5‐HT_1B‐receptors and vascular reactivity in human isolated blood vessels: assessment of the potential craniovascular selectivity of sumatriptan

Abstract

Aims 5-HT 1B -receptor mediated vasoconstriction of cranial arteries is a potential mechanism by which 5-HT 1B/1D -receptor agonists such as sumatriptan produce their antimigraine effects. 5-HT 1B -receptors exist in other blood vessels which may give rise to unwanted vascular effects. Therefore we examined the distribution of 5-HT 1B -receptor immunoreactivity (i.r.) in human blood vessels (including target and nontarget vessels) and con®rmed the functionality of this receptor protein, by comparing the vasoconstrictor effects of sumatriptan and 5-HT (the endogenous ligand) in isolated vessels. Methods Blood vessels (middle meningeal, pial, temporal and uterine arteries and saphenous veins) were obtained from surgical patients (with consent). Sections of the vessels were prepared for routine immunohistochemical studies using speci®c 5-HT 1B -and 5-HT 1D -receptor antibodies. For functional studies, ring segments of the vessels were mounted in organ baths for isometric tension recording.Results 5-HT 1B -receptor i.r. was detected on the smooth muscle layer in middle meningeal, pial and uterine arteries and in saphenous vein and sumatriptan produced contractions in these vessels with potency values (mean pEC 50 ) of 7.00, 7.08, 6.44 and 6.61, respectively, the magnitude of contraction was greatest in the cranial arteries with E max values of 100.7, 60.3, 23.0 and 35.9%, respectively (expressed as a percentage of the reference agonist 45 mM KCl). 5-HT 1B -receptor i.r. was not detected in temporal artery and sumatriptan had no effect in this artery. 5-HT 1D -receptor i.r. was not detected in any of the vessels studied. Conclusions Sumatriptan can evoke vasoconstriction in antimigraine target vessels and also in nontarget vessels through an action at 5-HT 1B -rcceptors. Sumatriptan acts preferentially to cause contraction in human cranial arteries compared with the other blood vessels we examined and this effect is likely to be shared by other drugs of this class.

Tachyphylaxis to the Sumatriptan-Induced Contractile Effect in the Human Uterine Artery but Not in Human Cerebral Blood Vessels: Pharmacological Demonstration of the 5-HT_1B Receptor Functionality Loss

“…Our findings are partially in agreement with the findings by Razzaque et al [25] since 5-HT 1B receptor immunoreactivity was detected on the smooth muscle layer in the human uterine artery. However, 5-HT 1D receptor immunoreactivity was not.…”

“…Concerning the CR curves for the agonists, the results are consistent with those previously reported for sumatriptan and 5-HT in this particular vessel in the presence [24,25] , as well as in the absence, of endothelium [23] . Because there was a great variability in the contractile responses to both agonists there were no significant differences between 5-HT and sumatriptan potency and intrinsic activity in this peripheral blood vessel, although sumatriptan tended to be the less potent and showed the least intrinsic activity.…”

“…A great variability of the human uterine artery contractile response to sumatriptan was also demonstrated by other authors' results. While in the study by Karlsson et al [24] , the sumatriptan maximum contraction was 16% of that obtained with 5-HT, in the study by Razzaque et al [25] , the sumatriptan maximum contraction was 47% of the maximum response to 5-HT.…”

“…However, contradic- tory results concerning the presence of 5-HT 1B receptors in human blood vessels have been described. For example, while Razzaque et al [25] found no 5-HT 1B receptor immunoreactivity and no significant sumatriptan effect in the temporal artery, Verheggen et al [6] , through pharmacological techniques and mRNA analysis by RT-PCR, concluded that the sumatriptan effect in that cerebral blood vessel was mediated by 5-HT 1B receptors. Because 5-HT 1D receptors have been described as having a presynaptic location, rather than a postsynaptic one, with little or no contribution to vasoconstriction [35,36] , their involvement in the contractile response to triptans has not been considered in most studies.…”

“…Razzaque et al [25] , by immunohistochemical studies, concluded that the 5-HT 1 receptor subtype involved in the triptan-induced contraction in the human uterine artery is most probably the 5-HT 1B receptor.…”