CGRP-induced relaxation remains unaffected in a porcine acute ischaemic stroke model

Abstract text (incl. figure legends and references)

Objective Calcitonin gene-related peptide (CGRP) plays an important role in migraine attacks and is thought to be protective in ischaemic events. We investigated functional responses to exogenous CGRP of the middle cerebral artery (MCA) harvested from a gyrencephalic model of focal cerebral ischaemia.

Methods Female pigs (n=25; weight 51±3kg) underwent a craniotomy to occlude right-sided MCAs with aneurysm clips for 1 (n=5), 2 (n=5), or 4 (n=5) hours followed by 4-h recanalization, or for 8 h without recanalization (n=5). Two animals underwent a sham procedure. After euthanasia, the right-sided MCA was dissected for tension measurements. KCl-induced contraction (30–100 mM) was measured and endothelial function was assessed by bradykinin (BK)- or substance P (SP)-induced relaxation (10–100 nM) after precontraction with thromboxane A₂ analogue U46619 (10–100 nM). Concentration-response curves were constructed to CGRP (0.1–100 nM) after precontraction with 30 mM KCl.

Results Relaxation to SP and BK was significantly reduced after 8 h occlusion (P<0.05), but not after occlusion followed by recanalization. Contraction to KCl was only reduced after 8 h occlusion (P<0.001). No differences were found in response to CGRP between groups (Figure).

Conclusions CGRP-induced relaxation remained unaffected after 8 h MCA occlusion, whereas SP- and BK-induced relaxation did not. These results suggest that CGRP acts via an endothelium-independent mechanism and that its potential protective effects after stroke depend on its local release rather than changes at the CGRP receptor level.

Figure: (A) No altered CGRP-induced relaxation after (recanalized) MCA occlusion. Reduced endothelial (B) and contractile (C) function after 8 h MCA occlusion. Results depicted as mean ± SEM.