ABSTRACT
1. Reactive oxygen species (ROS) cause vascular complications and impair vasodilation in diabetes mellitus. Large-conductance Ca(2+)-activated potassium channels (BK(Ca)) modulate vascular tone and play an important negative feedback role in vasoconstriction. In the present study, we tested the hypothesis that ROS regulate the function of BK(Ca) in diabetic cerebral artery smooth muscle cells. 2. Diabetes was induced in male BALB/c mice by injection of streptozotocin (STZ; 180 mg/kg, i.p., dissolved in sterile saline). Control and diabetic mice were treated with 12.7 micromol/L rotenone, an inhibitor of the mitochondrial electron transport chain complex I, or placebo every other day for 5 weeks. The whole-cell patch clamp-technique and functional vasomotor methods were used to record BK(Ca) currents and myogenic tone of cerebral artery smooth muscle cells. 3. In the diabetic group, there was a significant decrease in spontaneous transient outward currents in cerebral artery smooth muscle cells compared with control. Although the currents were only moderately increased in rotenone-treated diabetic mice, they remained significantly lower than in the control group. Furthermore, the macroscopic BK(Ca) currents that were decreased in diabetic mice were partially recovered in rotenone-treated diabetic mice (P < 0.05 vs untreated diabetic group). 4. The posterior cerebral artery from diabetic mice had a significantly higher myogenic tone than the control group, but this impaired contraction was partially reversed in the rotenone-treated diabetic group (P < 0.05 vs untreated diabetic group). 5. The H(2)O(2) concentration was significantly increased in cerebral arteries from diabetic mice compared with control. This increase in H(2)O(2) was significantly blunted by rotenone treatment. 6. In conclusion, rotenone partially reverses the decreased macroscopic BK(Ca) currents in STZ-induced Type 1 diabetic mice and this reversal of BK(Ca) currents may be related to the inhibitory effects of rotenone on H(2)O(2) production. Reactive oxygen species, particularly H(2)O(2), are important regulators of BK(Ca) channels and myogenic tone in diabetic cerebral artery.
Subject(s)
Cerebral Arteries/drug effects , Diabetes Mellitus, Experimental/physiopathology , Large-Conductance Calcium-Activated Potassium Channels/drug effects , Muscle, Smooth, Vascular/drug effects , Rotenone/pharmacology , Streptozocin , Animals , Calcium Signaling/drug effects , Cerebral Arteries/metabolism , Cerebral Arteries/pathology , Cerebral Arteries/physiopathology , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Drug Evaluation, Preclinical , Hydrogen Peroxide/metabolism , Hydrogen Peroxide/pharmacology , Insecticides/pharmacology , Large-Conductance Calcium-Activated Potassium Channels/metabolism , Large-Conductance Calcium-Activated Potassium Channels/physiology , Male , Membrane Potentials/drug effects , Mice , Mice, Inbred BALB C , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/pathology , Muscle, Smooth, Vascular/physiopathology , Myocytes, Smooth Muscle/drug effects , Myocytes, Smooth Muscle/pathology , Myocytes, Smooth Muscle/physiology , Patch-Clamp Techniques , Vasoconstriction/drug effectsABSTRACT
The aim of present study is to investigate the cardioprotective effect of a new compound acetyl ferulaic isosorbide (AFI), composed of ferulaic acid (FA) and isosorbide mononitrate (ISMN) by esterification in myocardial ischemia/reperfusion (MI/R). Male Sprague-Dawley rats, subjected to 30 minutes of myocardial ischemia and 3 hours of reperfusion, randomly received one of the following treatments separately: SHAM, I/R (MI/R + solvent), SF (MI/R+SF, 40 mg x kg(-1), ig), ISMN (MI/R + ISMN, 30 mg x kg(-1), ig), SF + ISMN (MI/R + SF + ISMN, 40 mg x kg(-1) + 30 mg x kg(-1), ig) and AFI (MI/R + AFI, 10 mg x kg(-1), ig). Left ventricle developed pressures (LVDP) and the maximal first derivative of developed pressure ( +/-dP / dtmax) were monitored throughout the experiments. Myocardial infarction size, serum creatine kinase (CK) activity, lactate dehydrogenase (LDH) activity, superoxide dismutase (SOD) activity, hydrogen peroxide (H2O2), malondialdehyde (MDA) and nitric oxide (NO) production were determined at the end of reperfusion. Compared with SF, ISMN or SF + ISMN treatment groups, AFI treatment decreased infarction size (n=8, P < 0.01), improved cardiac function as evidenced by increased LVDP and +/- dP/dtmax (n=8, P < 0.05), increased serum SOD activity, reduced serum CK and LDH activities, H2O2 and MDA production (n=8, P < 0.05). The new compound AFI showed a stronger cardioprotective effect against MI/R injury than SF, ISMN or their combined administration did.