Abnormal cannabidiol confers cardioprotection in diabetic rats independent of glycemic control

Eur J Pharmacol. 2018 Feb 5;820:256-264. doi: 10.1016/j.ejphar.2017.12.039. Epub 2017 Dec 20.

Abstract

Chronic GPR18 activation by its agonist abnormal cannabidiol (trans-4-[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol; abn-cbd) improves myocardial redox status and function in healthy rats. Here, we investigated the ability of abn-cbd to alleviate diabetes-evoked cardiovascular pathology and the contribution of GPR18 to this effect. Four weeks after diabetes induction by streptozotocin (STZ, 55mg/kg; i.p), male Wistar rats received abn-cbd, the GPR18 antagonist (1,3-dimethoxy-5-methyl-2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-,cyclohexen-1-yl]benzene;O-1918), their combination (100µg/kg/day, i.p, each) or their vehicle for 2 weeks. Abn-cbd had no effect on diabetes-evoked cardiac hypertrophy or impaired glycemic control (hyperglycemia and hypoinsulinemia), but alleviated the associated reductions in left ventricular (LV) contractility (dP/dtmax) and relaxation (dP/dtmin) indices, and the increases in LV end diastolic pressure (LVEDP) and cardiac vagal dominance. Abn-cbd also reversed myocardial oxidative stress by restoring circulating and cardiac nitric oxide (NO) and adiponectin (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. Collectively, the current findings present evidence for abn-cbd alleviation of diabetes-evoked cardiovascular anomalies likely via GPR18 dependent restoration of cardiac adiponectin-Akt-eNOS signaling and the diminution of myocardial oxidative stress.

Keywords: Abnormal cannabidiol; Adiponectin; Cardiac dysfunction; Diabetes; GPR-18; O-1918.

MeSH terms

  • Adiponectin / blood
  • Animals
  • Blood Glucose / metabolism
  • Cardiotonic Agents / pharmacology*
  • Cardiotonic Agents / therapeutic use
  • Diabetes Mellitus, Experimental / blood
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / physiopathology
  • Gene Expression Regulation / drug effects
  • Hemodynamics / drug effects
  • Male
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Myocardium / metabolism
  • Nitric Oxide / blood
  • Nitric Oxide Synthase Type III / metabolism
  • Oxidative Stress / drug effects
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Rats, Wistar
  • Receptors, Cannabinoid / metabolism
  • Resorcinols / pharmacology*
  • Resorcinols / therapeutic use
  • Ventricular Dysfunction, Left / drug therapy

Substances

  • 4-(3-3,4-p-menthadien-(1,8)-yl)olivetol
  • Adiponectin
  • Blood Glucose
  • Cardiotonic Agents
  • GPR18 protein, rat
  • Receptors, Cannabinoid
  • Resorcinols
  • Nitric Oxide
  • Nitric Oxide Synthase Type III
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3