CISPLATIN-INDUCED INHIBITION OF THE CALCIUM-CALMODULIN COMPLEX, NEURONAL NITRIC-OXIDE SYNTHASE ACTIVATION AND THEIR ROLE IN STOMACH DISTENSION

Cisplatin (8 mg/kg; i.p.) treatment of Wistar rats produced no change in nitric oxide synthase (NOS) localization or its intensity for up to 5 days. However, immunohistochemically the levels of L-citrulline and the Ca2+-calmodulin complex were decreased after only 3 days. An in v itro experiment using an analog of calmodulin, Mero-Calmodulin-1, show ed that cis-diammine-diaquacisplatinum(II), a hydrolyzed form of cispl atin, inhibited the calmodulin conformational shift from occurring thr ough a direct interaction with the calmodulin molecule. The results in dicate that distention of the stomach was due to inhibition of neurona l NOS activation by a direct interaction between cisplatin and the cal cium binding sites of the calmodulin molecule.