Abstract 13153: Fasudil and Vardenafil Improve Myocardial Function and Attenuate Fibrosis in Experimental Diabetic Mellitus
Introduction: Cardiovascular complications are the leading cause of morbidity and mortality in diabetic patients. Fasudil, a Rho-kinase inhibitor, and Vardenafil, a PDE-5 inhibitor, are promising therapies in diabetic (DM) cardiac disorders. These two drugs impact RhoA/Rho kinase and cGMP pathways which have both been shown to participate in cardiac fibrosis and homeostasis. Hypothesis: Inhibition of Rho-kinase and PDE-5 may minimize cardiac structural and functional damage in a rat diabetic model.
Methods: DM was induced in male Wistar rats using Streptozotocin. After establishing diabetes, rats were divided into three groups; group one received no treatment; group two received Fasudil; and group three received Vardenafil. Echocardiography assessed LV structure and function. Plasma humoral profiles were assessed and heart sections were stained for fibrosis and collagen III. Snap frozen tissues were used for protein expression of ROCK1 and active ROCK1 by Western Blot.
Results: Left ventricular hypertrophy (LVH) was significantly lower in the Vardenafil treated group compared to the untreated or Fasudil treated groups. Systolic and diastolic myocardial function, as measured by circumferential systolic strain (CsC%) and early diastolic strain rate (Csr-E (s−1), was significantly better in both Vardenafil and Fasudil treated groups compared to the untreated group. However, Fasudil appeared to be slightly superior to Vardenafil. BNP, renin, and aldosterone were significantly lower in both Vardenafil and Fasudil treated groups compared to the untreated group. Percent LV fibrosis was reduced with Vardenafil treatment (5.64±3.6) as compared to untreated diabetic controls (8.99±2.2) and profoundly reduced with Fasudil treatment (2.89±0.9). Fasudil significantly reduced the ROCK1 ratio in LV. Conversely, Vardenafil did not affect the ROCK 1 ratio.
Conclusion: Rho-kinase and PDE-5 inhibition with Vardenafil or Fasudil attenuated LVH and improved LV systolic and diastolic myocardial function. Fibrosis was greatly attenuated by Fasudil in LV, with a greater effect on ROCK1 ratio than by Vardenafil. These results suggest that both Fasudil and Vardenafil improve cardiac fibrosis in DM, each by distinct mechanisms.
- © 2010 by American Heart Association, Inc.