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)

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• 作者：Nissar A. Darmani ; Weixia Zhong ; Seetha Chebolu ; Mariam Vaezi ; Tursun Alkam
• 关键词：Least shrew ; Emesis ; L-type calcium channel ; 5-HT3 receptor ; D2 receptor ; NK1 receptor ; M1 receptor ; FPL 64176 ; Nifedipine ; Palonosetron ; 2-Me-5-HT ; Apomorphine ; Quinpirole ; McN-A-343 ; Cisplatin
• 刊名：European Journal of Pharmacology
• 出版年：5 January, 2014
• 年：2014
• 卷：722
• 期：Complete
• 页码：2-12
• 全文大小：675 K

文摘

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 Ca²⁺ entry into cells for the transmitter release process. Agonists of 5-HT₃ receptors increase calcium influx through both 5-HT₃ receptors and L-type Ca²⁺ 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.