Cannabidiol selectively inhibits the contraction of rat small resistance arteries: Possible role for CGRP and voltage-gated calcium channels

The pharmacology of cannabidiol, the non-psychoactive major component of Cannabis saliva, is of growing interest as it becomes more widely prescribed. This study aimed to examine the effects of cannabidiol on a wide range of contractile agents in rat small resistance arteries, in comparison with large arteries, and to explore its mechanism of action. The vascular actions of cannabidiol were also contrasted with effects on the contractions of bronchial, urogenital, cardiac and skeletal muscles. Isolated small or large arteries were incubated with cannabidiol (0.3-3 mu M) or vehicle and concentration-contraction response curves were completed to various agents, including endothelin-1, arginine vasopressin, methoxamine, 5-HT, alpha-methyl 5-HT and U46619. In small arteries, the effects of cannabidiol were tested in the presence of antagonists of CB1 or CB2 receptors, calcitonin generelated peptide (CGRP), nitric oxide synthase, cyclooxygenase, PPAR gamma or a combination. The role of L-type voltage-operated calcium channels was also assessed. Cannabidiol 1-3 mu M significantly inhibited the contraction of small resistance arteries to all tested agents through a combination of mechanisms that include CGRP and L-type calcium channels. However, large arteries were insensitive to cannabidiol. Cannabidiol (10-100 mu M) was largely without effect in bronchi, atria and hemidiaphragm, but 100 mu M attenuated maximum contractions in vasa deferentia. Cannabidiol's effects in the clinical range (1-3 mu M) appear to be specific to small resistance arteries. This high sensitivity of the resistance arterial circulation to cannabidiol may offer a therapeutic opportunity in peripheral vascular disease that excludes off-target sites such as the heart and non-vascular smooth muscle.

Automated summary

This study demonstrates that cannabidiol inhibits the contraction of small resistance arteries through a combination of mechanisms involving CGRP and L-type calcium channels, while large arteries are insensitive to cannabidiol. Moreover, cannabidiol has little effect on bronchi, atria, and hemidiaphragm, but can attenuate maximum contractions in vasa deferentia. The high sensitivity of resistance arterial circulation to cannabidiol in the clinical range may present a therapeutic opportunity in peripheral vascular disease.