Effects of donitriptan on carotid haemodynamics and cardiac output distribution in anaesthetized pigs.
We investigated the effects of donitriptan, which possesses a uniquely high affinity and efficacy at 5-HT1B/1D receptors, on carotid and systemic haemodynamics in anaes thetized pigs. Donitriptan (0.16-100 microg kg(-1), i.v.) dose-dependently decreased total carotid blood flow and vascular conductance (maximum response: -25 +/- 3%). This effect was entirely due to a selective reduction in the cephalic arteriovenous anastomotic fraction (maximum response: - 63 +/- 3%; ED50%: 92 +/- 31 nmol/kg); the nutrient vascular conductance increased. Donitriptan did not decrease vascular conductances in or blood flow to a number of organs, including the heart and kidneys; in fact, vascular conductances in the skin, brain and skeletal muscles increased. Cardiac output was slightly decreased by donitriptan, but this effect was confined to peripheral arteriovenous anastomoses. The haemodynamic effects of donitriptan were substantially reduced by the 5-HT1B/1D receptor antagonist GR127935. These results show that donitriptan selectively constricts arteriovenous anastomoses via 5-HT1B receptor activation. The drug should be able to abort migraine headaches and it is unlikely to compromize blood flow to vital organs.
Tom
B
B
Department of Pharmacology, Cardiovascular Research Institute, COEUR, Erasmus University Medical Centre Rotterdam, The Netherlands.
De Vries
P
P
Heiligers
J P C
JP
Willems
E W
EW
Kapoor
K
K
John
G W
GW
Saxena
P R
PR
D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects*; D001921:Brain / Q000098:blood supply*; D002302:Cardiac Output / Q000187:drug effects*; D002339:Carotid Arteries / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects*; D009570:Nitriles / Q000494:pharmacology*; D010069:Oxadiazoles / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000187:drug effects*; D012039:Regional Blood Flow / Q000187:drug effects; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013552:Swine; D014363:Tryptamines; D014655:Vascular Resistance / Q000187:drug effects
D009570:Nitriles; D010069:Oxadiazoles; D010879:Piperazines; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; C090701:GR 127935; C120143:donitriptan