Protective action of doxycycline against diabetic cardiomyopathy in rats.

BACKGROUND AND PURPOSE: Reactive oxygen and nitrogen species play an important role in the development of diabetic cardiomyopathy. They can activate matrix metalloproteinases (MMPs), and MMP-2 in particular is known to mediate early consequences of oxidative stress injury in the heart. Therefore, we investigated the role of MMP-2 and the effect of the MMP inhibitor doxycycline on the changes of heart function caused by diabetes. EXPERIMENTAL APPROACH: Using streptozotocin-induced diabetic rats, we evaluated the effect of doxycycline on both mechanical and electrical function of isolated hearts, papillary muscle and cardiomyocytes. KEY RESULTS: Doxycycline abolished the diabetes-induced depression in left ventricular developed pressure and the rates of changes in developed pressure in isolated hearts and normalized the prolongation of the action potential in papillary muscles. In cardiomyocytes isolated from doxycycline-treated diabetic rats, the altered kinetic parameters of Ca(2+) transients, depressed Ca(2+) loading of sarcoplasmic reticulum and basal intracellular Ca(2+) level, and the spatio-temporal properties of Ca(2+) sparks were significantly restored. Gelatin zymography and western blot data indicated that the diabetes-induced alterations in MMP-2 activity and protein level, level of tissue inhibitor of matrix metalloproteinase-4 and loss of troponin I were restored to control levels with doxycycline. CONCLUSIONS AND IMPLICATIONS: Our data suggest that these beneficial effects of doxycycline on the mechanical, electrical and biochemical properties of the diabetic rat heart appear, at least in part, to be related to inhibition of MMP activity, implying a role for MMPs in the development of diabetic cardiomyopathy.

Effects of N-nitro l-arginine methyl ester (l-NAME), a potent nitric oxide synthase inhibitor, on visual evoked potentials of rats exposed to different experimental stress models.

AIM: The aim of our study was to investigate the effects of the nitric oxide synthase inhibitor, N-nitro l-arginine methyl ester (l-NAME, 10 mg kg-1 day-1 i.p.), on visual evoked potentials (VEPs) and lipid peroxidation expected to occur during chronic stress (15 days). METHODS: Eight experimental groups, each consisting of 10 rats, were formed: control group (C), the group injected with l-NAME (L), groups exposed to cold stress (CS), immobilization stress (IS), and both cold and immobilization stress (CIS), groups exposed to stress and injected with l-NAME (CSL, ISL, CISL). RESULTS: l-NAME decreased brain and retina nitrite levels in all experimental groups compared with their corresponding control groups. l-NAME decreased glutathione peroxidase (GSH-Px) activity in the brain and retina in the L group, but increased it in the CSL and CISL groups compared with the C group. Lipid peroxidation was increased in the brain and retina tissues of all stress groups with respect to the C group. l-NAME markedly increased brain thiobarbituric acid reactive substances (TBARS) levels in the L group, while significantly decreasing brain and retina TBARS levels in all stress groups in comparison with their respective control groups. l-NAME caused a significant delay in all components of VEPs in the L group compared with the C group. However, l-NAME significantly decreased latencies of P1, N1, P2 and P3 components in the CSL group and all components in the ISL and CISL groups with respect to their corresponding control groups. CONCLUSION: This study clearly indicated that lipid peroxidation may be one possible factor affecting VEP components.