Differential Effects of Cannabinoid Receptor Stimulation in Smooth Muscle

The use of cannabis as an herbal medicine can be traced back over 5000 years in China, and modern medicine now has well‐documented evidence for cannabis use for treatment of many illnesses. Medicinal marijuana is currently legal in over half of the states in the U.S., and eight states have passed legislation providing for recreational use. A recent survey shows that marijuana legalization support has increased significantly in 2015, nearly doubling in all age groups when compared to 2001. It is estimated that 8.1 million people in the U.S. use marijuana daily. With the increase in use, however, there is an alarming increase in reports of adverse events following marijuana exposure. A French study recently analyzed 35 reports of “remarkable” cardiovascular complications following marijuana use. The cardiovascular events were categorized into cardiac or extra‐cardiac (i.e. vascular) events: Acute coronary syndrome (ACS) composed 57% of the reports; heart rate disorders 5.7%; cerebral vascular events 8.6%; and peripheral vascular events 28.7%. Another study focused on 124 patients admitted for myocardial infarction concluded that there is a 4.8 fold increase in risk of myocardial infarction in the hour immediately following marijuana exposure. We hypothesized that direct stimulation of cannabinoid receptors on smooth muscle could potentiate contractility of vascular smooth muscle. To explore this hypothesis, we first quantified CB1 and CB2 expression in multiple tissues. Interestingly, we found expression of each receptor in every tissue examined. We used isolated vascular (portal vein) and visceral smooth muscle (ileum) preparations to quantify the effects of cannabinoid receptor stimulation. In visceral smooth muscle, stimulation of both CB1 and CB2 with anandamide (a non‐selective cannabinoid receptor agonist) resulted in marked relaxation of contraction while stimulation of CB1 with NADA had no effect on visceral contractility. Because relaxation was not induced through stimulation of solely CB1, the data suggests that relaxation of the visceral smooth muscle is likely regulated through CB2. Conversely, in vascular smooth muscle, stimulation with either CB1 or CB1/2 specific agonists increased contractility. These data suggest that cannabinoid receptor stimulation has a differential effect on visceral and vascular contractility. Future work will be aimed at elucidating the mechanisms underlying differential action of cannabinoid receptor stimulation and will serve to further our understanding of the increase in vascular events correlating with marijuana use. Support or Funding Information NIH NHLBI 1R25HL103286