ABSTRACT
Purpose: Sodium thiosulfate (STS) is clinically reported to be a promising drug in preventing nephrolithiasis. However, its mechanism of action remains unclear. In the present study, we investigated the role of mitochondrial KATP channel in the renal protection mediated by STS. Materials and Methods: Nephrolithiasis was induced in Wistar rats by administrating 0.4% ethylene glycol (EG) along with 1% ammonium chloride for one week in drinking water followed by only 0.75% EG for two weeks. Treatment groups received STS, mitochondrial KATP channel opener and closer exclusively or in combination with STS for two weeks. Results: Animals treated with STS showed normal renal tissue architecture, supported by near normal serum creatinine, urea and ALP activity. Diazoxide (mitochondria KATP channel opening) treatment to the animal also showed normal renal tissue histology and improved serum chemistry. However, an opposite result was shown by glibenclamide (mitochondria KATP channel closer) treated rats. STS administered along with diazoxide negated the renal protection rendered by diazoxide alone, while it imparted protection to the glibenclamide treated rats, formulating a mitochondria modulated STS action. Conclusion: The present study confirmed that STS render renal protection not only through chelation and antioxidant effect but also by modulating the mitochondrial KATP channel for preventing urolithiasis.
Subject(s)
Animals , Male , Antioxidants/pharmacokinetics , Chelating Agents/pharmacology , Ethylene Glycol , Nephrolithiasis/prevention & control , Potassium Channels/pharmacology , Thiosulfates/pharmacology , Antioxidants/therapeutic use , Calcium Oxalate/metabolism , Chelating Agents/therapeutic use , Disease Models, Animal , Electrophoresis, Agar Gel , Kidney/drug effects , Kidney/pathology , Lipid Peroxidation/drug effects , Nephrolithiasis/pathology , Potassium Channels/therapeutic use , Random Allocation , Rats, Wistar , Reproducibility of Results , Treatment Outcome , Thiosulfates/therapeutic useABSTRACT
This study aimed to determine the role of mitochondrial adenosine triphosphate-sensitive potassium (mitoKATP) channels and protein kinase C (PKC)-ε in the delayed protective effects of sevoflurane preconditioning using Langendorff isolated heart perfusion models. Fifty-four isolated perfused rat hearts were randomly divided into 6 groups (n=9). The rats were exposed for 60 min to 2.5% sevoflurane (the second window of protection group, SWOP group) or 33% oxygen inhalation (I/R group) 24 h before coronary occlusion. The control group (CON) and the sevoflurane group (SEVO) group were exposed to 33% oxygen and 2.5% sevoflurane for 60 min, respectively, without coronary occlusion. The mitoKATP channel inhibitor 5-hydroxydecanoate (5-HD) was given 30 min before sevoflurane preconditioning (5-HD+SWOP group). Cardiac function indices, infarct sizes, serum cardiac troponin I (cTnI) concentrations, and the expression levels of phosphorylated PKC-ε (p-PKC-ε) and caspase-8 were measured. Cardiac function was unchanged, p-PKC-ε expression was upregulated, caspase-8 expression was downregulated, cTnI concentrations were decreased, and the infarcts were significantly smaller (P<0.05) in the SWOP group compared with the I/R group. Cardiac function was worse, p-PKC-ε expression was downregulated, caspase-8 expression was upregulated, cTnI concentration was increased and infarcts were larger in the 5-HD+SWOP group (P<0.05) compared with the SWOP group. The results suggest that mitoKATP channels are involved in the myocardial protective effects of sevoflurane in preconditioning against I/R injury, by regulating PKC-ε phosphorylation before ischemia, and by downregulating caspase-8 during reperfusion.
Subject(s)
Animals , Male , Ischemic Preconditioning, Myocardial/methods , Methyl Ethers/pharmacology , Myocardial Reperfusion Injury/prevention & control , Platelet Aggregation Inhibitors/pharmacology , Potassium Channels/pharmacology , Protein Kinase C/pharmacology , Anti-Arrhythmia Agents/pharmacology , Blotting, Western , /analysis , Decanoic Acids/pharmacology , Heart/drug effects , Heart/physiopathology , Hemodynamics/drug effects , Hydroxy Acids/pharmacology , Ischemia/prevention & control , Protective Agents/pharmacology , Random Allocation , Rats, Sprague-Dawley , Reproducibility of Results , Time Factors , Troponin I/analysisABSTRACT
The effects of the Ca 2+ channel blocker diltiazem were investigated and compared with those of pinacidil a K + channel activator on the agonist-induced contractions of the isolated rabbit aortic strip, rat fundus, guinea pig ileum and tracheal chain. Both diltiazem and pinacidil showed a concentration-dependent inhibition of the norepinephrine [NE]-induced contraction of the isolated rabbit aortic strip. The effective concentration [EC50] of diltiazem was 6 x 10 -6 mmol +/- 0.39 and that of pinacidil was 4 x 10 -5 mmol +/- 0.02. Diltiazem and pinacidil, even at high concentrations, were without any effect on the agonist induced contractions of the different non-vascular smooth muscle preparations used in the study. The results suggested that the antispamogenic effect of diltiazem and pinacidil may be restricted to the vascular smooth muscle fibers, since both drugs failed to inhibit the response of non-vascular smooth muscle preparation to their agonists