Abstract 1163: Chronic Daily Therapy With Tadalafil Improves Multiple Cardiovascular Risk Factors in Obese, Diabetic Mice
Background: Obesity and insulin resistance lead to impaired nitric oxide (NO) bioavailability, chronic inflammation, atherosclerosis and acute coronary syndromes. Phosphodiesterase-5 (PDE-5) inhibitors restore NO signaling, reduce infarct size, and may reduce levels of circulating tumor necrosis factor-α (TNF-α). We hypothesized that daily administration of the long acting PDE-5 inhibitor, tadalafil (TAD) will attenuate inflammatory markers, improve fasting serum glucose levels, and reduce infarct size (IS) after ischemia/reperfusion (I/R) in obese, diabetic mice.
Methods and Results: Adult male homozygous leptin receptor null (db/db) mice underwent daily treatment with TAD (1 mg/kg ip) or 10% DMSO for 28 days. Body weight was monitored daily and fasting serum glucose level was determined weekly using a handheld glucometer. Upon completion of therapy, all hearts were isolated and subjected to 30 min global ischemia followed by 60 min reperfusion in Langendorff mode. Serum samples were taken for cytokine and chemokine analysis and IS was measured using computer morphometry of tetrazolium stained sections. Treatment with TAD caused a 53% reduction in IS in the diabetic heart [Fig 1A⇓] and reduced fasting glucose levels as compared to DMSO (196±14 mg/dL vs. 411±22 mg/dL, P<0.001). Circulating cytokines, macrophage inflammatory protein-1β (MIP-1β), monocyte chemotactic protein-1 (MCP-1) and chemokine (C-C motif) ligand 5 (CCL5) levels were also significantly reduced [Fig 1B⇓].
Conclusion: TAD could be an attractive therapy for reducing cardiovascular risk factors while providing a powerful cardioprotective effect in diabetic patients.