Cannabidiol attenuates visceral sympathoexcitatory cardiovascular responses through GPR18 receptors in rats

Cannabidiol (CBD) is widely used to manage various clinical disorders. However, its efficacy and the mechanisms underlying the regulation of high blood pressure (BP) remain controversial. A previous study showed that abnormal CBD, a synthetic analog of CBD, lowers normal BP via a mechanism dependent on the G protein-coupled receptor 18 (GPR18). Stimulation of visceral afferents causes a reflex increase in BP. There is no information on whether CBD attenuates sympathoexcitatory cardiovascular reflexes induced by visceral stimulation, nor on the underlying mechanisms. Thus, we hypothesized that CBD inhibits sympathoexcitatory cardiovascular responses through a GPR18 receptor mechanism. In Sprague-Dawley male rats, repeated gastric distension (GD) was performed under ketamine and α-chloralose anesthesia to induce sympathoexcitatory cardiovascular responses. We observed that repetitive GDs every 30 minutes for 4 times elicited consistent elevations in BP but not heart rate, even when the vehicle for CBD (Ethanol: Tween 80: Sesame oil; 1:4:5) was administered (1 ml/kg, IP) after the 2 GDs (n=6). Application of CBD (20 mg/1 ml/kg, IP; n=6) 30 minutes before the third GD did not lower baseline BP and HR but significantly reduced the increased BP reflex responses induced by the following 2 GDs (all P< 0.05). The inhibitory effect of CBD on the GD-induced increases in BP was reversed when a GPR18 receptor antagonist, O-1918 (100 µg/0.5 ml/kg; IV; n=5), was pre-administered 5 minutes before CBD. Crucially, the same inhibitory effect of CBD remained intact when the control vehicle (25% dimethyl sulfoxide in 0.1M phosphate buffer solution, 0.5 ml/kg; n=5) was given instead of the antagonist. These data suggest that CBD attenuates GD-induced pressor cardiovascular reflex responses, likely through GPR18 receptors. Supported by the Center for Medicinal Cannabis Research grant, P64-06-005. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.