RABBIT SKELETAL-MUSCLE SARCOPLASMIC-RETICULUM CA2+-ATPASE ACTIVITY - STIMULATION IN-VITRO BY THYROID-HORMONE ANALOGS AND BIPYRIDINES

Sarcoplasmic reticulum-enriched membranes from rabbit skeletal muscle contained Ca2+-ATPase activity which was significantly enhanced (26% increase, P<0.001) in vitro by physiological concentrations (10(-10) M) of L-thyroxine (T-4) and 3,3',5-triiodo-L-thyronine (T-3). In contrast, the biologically inactive iodothyronine analogues D-T-4 and 3,3',5,5'-tetraiodothyroacetic acid (Tetrac) (10(-10) M) were without effect on enzyme activity. 3,5-Dimethyl-3'-isopropyl-L-thyronine (Dimit), a bioactive analogue, was highly effective as a Ca2+-ATPase stimulator, increasing enzyme activity by 43% (P<0.02 vs. T-4 effect). A bipyridine cardiac inotropic agent, milrinone, has been reported to be thyromimetic in a myocardial membrane Ca2+-ATPase system, and in concentrations from 10(-10) to 10(-5) M enhanced skeletal muscle SR membrane Ca2+-ATPase activity in vitro (P<0.001). Milrinone analogues which have been previously shown to enhance rabbit myocardial membrane Ca2+-ATPase activity, and which have a twist relationship of the pyridine rings, were also striated muscle Ca2+-ATPase stimulators. We conclude that (1) striated muscle is a mammalian tissue in which physiological levels of biologically relevant thyroid hormone analogues, particularly Dimit, stimulate Ca2+-ATPase activity in vitro by a non-genomic mechanism; (2) cardiac bipyridine analogues which are thyromimetic in vitro in rabbit heart, and which have structural homologies with thyroid hormone, are stimulators of rabbit striated muscle sarcoplasmic reticulum Ca2+-ATPase activity.