reperfusion, acute superfusion of physiological concentrations of testosterone seemed to be anti‐arrhythmic by removing a pro‐arrhythmic substrate (APD90 dispersion), inducing conduction blocks and decreasing triggered activities (PVC occurrence). Further experiments are warranted to confirm our results.

Long delay to onset of ACE inhibitors-induced cough: Reason of difficult diagnosis in primary care? ☆

Angiotensin converting enzyme inhibitors (ACEI) were first introduced in 1981. They are widely used in the field of hypertension, heart failure and kidney dysfunction. In general, ACEI are effective in a high percentage of patients and are well tolerated. However, cough might sometimes appear. The cough is typically dry and is associated with a tickling or scratching sensation in the throat [1]. ACEI-induced cough is not dose-dependant [2]. In a metanalysis of clinical trials, Bangalore et al. showed that ACEI cough appears in 11.48% of cases and authors suggested that ACEI-induced cough was generally underestimated [3]. Vegter et al. have previously shown that an excess of patients who were taking ACEI and reported cough initially received antitussives and pointed that cough was not recognized as an ACEI adverse event [4]. These results are in line with previous reports that ACEI-induced cough is a difficult diagnosis in daily clinical practice [5]. It is admitted that cough develops within a month of starting treatment, although others suggest that cough may occur at any time [6]. Therefore, our study objective was to determine the ACEI-induced cough delay of onset after treatment initiation in the French pharmacovigilance database (FPD). The French pharmacovigilance systemconsists of a network of 31 regional centers established in 1985 to record spontaneously occurring adverse events. Case causality assessment is performed for all adverse effects registered in the FPB in accordancewith the French standardized practice [7]. It contains 5 intrinsic causality levels: I0, excluded; I1, dubious; I2, plausible; I3, likely; I4, very likely. Spontaneous cough reports submitted to the FPD by general practitioners and pharmacists, from 1 January 1985 to 31 April 2015, in which ACEI were reported (whatever the dosages and formulations) and considered as ‘suspected’ (I1, I2, I3 and I4 levels of causality assessment), were extracted. A total number of 446 spontaneous notifications were registered in the FPD fromprimary care. Themale:female sex ratio was 0.5 and themean agewas 64 years (range 22–92). Patientswere essentially treated for hypertension (93.1%) with enalapril (30.3%), captopril (24.2%) or ramipril (14.3%).When reported (n= 179) average time from ACE

Electrophysiological and Antiarrhythmic Properties of Potassium Canrenoate During Myocardial Ischemia–Reperfusion

Introduction: Recent clinical studies have reported the potential benefit of an early mineralocorticoid receptor (MR) blockade with potassium canrenoate (PC) on ventricular arrhythmias (VAs) occurrence in patients experiencing an ST-segment elevation myocardial infarction (STEMI). However, most of the electrophysiological properties of PC demonstrated to date have been investigated in normoxic conditions, and therefore, in vitro experiments during an acute myocardial ischemia–reperfusion were lacking. Materials and Methods: We used rabbit in vitro models and standard microelectrode technique to assess the electrophysiological impact of PC during myocardial ischemia–reperfusion, including right ventricle mimicking the “border zone” existing between normal and ischemic/reperfused areas (1 µmol/L, 10 and 100 nmol/L), isolated right ventricle, and sinoatrial node (SAN) experiments (1 µmol/L, respectively). Results: During ischemia–reperfusion, acute superfusion of PC 100 nmol/L prevented the increase in action potential (AP) duration at 90% of repolarization (APD90) dispersion between ischemic and nonischemic areas and in VAs occurrence induced by aldosterone 10 nmol/L (86 ± 3 vs 114 ± 4 milliseconds for aldosterone alone, P < .05). Potassium canrenoate also induced conduction blocks and significantly decreased Vmax during simulated ischemia (from 25 ± 5 to 12 ± 4, 14 ± 3, and 14 ± 5 V/s, respectively, for PC 1 µmol/L, 100, and 10 nmol/L, P < .05). Potassium canrenoate 1 µmol/L demonstrated cycle length (CL)-dependent effects on APD90 and on Vmax, and it also reduced SAN beating CL (from 446 ± 28 to 529 ± 24 millisecond, P < .05). Conclusion: Our experimental study highlights new evidence for an antiarrhythmic impact of PC during myocardial ischemia–reperfusion via multiple channels modulation. These results are in line with recent clinical trials suggesting that an early MR blockade in STEMI may be preventive of VAs.

Systèmes d’acquisition de potentiels d’action : comment mesurer les Vmax élevées ?

This investigation was aimed at increasing both accuracy and performance of systems used to obtain and measure V(max) (dV/dt(max)), an important yet underevaluated physiological parameter. A method is presented to correct measured V(max) (V(mes)) based on an algorythm adapted to 2 tested systems: IOX and DataPac. We also investigated 89 rabbit Purkinje fibres (before and 30 min following drugs effective on ventricular repolarization) to derive experimental electrophysiological correlations. In fact, no method may be reliable without knowing its accuracy over a large scale of representative physiological values. This is why it is essential to estimate accuracy, precision and fidelity of systems aimed at action potential recording before pharmacological or pathophysiological investigations are performed, even more if therapeutical consequences might ensue. A formula is presented to obtain real V(max), based on V(mes) [V(max)=V(mes)/1 - (tau.V(mes)/APA)(2.p)], where tau=49.64 µs, p=0.72 and APA=action potential amplitude. This formula is reliable up to V(max) values of 1000 V/s which may be seen in rabbit Purkinje fibres, a classical model for in vitro studies. Using this formula may have practical implications in cellular electrophysiology which may impact on safety pharmacology and therapeutics.

Cardiac Arrests Associated with Low Plasma and Tissue Levels of Local Anaesthetics.

Although local anaesthetics cardiac toxicity is usually the result of high local anaesthetics dose, based on a pharmacovigilance case report and an analyze of the French Pharmacovigilance Database between January 1st, 2007 and December 31st, 2013, we hypothesized that in some patients, the combination of medical or drug risk factors may be responsible for cardiac anaesthetics toxicity at lower plasma concentrations.