ABSTRACT
Clinical trials have shown dexamethasone's beneficial effects on the pulmonary status of infants with bronchopulmonary dysplasia; however, hypertrophic cardiomyopathy has been a reported complication of this therapy with no known mechanism. Our study was designed to test the hypothesis that therapeutic dexamethasone doses would induce myocardial hypertrophy. Newborn Sprague-Dawley rats were randomly assigned to receive dexamethasone 0.125 mg/kg/day, while paired littermate controls received saline placebo. The daily body weights were recorded and pups were sacrificed after 5 or 7 days of treatment. The heart weight to body weight ratio was used as a gross index of myocardial mass. Myocardial protein content, total protein to total DNA ratio, actin content and myosin heavy chain content were used as biochemical indices of hypertrophy. Our results included an increased heart weight to body weight ratio with elevation of the total protein content, actin content and total protein to total DNA ratio after both 5 and 7 days. We conclude that dexamethasone induces myocardial hypertrophy in neonatal rats.
Subject(s)
Body Weight/physiology , Cardiomegaly/chemically induced , Dexamethasone/adverse effects , Glucocorticoids/adverse effects , Heart/physiology , Actins/analysis , Actins/metabolism , Animals , Animals, Newborn , Body Weight/drug effects , DNA/analysis , DNA/metabolism , Dexamethasone/administration & dosage , Female , Glucocorticoids/administration & dosage , Heart/anatomy & histology , Heart/drug effects , Injections, Intraperitoneal , Myosins/analysis , Myosins/metabolism , Organ Size/drug effects , Organ Size/physiology , Pregnancy , Proteins/analysis , Proteins/metabolism , Random Allocation , Rats , Rats, Sprague-Dawley , Time FactorsABSTRACT
Thyroid hormone exerts marked effects on cardiovascular function. Expression of cardiac alpha- and beta-myosin heavy chain (MHC) isoforms can be altered in response to thyroid hormone as well as by hemodynamic changes imposed on the heart. The molecular mechanisms that mediate these changes are not completely known. We studied the contractile and thyroid hormone responsiveness of the betaMHC promoter in both cultured cardiac myocytes and in vivo by direct DNA transfer. Using transient transfection of neonatal rat cardiomyocytes, the activities of recombinant reporter plasmids containing betaMHC 5'-flanking sequences terminating at positions -2250, -1145, -670, and -354 were decreased significantly in cultures containing L-T3 (50 nM). Similar deletion analysis showed that 5'-flanking regions terminating within -2250 to -151 bp were contractility responsive; however, deletion to position -126 attenuated this response. In vivo betaMHC promoter activity, determined by injecting the recombinant plasmid into the myocardium, was significantly higher by 2-fold in hyperthyroid than in euthyroid ventricles (2.47 +/- 0.41 vs. 1.33 +/- 0.25 luciferase/ chloramphenicol acetyltransferase; P<0.05). Increased ventricular workload, produced by aortic coarctation for 5 days, resulted in ventricular hypertrophy (heart/body weight, 4.05 +/- 0.19 vs. 3.42 +/- 0.16 mg/g; P < 0.02) and a 3.4-fold increase in betaMHC messenger RNA content. However, betaMHC promoter activity in vivo was not significantly different between rats experiencing aortic coarctation and sham-operated rats (1.49 +/- 0.41 vs. 0.96 +/- 0.27 luciferase chloramphenicol acetyltransferase, respectively) and was similar to that in euthyroid animals. These results show that betaMHC promoter activity is T3 responsive in cultured myocytes and in vivo, but that the increase in betaMHC messenger RNA observed in the in vivo pressure overloaded myocardium cannot be explained entirely by transcription control mechanisms.
