INFLUENCE OF ENDOTHELIAL CANNABINOID 1 RECEPTOR ACTIVATION ON CEREBROVASCULAR REGULATION IN SWINE
Date
2021-09-29
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
ORCID
Type
Thesis
Degree Level
Masters
Abstract
Cannabinoid receptors 1 & 2 (CB1R & CB2R) are present throughout the cardiovascular system
and evidence indicates that CB1R activation causes vasodilation in peripheral vascular beds.
However, it remains unclear what the direct effects of CB1R or CB2R activation are in cerebral
arteries. The present study tested the hypothesis that CB1R and not CB2R receptor activation elicits
endothelial-dependent vasorelaxation in the cerebrovasculature. Female Landrace pigs (age=2
months; N=16) were euthanized, their brains were harvested, and pial arteries branching from the
middle cerebral artery were isolated for wire myography. Arteries were pre-contracted with a
thromboxane A2 analogue (U-46619; 1x10-6 M to 1x10-4 M). Thereafter, vasorelaxation in response
to a dual CB1R & CB2R receptor agonist CP55940 (3x10-11 M to 1x10-6 M; half log doses) was
examined under the following conditions: 1) untreated; 2) CB1R blockade (AM251; 1x10-7 M); or
3) CB2R receptor blockade (AM630; 1x10-7 M). The data revealed that CP55940 elicits a CB1Rdependent
relaxation in cerebral arteries. Subsequently, to determine the role of different
endothelial-dependent pathways, CB1R-mediated vasorelaxation was examined under the
following conditions: 1) inhibition of nitric oxide synthase (NOS) using L-NAME (3x10-4 M;
reveals contributions from nitric oxide); 2) inhibition of in a cyclooxygenase (COX) using
Naproxen (3x10-4 M; reveals contributions from prostaglandins); 3) combined NOS and COX
inhibition (reveals contributions from endothelial hyperpolarizing factor); and 4) endothelial
removal (denudation of the artery; reveals total contribution of the endothelium). These data
demonstrated that CB1R-mediated vasorelaxation was attenuated by NOS inhibition and the
magnitude of this effect was increased with the combination of NOS + COX inhibition as well as
endothelial removal (P<0.05). However, reductions in vasorelaxation during COX inhibition alone
only approached significance (P=0.07). Overall, the data indicate CB1R-mediated vasorelaxation
is endothelial-dependent and involves contributions from multiple dilatory pathways.
Understanding how the CBRs modulate cerebrovascular function is critical when evaluating the
short-term and long-term physiological effects, safety and prescriptive use of cannabis and
cannabinoids in any clinical context.
Description
Keywords
Vascular Biology, Cerebrovascular regulation, Cannabis
Citation
Degree
Master of Science (M.Sc.)
Department
Veterinary Biomedical Sciences
Program
Veterinary Biomedical Sciences