Abstract
BackgroundRacemic 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.MethodsHuman 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.ResultsThe 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.ConclusionThe 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.
Highlights
Racemic isometheptene [(RS)-isometheptene] is an antimigraine drug that due to its cardiovascular side-effects was separated into its enantiomers, (R)- and (S)-isometheptene
Isometheptene racemate and its enantiomers did not induce any significant contraction, except when they were administered at the highest concentration studied (100 μM, a supratherapeutic concentration), where the enantiomers only induced a modest contraction (20–40% of 100 mM KCl; P = 0.002; n = 7; Fig. 1)
Within this context: the use of different human isolated blood vessels allows us to discern possible vascular side effects induced by potential antimigraine agents; and the rat closed-cranial window is an in vivo neurovascular migraine model that focuses on the pathophysiological interaction of the trigeminal system with neurogenic dural vasodilation [21]
Summary
Racemic isometheptene [(RS)-isometheptene] is an antimigraine drug that due to its cardiovascular side-effects was separated into its enantiomers, (R)- and (S)-isometheptene. Its exact pathophysiology has not been elucidated completely, The triptans, serotonergic agonists with selective affinity for 5-HT1B/1D/(1F) receptors, are specific drugs for the acute treatment Their mechanism of action has been attributed to a dural perivascular inhibition of CGRP release, an inhibition of central nociception and/or a postjunctional constriction of (cranial) blood vessels [4– 6]. (R)-isometheptene is an imidazoline I1 receptor agonist [12], and previous studies have shown that: (i) imidazoline I1 receptor knockout mice have a potentiated nociceptive perception, suggesting that this receptor could be associated with an endogenous analgesia system [13]; (ii) (R)-isometheptene decreased trigeminal sensitivity in two rat models of chronic migraine [14]; and (iii) imidazoline I1 receptor agonists, like moxonidine and agmatine induced a prejunctional inhibition of the vasodepressor sensory CGRPergic outflow in pithed rats [15] Together, these findings suggest that a potential antimigraine action of (R)-isometheptene could be mediated by inhibition of the trigeminal system. We hypothesized that the use of only (R)-isometheptene will maintain its antimigraine therapeutic effect, while the major side effects associated with the racemate or (S)-isometheptene (i.e. cranial vasoconstriction) will be diminished [16]
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