Broad-spectrum antiemetic efficacy of the L-type calcium channel blocker amlodipine in the least shrew (Cryptotis parva)

The dihydropyridine L-type calcium (Ca2+) channel blockers nifedipine and amlodipine reduce extracellular Ca2+ entry into cells. They are widely used for the treatment of hypertensive disorders. We have recently demonstrated that extracellular Ca2+ entry via L-type Ca2+ channels is involved in emesis and that nifedipine has broad-spectrum antiemetic activity. The aim of this study was to evaluate the antiemetic efficacy of the longer-acting L-type Ca2+ channel blocker, amlodipine. Fully effective emetic doses of diverse emetogens such as the L-type Ca2+ channel agonist (FPL 64176) as well as selective and/or nonselective agonists of serotonergic 5-HT3 (e.g. 5-HT or 2-Me-5-HT)-, dopamine D-2 (e.g. apomorphine or quinpirole)-, cholinergic M-1 (e.g. pilocarpine or McN-A343)- and tachykininergic Nk(1) (e.g. GR73632)-receptors, were administered intraperitoneally (i.p.) in the least shrew to induce vomiting. The broad-spectrum antiemetic potential of amlodipine was evaluated against these emetogens. Subcutaneous (s.c.) administration of amlodipine (0.5-10 mg/kg) attenuated in a dose-dependent and potent manner both the frequency and percentage of shrews vomiting in response to intraperitoneal (i.p.) administration of FPL 64176 (10 mg/kg), 5-HT (5 mg/kg), 2-Me-5-HT (5 mg/kg), apomorphine (2 mg/kg), quinpirole (2 mg/kg), pilocarpine (2 mg/kg), McN-A343 (2 mg/kg), or GR73632 (5 mg/kg). A combination of non-effective doses of amlodipine (0.5 mg/kg, s.c.) and the 5-HT3 receptor antagonist palonosetron (0.05 mg/kg, s.c.) was more effective against FPL 64176-induced vomiting than their corresponding doses tested alone. Amlodipine by itself suppressed the frequency of acute cisplatin (10 mg/kg, i.p)-induced vomiting in a dose-dependent manner. Moreover, a combination of a non-effective dose of amlodipine (1 mg/kg) potentiated the antiemetic efficacy of a semi-effective dose of palonosetron (0.5 mg/kg, s.c.) against acute vomiting caused by cisplatin. We confirm that influx of extracellular Ca-2 +/- ion underlies vomiting due to diverse causes and demonstrate that L-type Ca2+ channel blockers are a new class of broad-spectrum antiemetics. (C) 2014 Elsevier Inc. All rights reserved.