Cranial vascular effects of zolmitriptan, a centrally active 5-HT1B/1D receptor partial agonist for the acute treatment of migraine.
The anti-migraine drug zolmitriptan is a novel 5-HT1B/1D receptor partial agonist which, unlike sumatriptan, has been shown to cross the intact blood-brain barrier. In this study we examined whether or not the ability to access the cerebro-vascular intima affects the way in which a centrally-active 5-HT1B/1D receptor agonist influences cranial haemodynamics. The effects of zolmitriptan on carotid arterial blood flow distribution were studied in anaesthetised cats using radiolabelled microspheres. Zolmitriptan (10-1000 microg kg(-1) i.v.) selectively reduced arteriovenous-anastomotic (AVA) conductance producing a maximum decrease of 92.5+/-2.3%. The drug also produced a modest reduction in extra-cerebral conductance (23.9+/-6.5% maximum reduction at 30 microg kg(-1), i.v.), but was without effect on cerebral conductance. Using laser doppler flowmetry in anaesthetised cats, zolmitriptan (1-30 microg kg(-1), i.v.) produced dose-dependent decreases in ear microvascular conductance (15+/-5 to 60+/-6%) which mirrored decreases in carotid arterial conductance (12+/-11 to 61+/-5%). By contrast, zolmitriptan at doses up to 1000 microg kg(-1) was without effect on cerebral microvascular conductance. Although zolmitriptan crosses the blood-brain barrier and can therefore access the cerebro-vascular intima, this study suggests that this property does not adversely affect cerebrovascular function.
MacLennan
S J
SJ
Receptor Pharmacology Group, Wellcome Research Laboratories, Beckenham, Kent, UK. stephen.maclennan@roche.com
Cambridge
D
D
Whiting
M V
MV
Marston
C
C
Martin
G R
GR
D000818:Animals; D001163:Arteriovenous Anastomosis / Q000187:drug effects; D001783:Blood Flow Velocity / Q000187:drug effects; D002339:Carotid Arteries / Q000187:drug effects / Q000502:physiology; D002415:Cats; D002540:Cerebral Cortex / Q000098:blood supply; D004195:Disease Models, Animal; D004285:Dogs; D008297:Male; D008881:Migraine Disorders / Q000188:drug therapy*; D010080:Oxazoles / Q000494:pharmacology / Q000627:therapeutic use*; D023303:Oxazolidinones; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000187:drug effects*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D014363:Tryptamines
D010080:Oxazoles; D023303:Oxazolidinones; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; C089750:zolmitriptan