Abstract 18480: Attenuation of Cardiac Autonomic Neuropathy and Left Ventricular Function by Inhibition of Matrix Metalloproteinase 2&9 in Diabetic Rats

Abstract

Cardiovascular autonomic neuropathy (CAN) is a serious and common complication of diabetes. Along with other cardiovascular dysfunction CAN further worsen the performance of heart in diabetics. We hypothesized that MMP-2 and MMP-9 inhibition can attenuate cardiovascular autonomic neuropathy in diabetics. The present study was designed to investigate effect of MMP-2 and MMP-9 inhibition on cardiac autonomic neuropathy and left ventricular function in streptozotocin-induced (55 mg/kg i.p.) diabetic rats by analysis of heart rate variability (HRV) and left ventricular functions. Minocycline (50mg/kg) was used as a MMP-2 and MMP-9 inhibitor. Eight weeks after induction of diabetes, rats were administered Minocycline (50 mg/kg) over a four-week period. Gelatine zymography was performed to evaluate MMP-2 and MMP-9 levels in vagus nerve and heart. Diabetes resulted in reduction in heart rate (290±31 vs. 376±29 beat per min; P<0.0001). This bradycardia was partly reversed with MMP-2 and MMP-9 inhibitor Minocycline (352 ± 42 beat per min; P<0.05 vs. diabetic control). Both time- and frequency-domain parameters of HRV were significantly reduced in diabetic rats. Spectral power was reduced around 45% at high frequencies and about 65% at low frequencies in diabetic rats. This suggested a decrease of parasympathetic activity. Ratio of low/high frequency was also significantly decreased in diabetic rats suggesting decreased sympathetic tone. Standard deviation of heart rate in minocycline treated rats was significantly higher than in untreated diabetic rats (P<0.05). Significant attenuation (P<0.05) was also observed in power spectrum of treated animals. Treatment also significantly ameliorated left ventricular functions dp/dt_max and dp/dt_min compared to diabetic control. MMP-2 and MMP-9 levels were significantly decreased in minocycline treated group compared to diabetic control. In conclusion, inhibition of MMP-2 and MMP-9 by minocycline prevented development of cardiovascular autonomic neuropathy and ameliorated left ventricular function in streptozotocin-induced diabetes in rats.