Alpha1-adrenoceptor subtypes mediating vasoconstriction in the carotid circulation of anaesthetized pigs: possible avenues for antimigraine drug development.
It has recently been shown that the alpha-adrenoceptors mediating vasoconstriction of porcine carotid arteriovenous anastomoses resemble both alpha1- and alpha2-adrenoceptors, but no attempt was made to identify the specific subtypes (alpha1A, alpha1B and alpha1D) involved. Therefore, the present study was designed to elucidate the specific subtype(s) of alpha1-adrenoceptors involved in the above response, using the alpha1-adrenoceptor agonist phenylephrine and alpha1-adrenoceptor antagonists 5-methylurapidil (alpha1A), L-765 314 (alpha1B) and BMY 7378 (alpha1D). Ten-minute intracarotid infusions of phenylephrine (1, 3 and 10 microgkg-1.min-1) induced a dose-dependent decrease in total carotid and arteriovenous anastomotic conductance, accompanied by a small tachycardia. These carotid vascular effects were abolished by L-765 314 (1000 microgkg-1; i.v.), while these responses were only attenuated by 5-methylurapidil (1000 microgkg-1; i.v.), and BMY 7378 (1000 microgkg-1; i.v.). Furthermore, intravenous bolus injections of phenylephrine (3 and 10 microgkg-1) produced a dose-dependent vasopressor response, which was only affected by 1000 microgkg-1 of 5-methylurapidil, while the other antagonists were ineffective. These results, coupled to the binding affinities of the above antagonists at the different alpha1-adrenoceptors, suggest that both alpha1A- and alpha1B-adrenoceptors mediate constriction of carotid arteriovenous anastomoses in anaesthetized pigs. In view of the less ubiquitous nature of alpha1B- compared to alpha1A-adrenoceptors, the development of potent and selective alpha1B-adrenoceptor agonists may prove to be important for the treatment of migraine.
Willems
E W
EW
Department of Pharmacology, Dutch Migraine Research Group and Cardiovascular Research Institute 'COEUR', Erasmus University Medical Centre Rotterdam, 3000 DR Rotterdam, The Netherlands.
Heiligers
J P
JP
De Vries
P
P
Kapoor
K
K
Tom
B
B
Villalón
C M
CM
Saxena
P R
PR
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D002339:Carotid Arteries / Q000294:innervation*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D007261:Infusions, Intra-Arterial; D008881:Migraine Disorders / Q000503:physiopathology*; D010656:Phenylephrine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011224:Prazosin / Q000031:analogs & derivatives / Q000494:pharmacology; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; C111640:L 765314; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; C057446:5-methylurapidil; D010656:Phenylephrine; C053428:BMY 7378; D011224:Prazosin