Lack of effect of the antimigraine drugs, sumatriptan, ergotamine and dihydroergotamine on arteriovenous anastomotic shunting in the dura mater of the pig

Abstract

1 In anaesthetized animals, the antimigraine drugs, sumatriptan, ergotamine and dihydroergotamine, reduce carotid arteriovenous anastomotic shunting. Within the carotid vascular bed arteriovenous anastomoses are located, amongst other places in the dura mater, which is a putative site of the pain during a migraine attack. 2 In this investigation, we have localized and measured the arteriovenous shunting within the carotid vascular bed of the pig by using simultaneous intracarotid injections of radiolabelled microspheres of three different sizes (10, 15 and 50gm), which provides an index of blood flow via arteriovenous anastomoses larger than approximately 14, 27 and 90 gm diameter, respectively. The effects of sumatriptan (0.3 mg kg-'), ergotamine (0.02 mg kg-'), dihydroergotamine (0.1 mg kg-') and saline were studied by repeating the injections of 15 and 50 gm spheres after the treatments. 3 There was no difference in shunting or entrapment between the 10 and 15 gm microsphere, indicating the absence of arteriovenous anastomoses with a diameter between 14 and 27 gm. 4 Arteriovenous anastomoses with a diameter between 27 and 90 gm, as indicated by the difference in blood flow measured by 15 and 50 gm spheres, were located in the dura mater, ears, skin, fat and, to a lesser extent, in the skeletal muscles and eyes. 5 Sumatriptan, ergotamine and dihydroergotamine reduced the overall flow in the smaller arteriovenous anastomoses (diameter between 27 and 90 gm), and even more in larger shunts (wider than 90 gm).6 Locally, blood flow in the smaller arteriovenous shunts was reduced in the skin and fat, but not in the dura mater, ears, eyes and muscles. It is not possible to determine in which tissues blood flow in the larger arteriovenous anastomoses was reduced. 7 Tissue blood flow measured with 15 gm microspheres remained unchanged after the three antimigraine drugs, implying a lack of effect on capillary flow. 8 It is concluded that in the anaesthetized pigs the only evident effect of these antimigraine drugs on carotid haemodynamics is a decrease in blood flow in both smaller and larger arteriovenous anastomoses; the smaller arteriovenous anastomoses were affected in the skin and fat, but not in other tissues.

Carotid blood flow distribution, haemodynamics and inotropic responses following calcitonin gene-related peptide in the pig

“…As previously reported (Den Boer et al, 1993;Van Gelderen et al, 1995), approximately 21% of the carotid blood flow (compared to over 70% in anaesthetized pigs, Den Boer et al, 1992a) was shunted through arteriovenous anastomoses, indicating that, at baseline, these vessels were largely under sympathetic constrictor tone. Despite its potent vasodilator action, human a-CGRP failed to affect blood flow through arteriovenous anastomoses.…”

“…Thus, it is plausible that enhanced dural blood flow, together with increased vascular pulsatility, contributes to migraine headache. However, in spite of an increase in carotid vascular resistance indicating vasoconstriction, antimigraine drugs like dihydroergotamine and sumatriptan failed to reduce dural blood flow in pigs (Den Boer et al, 1992a), whereas sumatriptan reduced feline pial diameter only after topical application (Connor et al, 1992). Moreover, in the present study with presumably high levels of CGRP, both sumatriptan and dihydroergotamine only slightly reduced dural blood flow and failed to reduce carotid vascular pulsations.…”

“…The antimigraine drugs, dihydroergotamine and sumatriptan, have been shown to reduce blood flow through arteriovenous anastomoses in pigs with a high shunt flow (Den Boer et al, 1992a). Since arteriovenous anastomoses were largely closed and repeated infusions with human a-CGRP failed to increase arteriovenous anastomotic blood flow, such a constrictor action could not be detected in the present experiments.…”

“…In keeping with the observations in rats (Gardiner et al, 1989(Gardiner et al, , 1991, human a-CGRP elevated common carotid blood flow dose dependently, associated with pronounced increases in regional tissue blood flow, indicating arteriolar dilatation. In the presence of a high concentration of human a-CGRP, sumatriptan and dihydroergotamine reduced carotid blood flow to an extent similar to that reported in the absence of the peptide (Den Boer et al, 1992a), suggesting that their vasoconstrictor action in this vessel does not depend on the level of circulating human a-CGRP.…”

“…Either drug tended to reduce mean arterial blood pressure, significantly so only in the case of sumatriptan. Since the latter was shown previously to reduce cardiac output in anaesthetized pigs (Den Boer et al, 1992b), the small change in this variable may have accounted for the additional reduction in blood pressure. As no significant changes in systemic vascular conductance were observed with either dihydroergotamine or sumatriptan, both drugs exerted a selective vasoconstrictor effect in the carotid vasculature.…”