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Abstract The results of the present study revealed that: Compared to STZ diabetic rats, abn-cbd; • Had no effect on diabetes-evoked cardiac hypertrophy, or the associate impaired glycemic control (hyperglycemia and hypoinsulinemia). • Alleviated the reductions in LV contractility (dP/dtmax) and relaxation (dP/dtmin) indices, and the increases in LVEDP and cardiac vagal dominance. • Reversed myocardial oxidative stress by restoring circulating and cardiac NO and ADN levels and enhancing GPR18 expression and phosphorylation of Akt, ERK1/2 and eNOS in diabetic rats’ hearts. Concurrent GPR18 blockade (O-1918) abrogated all favorable effects of abn-cbd in diabetic rats. In conclusion, abn-cbd improves cardiovascular functions in diabetes via activation of the endocannabinoid receptor, GPR18, which is expressed in the myocardium. The signaling mechanisms that mediate the abn-cbd –evoked cardiovascular effects include activation of Akt and ERK1/2 signaling pathways as well as adiponectin mediated elevation of nitric oxide levels and reduction of oxidative stress. GPR18 can be considered as a viable molecular target for developing new therapeutics that simultaneously improves cardiac function in diabetes. |