Role of Calcium in Vomiting

Abstract

Cisplatin-like chemotherapeutics cause vomiting via calcium (Ca 2+)-dependent release of multiple neurotransmitters/mediators (dopamine, serotonin, substance P, prostaglandins and leukotrienes) from the gastrointestinal enterochromaffin cells and/or the brainstem. Intracellular Ca 2+ signaling is triggered by activation of diverse emetic receptors (including neurokininergic NK 1 , serotonergic 5-HT 3 , dopaminergic D 2 , cholinergic M 1 , or histaminergic H 1) , whose stimulation in vomit-competent species evokes emesis. Other emetogens such as cisplatin, rotavirus NSP4 protein, and bacterial toxins can also induce intracellular Ca 2+ elevation. Our findings demonstrate that application of the L-type Ca 2+ channel (LTCC) agonist FPL 64176 and the intracellular Ca 2+ mobilizing agent thapsigargin (a sarco/endoplasmic reticulum Ca 2+-ATPase inhibitor) cause vomiting in the least shrew. On the other hand, blockade of LTCCs by corresponding antagonists (nifedipine or amlodipine) not only provide broad-spectrum antiemetic efficacy against diverse agents that specifically activate emetogenic receptors such as 5-HT 3 , NK 1 , D 2 , and M 1 receptors, but can also potentiate the antiemetic efficacy of palonosetron against the nonspecific emetogen, cisplatin. In this review, we will provide an overview of Ca 2+ involvement in the emetic process; discuss the relationship between Ca 2+ signaling and the prevailing therapeutics in control of vomiting; highlight the current evidence for Ca 2+signaling blockers/inhibitors in suppressing emetic behavior and also draw attention to the clinical benefits of Ca 2+-signaling blockers/inhibitors for the treatment of nausea and vomiting.