Endothelin receptor antagonist prevents parathyroid cell proliferation of low calcium diet-induced hyperparathyroidism in rats

Secondary hyperparathyroidism, one of the most frequently encountered disor ders of the calcium homeostasis, is characterized by an increase in parathy roid epithelial (PT) cell number, which is crucial from a functional viewpo int. However, it is still unknown what factors are involved in PT cell prol iferation. Endothelin-l (ET-1), a vasoconstrictive peptide, has been shown to act as a mitogen in a variety of cell types. Rat PT cells are reported t o synthesize ET-1 and possess its receptors. To test the hypothesis that ET -1 plays a role in PT cell proliferation, we used rat test subjects fed a l ow calcium diet for 8 weeks (low Ca rats). The number of the proliferating PT cells, measured by proliferating cell nuclear antigen immunostaining, wa s significantly increased, with striking immunoreactivity of ET-1 in the lo w Ca rats. An endothelin receptor antagonist, bosentan (100 mg/kg.day), pre vented any increase in the proliferation of PT cells in the low Ca rats (14 .3 +/- 2.7/1000 PT cells with no bosentan; 2.1 +/- 1.3 with bosentan; P < 0 .01). These results indicate that ET-1 is involved in PT cell proliferation in vivo and suggest that blocking of ET receptors may become one of the im portant therapeutic strategies for preventing secondary hyperparathyroidism .