title: Broad-spectrum antiemetic efficacy of the L-type calcium channel blocker amlodipine in the least shrew (Cryptotis parva).
abstract: The dihydropyridine l-type calcium (Ca(2+)) channel blockers nifedipine and amlodipine reduce extracellular Ca(2+) entry into cells. They are widely used for the treatment of hypertensive disorders. We have recently demonstrated that extracellular Ca(2+) entry via l-type Ca(2+) 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 Ca(2+) channel blocker, amlodipine. Fully effective emetic doses of diverse emetogens such as the l-type Ca(2+) 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 D2 (e.g. apomorphine or quinpirole)-, cholinergic M1 (e.g. pilocarpine or McN-A343)- and tachykininergic NK1 (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 (0.5-10mg/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 (10mg/kg), 5-HT (5mg/kg), 2-Me-5-HT (5mg/kg), apomorphine (2mg/kg), quinpirole (2mg/kg), pilocarpine (2mg/kg), McN-A343 (2mg/kg), or GR73632 (5mg/kg). A combination of non-effective doses of amlodipine (0.5mg/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 (10mg/kg, i.p)-induced vomiting in a dose-dependent manner. Moreover, a combination of a non-effective dose of amlodipine (1mg/kg) potentiated the antiemetic efficacy of a semi-effective dose of palonosetron (0.5mg/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 Ca(2+) channel blockers are a new class of broad-spectrum antiemetics.
authors.affiliation: Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, 309 East Second Street, Pomona, CA 91766, USA.
authors.forename: Weixia
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, 309 East Second Street, Pomona, CA 91766, USA.
authors.forename: Seetha
authors.initials: S
authors.lastname: Chebolu
authors.affiliation: Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, 309 East Second Street, Pomona, CA 91766, USA. Electronic address: ndarmani@westernu.edu.
authors.forename: Nissar A
authors.initials: NA
authors.lastname: Darmani
mesh_terms: D017311:Amlodipine / Q000494:pharmacology*; D000818:Animals; D000932:Antiemetics / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004639:Emetics / Q000008:administration & dosage; D005260:Female; D008297:Male; D012788:Shrews; D014839:Vomiting / Q000139:chemically induced / Q000517:prevention & control*
chemical_list: D000932:Antiemetics; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D004639:Emetics; D017311:Amlodipine
keywords: Amlodipine; Cisplatin; FPL 64176; GR73632; McN-A343; Quinpirole