title: Broad-spectrum antiemetic potential of the L-type calcium channel antagonist nifedipine and evidence for its additive antiemetic interaction with the 5-HT(3) receptor antagonist palonosetron in the least shrew (Cryptotis parva).
abstract: Cisplatin-like chemotherapeutics cause vomiting via release of multiple neurotransmitters (dopamine, serotonin (5-HT), or substance P (SP)) from the gastrointestinal enterochromaffin cells and/or the brainstem via a calcium dependent process. Diverse channels in the plasma membrane allow extracellular Ca(2+) entry into cells for the transmitter release process. Agonists of 5-HT3 receptors increase calcium influx through both 5-HT3 receptors and L-type Ca(2+) channels. We envisaged that L-type calcium agonists such as FPL 64176 should cause vomiting and corresponding antagonists such as nifedipine would behave as broad-spectrum antiemetics. Administration of FPL 64176 did cause vomiting in the least shrew in a dose-dependent fashion. Nifedipine and the 5-HT3 receptor antagonist palonosetron, potently suppressed FPL 64176-induced vomiting, while a combination of ineffective doses of these antagonists was more efficacious. Subsequently, we investigated the broad-spectrum antiemetic potential of nifedipine against diverse emetogens including agonists of serotonergic 5-HT3- (e.g. 5-HT or 2-Me-5-HT), SP tachykinin NK1- (GR73632), dopamine D2- (apomorphine or quinpirole), and cholinergic M1- (McN-A-343) receptors, as well as the non-specific emetogen, cisplatin. Nifedipine by itself suppressed vomiting in a potent and dose-dependent manner caused by the above emetogens except cisplatin. Moreover, low doses of nifedipine potentiated the antiemetic efficacy of non-effective or semi-effective doses of palonosetron against vomiting caused by either 2-Me-5-HT or cisplatin. Thus, our findings demonstrate that activation of L-type calcium channels causes vomiting, whereas blockade of these ion channels by nifedipine-like antagonists not only provides broad-spectrum antiemetic activity but can also potentiate the antiemetic efficacy of well-established antiemetics such as palonosetron. L-type calcium channel antagonists should also provide antiemetic activity against drug-induced vomiting as well as other emetogens including bacterial and viral proteins.
authors: Nissar A
authors: NA
authors: Darmani
authors: Weixia
authors: W
authors: Zhong
authors: Seetha
authors: S
authors: Chebolu
authors: Mariam
authors: M
authors: Vaezi
authors: Tursun
authors: T
authors: Alkam
mesh_terms: D000818:Animals; D000932:Antiemetics / Q000494:pharmacology / Q000627:therapeutic use; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D004357:Drug Synergism; D005260:Female; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D009543:Nifedipine / Q000494:pharmacology* / Q000627:therapeutic use; D000077924:Palonosetron; D011758:Pyrroles / Q000009:adverse effects; D011812:Quinuclidines / Q000494:pharmacology*; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism*; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000494:pharmacology; D012788:Shrews; D014839:Vomiting / Q000139:chemically induced / Q000188:drug therapy
chemical_list: D000932:Antiemetics; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D007546:Isoquinolines; D011758:Pyrroles; D011812:Quinuclidines; D044406:Receptors, Serotonin, 5-HT3; D058831:Serotonin 5-HT3 Receptor Antagonists; C071658:FPL 64176; D000077924:Palonosetron; D009543:Nifedipine