Pharmacological evidence that alpha1-and alpha2-adrenoceptors mediate vasoconstriction of carotid arteriovenous anastomoses in anaesthetized pigs

Abstract

Vasoconstriction of carotid arteriovenous anastomoses may be involved in the therapeutic action of acutely acting anti-migraine agents, including the triptans and ergot alkaloids. While 5-HT1B/1D receptors mediate the effect of triptans, ergotamine and dihydroergotamine also interact with alpha-adrenoceptors. In the present study, we investigated the potential role of alpha1- and alpha2-adrenoceptors in mediating vasoconstriction of carotid arteriovenous anastomoses in anaesthetized pigs. Ten minute intracarotid infusions of phenylephrine (1, 3 and 10 microg kg(-1) min(-1)) or BHT 933 (3, 10 and 30 microg kg(-1) min(-1)) produced dose-dependent decreases in total carotid and arteriovenous anastomotic conductances; no changes were observed in the capillary fraction. The carotid vascular effects of phenylephrine and BHT 933 were selectively abolished by prazosin (100 microg kg(-1), i.v.) and rauwolscine (300 microg kg(-1), i.v.), respectively. The responses to phenylephrine and BHT 933 were not affected by the selective 5-HT1B/1D receptor antagonist GR127935 (500 microg kg(-1), i.v.). These results show that both alpha1- and alpha2-adrenoceptors can mediate vasoconstriction of carotid arteriovenous anastomoses in anaesthetized pigs. Since vasoconstrictor activity in this in vivo model is predictive of anti-migraine activity, an agonist activity at particularly the alpha2-adrenoceptor subtypes, in view of their less ubiquitous nature, could provide migraine abortive potential. Thus, the present results may aid further understanding of the mode of action of some current anti-migraine agents and may eventually be helpful in the development of future treatment in migraine.

Figure 1

Effects of 10-min intracarotid infusions of phenylephrine on total carotid, arteriovenous anastomotic (AVA) and capillary conductances in anaesthetized pigs treated i.v. with vehicle (Veh; n=7), prazosin (Praz; 100 μg kg⁻¹; n=7), rauwolscine (Rauw; 300 μg kg⁻¹; n=3) or GR127935 (GR; 500 μg kg⁻¹ n=3). All data are presented as mean±s.e.mean. ^aP<0.05 vs baseline (ANOVA); ^bP<0.05 vs vehicle group (ANOVA).

Figure 2

Effects of 10-min intracarotid infusions of BHT933 on total carotid, arteriovenous anastomotic (AVA) and capillary conductances in anaesthetized pigs treated i.v. with either vehicle (Veh; n=7), prazosin (Praz; 100 μg kg⁻¹; n=3), rauwolscine (Rauw; 300 μg kg⁻¹; n=7) or GR127935 (GR; 500 μg kg⁻¹ n=3). All data are presented as mean±s.e.mean. ^aP<0.05 vs baseline (ANOVA); ^bP<0.05 vs vehicle group (ANOVA).

Figure 3

Per cent changes in arteriovenous anastomotic (AVA) conductance induced by 10-min intracarotid infusions of phenylephrine or BHT933 in anaesthetized pigs treated i.v with vehicle (Veh), prazosin (Praz; 100 μg kg⁻¹), rauwolscine (Rauw; 300 μg kg⁻¹) or GR127935 (GR; 500 μg kg⁻¹). All data are presented as mean±s.e.mean. ^aP<0.05 vs baseline (ANOVA); ^bP<0.05 vs vehicle group (ANOVA). The number of animals receiving phenylephrine and BHT933 in the vehicle, prazosin, rauwolscine and GR127935 group were: phenylephrine (7, 7, 3 and 3, respectively); BHT933 (7, 3, 7 and 3, respectively).

Figure 4

The effect of 10-min intracarotid infusions of phenylephrine (PHE) or BHT933 (BHT) on the distribution of total carotid conductance in different ipsilateral cranial tissues in anaesthetized pigs treated with vehicle (n=7 each). All data are presented as mean±s.e.mean. ^aP<0.05 vs baseline (ANOVA); ^bP<0.05 vs vehicle group (ANOVA).