Abstract Fri003: Novel Cannabinoid Agonist for Treatment of Diabetes-induced Heart Failure

Introduction: Aging of the population caused greater prevalence of diabetes mellitus (DM), which is associated with high morbidity and mortality because of progression to heart failure (HF). DM pathogenesis includes oxidative stress and inflammation, which predispose the diabetic heart to remodeling and hypertrophy resulting in cardiac dysfunction. It is essential the development of new therapeutic approaches that could act to improve the quality of life of diabetic patients with HF. The modulation of the endocannabinoid system could play an important role in improving cardiac dysfunction, since its activation has anti-inflammatory and antioxidant effects. A new agonist of cannabinoid receptors was designed, synthetized and evaluated on DM-induced HF in rats. Methods: Experimental protocols approved by Animal Care and Use Committee at Universidade Federal do Rio de Janeiro, Brazil. Intravenous injection of streptozotocin (60 mg/kg) into the caudal vein of Wistar rats used to induce DM. Animals were diabetic when fasting glucose was equal to or greater than 250 mg/dL. After 8 weeks of induction, diabetic animals were randomly divided in groups, either orally treated with vehicle or the new agonist of cannabinoid receptors (50 mg/kg) for 14 days. Under isoflurane anesthesia (3%), transthoracic echocardiography and cardiac catheterization used to obtain hemodynamic parameters. Results: Systolic and diastolic blood pressures increased after 8 weeks of DM induction, from 119.6 ± 2.3 to 134.5 ± 2.2 mmHg (P<0.05) and from 85.4 ± 4.5 to 112.6 ± 2.8 mmHg (P<0.05), respectively and normalized after oral administration of new cannabinoid. In diabetic animals, LV systolic pressure increased from 110.3 ± 4.2 to 128.8 ± 4.8 (P<0.05), and treatment with agonist of cannabinoid receptors reduced to 74.9 ± 5.9 mmHg. Additionally of improvement of LV dysfunction, synthetic cannabinoid reduced heart rate from 312.0 ± 7.0 to 254.0.± 18.0 bpm. DM induced reduction of ejection fraction (EF) from 86.3 ± 3.8 to 54.7 ± 3.2%, indicating HF with mildly reduced EF, which recovered to 67.7 ± 2.3% (P<0.05) after treatment with cannabinoid. Measurement of LV filling pressure (E/e') indicated increase from 10.1 ± 0.1 to 17.2 ± 2.2 and oral administration of cannabinoid reduced to 13.1 ± 1.2. Conclusion: Activation of endocannabinoid system by a novel cannabinoid agonist could improve HF, since the response of cannabinoid receptors could modulate DM pro-inflammatory profile.