delapril and Ventricular-Fibrillation

Angiotensin-converting enzyme inhibitors (ACE-I) improve clinical outcome in patients with myocardial infarction (MI) and chronic heart failure. We investigated potential anti-arrhythmic (AA) benefits in a mouse model of ischemic HF. We hypothesized that normalization of diastolic calcium (Ca(2+)) by ACE-I may prevent Ca(2+)-dependent reduction of inward rectifying K(+) current (IK1) and occurrence of arrhythmias after MI. Mice were randomly assigned to three groups: Sham, MI, and MI-D (6 weeks of treatment with ACE-I delapril started 24h after MI). Electrophysiological analyses showed that delapril attenuates MI-induced prolongations of electrocardiogram parameters (QRS complex, QT, QTc intervals) and conduction time from His bundle to ventricular activation. Delapril improved the sympatho-vagal balance (LF/HF) and reduced atrio-ventricular blocks and ventricular arrhythmia. Investigations in cardiomyocytes showed that delapril prevented the decrease of IK1 measured by patch-clamp technique. IK1 reduction was related to intracellular Ca(2+) overload. This reduction was not observed when intracellular free-Ca(2+) was maintained low. Conversely, increasing intracellular free-Ca(2+) in Sham following application of SERCA2a inhibitor thapsigargin reduced IK1. Thapsigargin had no effect in MI animals and abolished the benefits of delapril on IK1 in MI-D mice. Delapril prevented both the prolongation of action potential late repolarization and the depolarization of resting membrane potential, two phenomena known to trigger abnormal electrical activities, promoted by MI. In conclusion, early chronic therapy with delapril after MI prevented Ca(2+)-dependent reduction of IK1. This mechanism may significantly contribute to the antiarrhythmic benefits of ACE-I in patients at risk for sudden cardiac death.

Topics: Action Potentials; Angiotensin-Converting Enzyme Inhibitors; Animals; Calcium Signaling; Cells, Cultured; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Indans; Male; Mice; Myocardial Contraction; Myocardial Ischemia; Myocytes, Cardiac; Potassium; Potassium Channels, Inwardly Rectifying; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Thapsigargin; Ventricular Fibrillation

Angiotensin converting enzyme (ACE) inhibitors and Angiotensin II (AII) receptor blockers have previously been shown to be beneficial in treating patients with not only hypertension but also with cardiovascular diseases. Therefore, such drugs may potentially be used in patients with an implantable cardioverter defibrillator (ICD) who show cardiac dysfunctions.. This study aimed to determine effects of short-term administration of the ACE inhibitor (CV-3317) and the AII receptor blocker (CV-11974, an active form of candesartan) on internal defibrillation threshold (DFT) in anesthetized canine hearts.. DFTs were evaluated using a "hot can" defibrillation lead system in: (a) seven dogs following three intravenous administrations of 20 cc saline; (b) 11 dogs that received intravenous CV-3317 doses of 1 mg/kg, 10 mg/kg, and 50 mg/kg; and in (c) 10 dogs that were intravenously given 0.1 mg/kg, 1 mg/kg, and 10 mg/kg CV-11974. DFTs were determined using a "down-up down-up" protocol.. Mean DFT delivered energies at baseline and following three consecutive intravenous saline injections were 16.4 +/- 9.3 J, 15.3 +/- 7.5 J, 15.9 +/- 7.1 J, and 15.5 +/- 5.6 J, respectively. Those at baseline and following 1 mg/kg, 10 mg/kg, and 50 mg/kg intravenous CV-3317 were 12.9 +/- 6.4 J, 12.2 +/- 6.4 J, 11.0 +/- 6.6 J, and 11.9 +/- 6.6 J, respectively. Similarly, those at baseline and after 0.1 mg/kg, 1 mg/kg, and 10 mg/kg CV-11974 were 13 +/- 6.6 J, 12.5 +/- 6 J, 12.9 +/- 5.8 J, and 13.2 +/- 6.6 J, respectively. There were no significant differences between DFT at baseline and the others in each treatment group.. Since an ACE inhibitor and an AII receptor blocker did not alter DFT, such drugs may be useful in ICD patients without a decrease in safety margins.

Topics: Analysis of Variance; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Defibrillators, Implantable; Dogs; Indans; Tetrazoles; Ventricular Fibrillation