tetracycline and Cardiomyopathies

Cell loss contributes to the pathogenesis of many inherited and acquired human diseases. We have developed a system to conditionally ablate cells of any lineage and developmental stage in the mouse by regulated expression of the diphtheria toxin A (DTA) gene by using tetracycline-responsive promoters. As an example of this approach, we targeted expression of DTA to the hearts of adult mice to model structural abnormalities commonly observed in human cardiomyopathies. Induction of DTA expression resulted in cell loss, fibrosis, and chamber dilatation. As in many human cardiomyopathies, transgenic mice developed spontaneous arrhythmias in vivo, and programmed electrical stimulation of isolated-perfused transgenic hearts demonstrated a strikingly high incidence of spontaneous and inducible ventricular tachycardia. Affected mice showed marked perturbations of cardiac gap junction channel expression and localization, including a subset with disorganized epicardial activation patterns as revealed by optical action potential mapping. These studies provide important insights into mechanisms of arrhythmogenesis and suggest that conditional lineage ablation may have wide applicability for studies of disease pathogenesis.

Topics: Action Potentials; Animals; Cardiomyopathies; Connexins; Diphtheria Toxin; Disease; Disease Models, Animal; Fluorescent Antibody Technique; Gap Junction alpha-5 Protein; Gene Targeting; Heart; Histocytochemistry; Humans; Mice; Mice, Transgenic; Myocardium; Promoter Regions, Genetic; Tachycardia, Ventricular; Tetracycline

Methods currently used to quantitate myocardial damage and necrosis produced by chemicals are usually time consuming and subjective. These studies were conducted to evaluate the utility of 3H-tetracycline as a means of quantitating myocardial necrosis produced by isoproterenol. Male, Sprague-Dawley derived rats (180-200 g) were treated with (+/-)-isoproterenol HCl (0.1-100 mg/kg, s.c.) or equivalent volumes of saline. After 90 minutes, all rats received 50 uCi/kg of 3H-tetracycline. Rats were sacrificed 3 hours after 3H-tetracycline administration and the hearts were removed and rinsed free of blood. The degree of radioactivity of the heart as determined by liquid scintillation counting was directly proportional to the dose of isoproterenol. Propranolol pretreatment decreased the accumulation of radioactivity in a dose-dependent fashion. Determination of 3H-tetracycline accumulation appears to be a rapid and reliable method for quantitating isoproterenol-induced myocardial necrosis.

Topics: Animals; Cardiomyopathies; Dose-Response Relationship, Drug; Isoproterenol; Male; Myocardium; Necrosis; Propranolol; Rats; Tetracycline

Topics: Animals; Cardiomyopathies; Disease Models, Animal; Isoproterenol; Myocardium; Rats; Technetium; Tetracycline; Tin