Broad-spectrum antiemetic potential of the L-type calcium channel antagonist nifedipine and evidence for its additive antiemetic interaction with the 5-HT3 receptor antagonist palonosetron in the least shrew (Cryptotis parva)

Role of Calcium in Vomiting: Revelations from the Least Shrew Model of Emesis

“…25 Voltage-gated L-type Ca 2+ channels (LTCCs) are activated by membrane depolarization, and serve as the principal route of Ca 2+ entry in electrically excitable cells such as neurons and muscle. 26,27 Our study 28 provided the first evidence that the opening of plasma membrane LTCCs by the corresponding selective agonist FPL-64176 29 produces robust vomiting both in terms of its frequency and the percentage of animals vomiting. All tested shrews vomited at the 10 mg/kg dose of FPL 64176 administered intraperitoneally (i.p.…”

“…28 Indeed, complete blockade of 2-Me-5-HT-induced vomiting was achieved at 10 mg/kg dose of nifedipine, whereas a 10 mg/kg dose of potent and selective 5-HT 3 receptor antagonists such as tropisetron, 47 or palonosetron, could not provide such complete protection against 2-Me-5-HT-induced vomiting in least shrews under similar experimental conditions. 28 These findings suggest that FPL 64176, 2-Me-5-HT, or serotonin, probably drive extracellular Ca 2+ through both L-type-and 5-HT 3 receptor-ion channels; and/or ligands of both proteins may interact with each other's binding site. In fact Hargreaves et al 6 have demonstrated that members of all three major classes of L-type Ca 2+ antagonists can reverse the ability of the 5-HT 3 receptor-selective agonist 1-(m-chlorophenyl)-biguanide to increase intracellular Ca 2+ concentration in cell lines that possess either one or both of these Ca 2+ -ion channels.…”

“…with respective ID 50 values 2-12 times larger than that of nifedipine. 28,33 Thus, comparatively nifedipine appears to be more potent than amlodipine in suppression of emetic behaviors evoked by 2-Me-5-HT.…”

“…requires more exposure time (30-45 min) to begin to induce emesis in the least shrew since only its metabolites are emetogenic. 39 Lack of antiemetic action of nifedipine versus the efficacy of amlodipine in reducing the frequency of cisplatin-induced vomiting by 80% 28,33 could be explained in terms of amlodipine having more exposure time not only to reach its sites of action, but also to compensate for its slower receptor binding kinetics. Another potential contributing factor for the efficacy of amlodipine against cisplatin-induced vomiting is its ability to bind an additional Ca 2+ site.…”

“…Relative to nifedipine, a short-acting LTCC antagonist; amlodipine is much longer acting, with a larger volume of distribution and more gradual elimination. [30][31][32] We have evaluated the broad-spectrum antiemetic potential of nifedipine 28 and amlodipine 33 against diverse specific (e.g. receptor selective or non-selective agonists) and non-specific (e.g.…”