TY - JOUR
T1 - Effects of two isometheptene enantiomers in isolated human blood vessels and rat middle meningeal artery - potential antimigraine efficacy
AU - Labastida-Ramírez, Alejandro
AU - Rubio-Beltrán, Eloísa
AU - Haanes, Kristian A
AU - de Vries, René
AU - Dammers, Ruben
AU - Bogers, A J J C
AU - van den Bogaerdt, Antoon
AU - Daugherty, Bruce L
AU - Danser, Alexander H J
AU - Villalón, Carlos M
AU - MaassenVanDenBrink, Antoinette
PY - 2019
Y1 - 2019
N2 - BACKGROUND: Racemic isometheptene [(RS)-isometheptene] is an antimigraine drug that due to its cardiovascular side-effects was separated into its enantiomers, (R)- and (S)-isometheptene. This study set out to characterize the contribution of each enantiomer to its vasoactive profile. Moreover, rat neurogenic dural vasodilatation was used to explore their antimigraine mechanism of action.METHODS: Human blood vessel segments (middle meningeal artery, proximal and distal coronary arteries, and saphenous vein) were mounted in organ baths and concentration response curves to isometheptene were constructed. Calcitonin gene-related peptide (CGRP)-induced neurogenic dural vasodilation was elicited in the presence of the enantiomers using a rat closed cranial window model.RESULTS: The isometheptene enantiomers did not induce any significant contraction in human blood vessels, except in the middle meningeal artery, when they were administered at the highest concentration (100 μM). Interestingly in rats, (S)-isometheptene induced more pronounced vasopressor responses than (R)-isometheptene. However, none of these compounds affected the CGRP-induced vasodilator responses.CONCLUSION: The isometheptene enantiomers displayed a relatively safe peripheral vascular profile, as they failed to constrict the human coronary artery. These compounds do not appear to modulate neurogenic dural CGRP release, therefore, their antimigraine site of action remains to be determined.
AB - BACKGROUND: Racemic isometheptene [(RS)-isometheptene] is an antimigraine drug that due to its cardiovascular side-effects was separated into its enantiomers, (R)- and (S)-isometheptene. This study set out to characterize the contribution of each enantiomer to its vasoactive profile. Moreover, rat neurogenic dural vasodilatation was used to explore their antimigraine mechanism of action.METHODS: Human blood vessel segments (middle meningeal artery, proximal and distal coronary arteries, and saphenous vein) were mounted in organ baths and concentration response curves to isometheptene were constructed. Calcitonin gene-related peptide (CGRP)-induced neurogenic dural vasodilation was elicited in the presence of the enantiomers using a rat closed cranial window model.RESULTS: The isometheptene enantiomers did not induce any significant contraction in human blood vessels, except in the middle meningeal artery, when they were administered at the highest concentration (100 μM). Interestingly in rats, (S)-isometheptene induced more pronounced vasopressor responses than (R)-isometheptene. However, none of these compounds affected the CGRP-induced vasodilator responses.CONCLUSION: The isometheptene enantiomers displayed a relatively safe peripheral vascular profile, as they failed to constrict the human coronary artery. These compounds do not appear to modulate neurogenic dural CGRP release, therefore, their antimigraine site of action remains to be determined.
KW - Adult
KW - Animals
KW - Calcitonin Gene-Related Peptide/pharmacology
KW - Coronary Vessels/drug effects
KW - Dose-Response Relationship, Drug
KW - Female
KW - Humans
KW - Male
KW - Meningeal Arteries/drug effects
KW - Methylamines/chemistry
KW - Middle Aged
KW - Migraine Disorders/drug therapy
KW - Organ Culture Techniques
KW - Rats
KW - Rats, Sprague-Dawley
KW - Saphenous Vein/drug effects
KW - Stereoisomerism
KW - Vasoconstrictor Agents/chemistry
KW - Vasodilation/drug effects
KW - Vasodilator Agents/chemistry
KW - Organ baths
KW - Vasodilation
KW - Migraine
KW - Isometheptene
KW - CGRP
KW - Isolated vessels
UR - http://www.scopus.com/inward/record.url?scp=85065230599&partnerID=8YFLogxK
U2 - 10.1186/s10194-019-1003-2
DO - 10.1186/s10194-019-1003-2
M3 - Journal article
C2 - 31053059
SN - 1129-2377
VL - 20
SP - 47
JO - The Journal of Headache and Pain Online
JF - The Journal of Headache and Pain Online
IS - 1
M1 - 47
ER -