Short Communication: The Peripheral Cannabinoid CB1 Receptor Antagonist AM6545 Modifies Cardiovascular Effects of Endocannabinoids in DOCA-Salt Rats.

Peripherally restricted ('second-generation') cannabinoid CB1 receptor (CB1R) antagonists have been suggested to have therapeutic potential in numerous diseases. However, their effects on the cardiovascular system require further research. The peripheral CB1R antagonist AM6545 failed to modify the decrease in blood pressure (BP) elicited by inhibition of anandamide degradation in spontaneously hypertensive rats. The aims of the present study were to examine the effect of AM6545 on BP and its interaction with endocannabinoid-evoked effects in deoxycorticosterone acetate (DOCA)-salt rats. For this purpose, we applied methanandamide (MethAEA), a stable analogue of anandamide, and URB597, an inhibitor of its degradation, in urethane-anesthetized animals. AM6545 did not affect BP by itself. MethAEA elicited a biphasic effect (a rise in BP, followed by its fall); both phases were antagonized by AM6545. URB597 induced a monophasic hypotensive effect, which was abolished by AM6545 in DOCA-salt rats but further enhanced in control animals. AM6545 also unmasked an additional increase in BP after URB597 in both groups of rats. In conclusion, AM6545 modifies the cardiovascular effects of endocannabinoids in hypertension in a model-dependent manner. The cardiovascular effects of CB1R antagonists should be carefully evaluated when assessing their potential therapeutic significance, as they may unmask an increase in BP.