BIBN4096BS is a potent competitive antagonist of the relaxant effects of alpha-CGRP on human temporal artery: comparison with CGRP(8-37)

Abstract

Release of CGRP during migraine may produce harmful dilatation of cranial arteries, thereby possibly causing pain. We have compared the antagonism by BIBN4096BS and CGRP(8-37) of the relaxant effects of alpha-CGRP on rings of human temporal artery. alpha-CGRP relaxed the arteries precontracted with 9 - 24 mM KCl (-logEC50=9.4) nearly as efficaciously as sodium nitroprusside (10 microM). BIBN4096BS (0.1 - 100 nM) antagonized the effects of alpha-CGRP in surmountable manner with slopes of Schild-plots not different from unity. -LogKB values of 10.1 and 10.4 were estimated for BIBN4096BS when administered before or during the KCl-contracture respectively. BIBN4096BS (1 microM) did not modify the relaxant effects of papaverine and sodium nitroprusside. CGRP(8-37) (1 - 10 microM) antagonized the effects of alpha-CGRP in a surmountable manner with slopes of Schild-plots not different from unity. -LogKB values of 6.6 and 6.7 were estimated for CGRP(8-37) administered before or during the KCl-contracture respectively. The high affinity of BIBN4096BS for CGRP receptors of human temporal artery makes it an excellent tool to explore the hypothesis of CGRP-evoked cerebral vasodilation in migraine.

Figure 1

Antagonism of the relaxant effects of α-CGRP by BIBN4096BS and CGRP(8-37). Original tracings from the temporal artery of a 29 year old male patient with epidural haemorrhage. Each panel represents a recording from a separate ring. After a challenge with 5-HT followed by acetylcholine and washout (W), KCl was titrated to obtain a contracture equivalent to ∼30 – 45% of the 5-HT-evoked contraction. After a stable KCl-contracture was observed, a cumulative concentration-effect curve for α-CGRP was determined followed by SNP administration. Shown are experiments in the absence (a) and presence of BIBN4096BS (b,c) and CGRP(8-37) (d).

Figure 2

Marginal contractions elicited by BIBN4096BS (a) and CGRP (8-37) (b). Data from 12 patients (a) and six patients (b). Only the effects of 10 nM BIBN4096BS and 10 μM CGRP (8-37), administered during the KCl-contracture, were statistically significant.

Figure 3

Antagonism of the relaxant effects of α-CGRP by BIBN4096BS, administered before (a) or during the KCl-contracture (b). Concentration-effect curves for α-CGRP are shown in the absence and presence of the indicated concentrations of BIBN4096BS. n=number of arterial rings. Data from 14 patients.

Figure 4

Antagonism of the relaxant effects of α-CGRP by CGRP(8-37) administered before (a) or during the KCl-contracture (b). Concentration-effect curves for α-CGRP are shown in the absence and presence of the indicated concentrations of CGRP (8-37). n=number of arterial rings. Data from 12 patients.

Figure 5

Schild-plots for BIBN4096BS and CGRP(8-37), administered before (solid circle) and during the KCl-contractures (open circle). For slopes and pK_B values see Table 1.

Figure 6

Lack of effects of BIBN4096BS (1 μM) on relaxations caused by papaverine (a) and SNP (b). Shown are curves obtained in the absence (solid square) and presence of BIBN4096BS (open square). Data from three patients with 5 – 6 arterial rings per group.