Inhibition of secretion of rat calcitonin by calmodulin inhibitors

Summary

Studies were designed to investigate the potential importance of calmodulin in release of calcitonin (CT) in response to an increase in the concentration of extracellular Ca.In vitro release of CT from baby rat thyroparathyroids incubated up to 8 h was examined at normal (1 mM) and high (2.5 mM) Ca in serum-free medium in the presence and absence of the potent calmodulin inhibitors, trifluoperazine (TFP) and N-(6-aminohexyl)-5-Cl-1-naphthalene sulfonamide (W-7). The drugs chloropromazine (CLP) and haloperiodol (HAL) which, like TFP, are anti-psychotic agents also were tested. In some studies release of parathyroid hormone (PTH) into medium also was studied. At 2.5 mM Ca, CT release was increased five- tenfold compared with 1 mM Ca while PTH was suppressed by ≈ 80%. The increased release of CT induced by 2.5 mM Ca was inhibited 60–90% by 10⁻⁴ M TFP and 10⁻⁴ M W-7, but was unaffected by 10⁻⁴M CLP or HAL. In the presence of 1 mM Ca, the increased release of PTH also was inhibited significantly by 10⁻⁴ M TFP and 10⁻⁴ M W-7. In relatedin vivo studies, administration of TFP i.v. to rats just before induction of hypercalcemia with i.v. CaCl₂ suppressed the increase in plasma CT normally observed 3 min later in a dose-related manner. The results show that calmodulin inhibitors can inhibitin vitro secretion of CT, and release of PTH as well. Additionally, inhibition of thein vivo CT response to a Ca challenge was observed within minutes of drug administration. The findings support the notion that calmodulin plays an important role in Ca-mediated release of CT from the C-cell.