Cyclosporin A does not block exercise-induced cardiac hypertrophy.

Abstract

Cyclosporin A (CsA) has been shown to inhibit pathophysiological models of overload-induced cardiac hypertrophy, indicating a role for the calcium dependent signal pathways. It is unclear what impact CsA may have on the myocardial response to exercise, a physiological model of overload. The purpose of the study was to determine whether CsA would alter exercise-induced cardiac hypertrophy. Thirty male rats were assigned to vehicle or CsA injection (15 mg.kg.d(-1)) and then assigned to sedentary or exercise training. Animals were swum for 60 min.d(-1) for 1 wk. One week of swim training significantly increased plantaris cytochrome oxidase activity, as well as significantly increasing left ventricular (LV) weight and the left ventricular:body weight (LV/BW) ratio. Exercise did not alter right ventricular (RV) weight or the RV/BW ratio. RNA analysis found that exercise significantly increased atrial natriuretic factor (ANF)-mRNA levels but did not influence alpha-myosin heavy chain (MHC) expression. CsA treatment, but not exercise, was associated with a significant increase in betaMHC expression. Western blot analysis determined that betaMHC protein was also significantly increased in the CsA-treated animals. CsA did not block exercise-induced cardiac hypertrophy but did significantly influence the myocardial phenotype. The CsA-sensitive calcium dependent pathways, important for pathological forms of overload-induced hypertrophy, were not essential to the early adaptations to exercise and that a different mechanism or signal transduction pathway was engaged. The data also indicate that CsA alone may induce a shift in the MHC isoform expression toward that associated with a pathological phenotype. Whether this phenotype shift contributes to the lowered exercise capacity found in transplant patients remains to be determined.