Pharmacological analysis of the increases in heart rate and diastolic blood pressure produced by (S)-isometheptene and (R)-isometheptene in pithed rats

The Journal of Headache and Pain

Research Article

Carlos M. Villalón¹  Oswaldo Hernández-Abreu¹  Eloísa Rubio-Beltrán¹  Alejandro Labastida-Ramírez¹  Antoinette MaassenVanDenBrink²  Bruce L. Daugherty³ 

[1] Department of Pharmacobiology, Cinvestav-Coapa, Czda. Tenorios 235, Col. Granjas-Coapa, Deleg. Tlalpan, 14330, Mexico City, Mexico;Division of Vascular Medicine and Pharmacology, Erasmus University Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands;Tonix Pharmaceuticals, Inc. 509 Madison Avenue, Suite 306, 10022, New York, NY, USA;

关键词: Isometheptene;    Enantiomers;    Vasopressor;    Adrenoceptors;    Rats;   

DOI  :  10.1186/s10194-017-0761-y

 received in 2017-01-25, accepted in 2017-04-22,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundIsometheptene is a sympathomimetic drug effective in acute migraine treatment. It is composed of two enantiomers with diverse pharmacological properties. This study investigated in pithed rats the cardiovascular effects of (S)- isometheptene and (R)-isometheptene, and the pharmacological profile of the more potent enantiomer.MethodsThe effects of i.v. bolus injections (0.03, 0.1, 0.3, 1 and 3 mg/kg) of isometheptene racemate, (S)-isometheptene or (R)-isometheptene on heart rate and blood pressure were analyzed in control experiments. The enantiomer producing more pronounced tachycardic and/or vasopressor responses was further analyzed in rats receiving i.v. injections of prazosin (0.1 mg/kg), rauwolscine (0.3 mg/kg), propranolol (1 mg/kg) or intraperitoneal reserpine (5 mg/kg, -24 h).ResultsCompared to (R)-isometheptene, (S)-isometheptene produced greater vasopressor responses, whilst both compounds equipotently increased heart rate. The tachycardic responses to (S)-isometheptene were abolished after propranolol, but remained unaffected by the other antagonists. In contrast, the vasopressor responses to (S)-isometheptene were practically abolished after prazosin. Interestingly, after reserpine, the tachycardic responses to (S)-isometheptene were abolished, whereas its vasopressor responses were attenuated and subsequently abolished by prazosin.ConclusionsThe different cardiovascular effects of the isometheptene enantiomers are probably due to differences in their mechanism of action, namely: (i) a mixed sympathomimetic action for (S)-isometheptene (a tyramine-like action and a direct stimulation of α1-adrenoceptors); and (ii) exclusively a tyramine like action for (R)-isometheptene. Thus, (R)-isometheptene may represent a superior therapeutic benefit as an antimigraine agent.

【 授权许可】

CC BY   
© The Author(s). 2017