CP55940-induced vasorelaxation is endothelial-dependent and mediated by the CB1R through NOS, COX and EDHF pathways in porcine cerebral arteries

Microvasc Res. 2023 May 23:104550. doi: 10.1016/j.mvr.2023.104550. Online ahead of print.

ABSTRACT

Using swine as an experimental model, we chose to examine whether the cannabinoid receptors, e.g. CB1R and the CB2R, could affect vasomotor tone in isolated pial arteries. It was hypothesized that the CB1R would specifically mediate cerebral artery vasorelaxation in an endothelial-dependent manner. First-order pial arteries were isolated from female Landrace pigs (age = 2 months; N = 27) for wire and pressure myography. Arteries were pre-contracted with a thromboxane A2 analogue (U-46619) and vasorelaxation in response to the CB1R and CB2R receptor mixed agonist CP55940 was examined in the following conditions: 1) untreated; 2) inhibition of the CB1R (AM251); or 3) inhibition of the CB2R receptor (AM630). The data revealed that CP55940 elicits a CB1R-dependent relaxation in pial arteries. CB1R expression was confirmed using immunoblot and immunohistochemical analyses. Subsequently, the role of different endothelial-dependent pathways in the CB1R-mediated vasorelaxation was examined using: 1) denudation (removal of the endothelium); 2) inhibition of cyclooxygenase (COX; Naproxen); 3) inhibition of nitric oxide synthase (NOS; L-NAME); 4) combined inhibition of COX + NOS. The data revealed CB1R-mediated vasorelaxation was endothelial-dependent, with contributions from COX-derived prostaglandins, NO, and endothelium-dependent hyperpolarizing factor (EDHF). Pressurized arteries underwent myogenic curves (20-100 mmHg) under the following conditions: 1) untreated; 2) inhibition of the CB1R. The data revealed CB1R inhibition increased basal myogenic tone, but not myogenic reactivity. As the vascular responses were assessed in isolated pial arteries, this work reveals that the CB1R modulates cerebrovascular tone independently of changes in brain metabolism.

PMID:37230164 | DOI:10.1016/j.mvr.2023.104550