EFFECT OF CALCITRIOL AND ITS ANALOGS, CALCIPOTRIOL (MC-903) AND 20-EPI-1-ALPHA,25-DIHYDROXYVITAMIN-D-3 (MC-1288), ON CALCIUM INFLUX AND DNA-SYNTHESIS IN CULTURED MUSCLE-CELLS

The fast actions of the secosteroid hormone 1 alpha,25-dihydroxyvitami n D-3 [1,25(OH)(2)D-3; calcitriol] and the synthetic analogues calcipo triol (MC 903) and 20-epi-1 alpha,25(OH)(2)D-3 (MC 1288) on cell calci um influx were compared in rat duodenum enterocytes as well as in cell s from chick embryo skeletal muscle (myoblasts) and heart (myocytes), at various concentrations (10(-12) to 10(-8) M) and treatment interval s (1-10 min). In enterocytes, at a concentration of 10(-11) M, MC 1288 was significantly more active than 1,25(OH)(2)D-3 in rapidly stimulat ing Ca-45(2+) uptake by enterocytes (80 vs 38% above controls, respect ively), whereas MC 903 was devoid of activity. However, calcipotriol i ncreased Ca2+ influx in myocytes and myoblasts to a greater extent tha n the natural hormone, whereas MC 1288 was more active only in myoblas ts. Analogously to 1,25(OH)(2)D-3, the fast MC 903- and MC 1288-induce d stimulation of Ca-45(2+) uptake in enterocytes and muscle cells coul d be blocked by both verapamil and nifedipine. In addition, MC 903 and MC 1288 were more effective than 1,25(OH)(2)D-3 in stimulating DNA sy nthesis in proliferating myoblasts and in inhibiting DNA synthesis in differentiating myoblasts. The results suggest, therefore, that modifi cations in the side-chain of the 1,25(OH)(2)D-3 molecule increase its ability to modulate muscle cell Ca2+ metabolism and growth. These find ings are potentially relevant for the development of analogues for the treatment of vitamin D-dependent myopathies. (C) 1997 Elsevier Scienc e Inc.