Effects of the CGRP receptor antagonist BIBN4096BS on capsaicin-induced carotid haemodynamic changes in anaesthetised pigs

Abstract

1. Calcitonin gene-related peptide (CGRP), a potent vasodilator released from capsaicin-sensitive trigeminal sensory nerves, seems to be involved in the pathogenesis of migraine. Hence, CGRP receptor antagonists may serve as a novel treatment for migraine. This study was therefore designed to investigate the effects of BIBN4096BS (100, 300 and 1000 microg kg-1, i.v.), a potent and selective CGRP receptor antagonist, on capsaicin-induced carotid haemodynamic changes in anaesthetised pigs. Both vagosympathetic trunks were cut and phenylephrine was infused into the carotid artery (i.c.) to support carotid vascular tone. 2. Infusions of capsaicin (0.3, 1, 3 and 10 microg kg-1 min-1, i.c.) did not alter the heart rate, but dose-dependently increased the mean arterial blood pressure. This moderate hypertensive effect was not modified by BIBN4096BS. 3. Capsaicin infusion (10 microg kg-1 min-1, i.c.) increased total carotid, arteriovenous anastomotic and tissue blood flows and conductances as well as carotid pulsations, but decreased the difference between arterial and jugular venous oxygen saturations. These responses to capsaicin were dose-dependently blocked by BIBN4096BS. 4. Capsaicin infusion (10 microg kg-1 min-1, i.c.) more than doubled the jugular venous plasma concentration of CGRP. This effect was not blocked, but rather increased, by BIBN4096BS. 5. The above results show that BIBN4096BS behaves as a potent antagonist of capsaicin-induced carotid haemodynamic changes that are mediated via the release of CGRP. Therefore, this compound may prove effective in the treatment of migraine.

Figure 1

Heart rate (HR), mean arterial blood pressure (MAP) and total carotid blood flow (TCBF), and vascular conductance (TCC) values at baseline (capsaicin 0 μg kg⁻¹ min⁻¹), and following infusions of capsaicin (0.3, 1,3, 10 μg kg⁻¹ min⁻¹, i.c.) in anaesthetised pigs before (control) and after i.v. administrations of vehicle (V, 5 ml three times; n=11) or BIBN4096BS (100, 300 and 1000 μg kg⁻¹, n=11). All values are expressed as mean±s.e.m. While HR was not affected, capsaicin increased MAP as well as TCBF and conductance (significance not shown for the sake of clarity). BIBN4096BS dose-dependently antagonised capsaicin-induced carotid haemodynamic changes, but not the increase in arterial blood pressure. ^#P<0.05 vs response after the corresponding volume of vehicle.

Figure 2

Maximum changes in carotid blood flow, vascular conductance and pulsations measured at baseline and following infusions of capsaicin (10 μg kg⁻¹ min⁻¹, i.c.) given in anaesthetised pigs before (control) and after i.v. administrations of vehicle (V, 5 ml three times; n=11) or BIBN4096BS (100, 300 and 1000 μg kg⁻¹, n=11). All values are expressed as mean±s.e.m. a.u., arbitrary units. *P<0.05 vs baseline values; ^#P<0.05 vs response after the corresponding volume of vehicle.

Figure 3

Total carotid, arteriovenous anastomotic (AVA) and capillary blood flows (left panel) and vascular conductances (right panel) measured at baseline and following infusions of capsaicin (10 μg kg⁻¹ min⁻¹, i.c.) given in anaesthetised pigs before (control) and after i.v. administrations of vehicle (V, 5 ml three times; n=7) or BIBN4096BS (100, 300 and 1000 μg kg⁻¹, n=6). All values are expressed as mean±s.e.m. *P<0.05 vs baseline values; ^#P<0.05 vs response after the corresponding volume of vehicle.

Figure 4

Distribution of carotid vascular conductances to head tissues measured at baseline (Bas) and following infusions of capsaicin (10 μg kg⁻¹ min⁻¹, i.c.) given in anaesthetised pigs before (Con) and after i.v. administrations of vehicle (V, 5 ml three times; n=7) or BIBN4096BS (100, 300 and 1000 μg kg⁻¹, n=6). All values are expressed as mean±s.e.m. *P<0.05 vs baseline values; ^#P<0.05 vs response after the corresponding volume of vehicle.

Figure 5

Differences between arterial and jugular venous oxygen saturations (A–V SO₂ difference) measured at baseline and following infusions of capsaicin (10 μg kg⁻¹ min⁻¹, i.c.) given in anaesthetised pigs before (control) and after i.v. administrations of vehicle (V, 5 ml three times; n=11) or BIBN4096BS (100, 300 and 1000 μg kg⁻¹, n=11). All values are expressed as mean±s.e.m. *P<0.05 vs baseline values; ^#P<0.05 vs response after the corresponding volume of vehicle.

Figure 6

Jugular venous plasma CGRP concentrations measured at baseline and after infusions of capsaicin (10 μg kg⁻¹ min⁻¹, i.c.) given in anaesthetised pigs before (control) and after i.v. administrations of vehicle (V, 5 ml three times; n=6) or BIBN4096BS (100, 300 and 1000 μg kg⁻¹, n=6). All values are expressed as mean±s.e.m. *P<0.05 vs baseline values; P<0.05 vs response after the corresponding volume of vehicle.