OBJECTIVETo compare the influence of different sulfonylureas on the myocardial protection effect of ischemic preconditioning (IPC) in isolated rat hearts, and ATP-sensitive potassium channel current (IK(ATP)) of rat ventricular myocytes.

METHODSIsolated Langendorff perfused rat hearts were randomly assigned to five groups: (1) control group, (2) IPC group, (3) IPC + glibenclamide (GLB, 10 micromol/L) group, (4) IPC + glimepiride (GLM, 10 micromol/L) group, (5) IPC + gliclazide (GLC, 50 micromol/L) group. IPC was defined as 3 cycles of 5-minute zero-flow global ischemia followed by 5-minute reperfusion. The haemodynamic parameters and the infarct size of each isolated heart were recorded. And the sarcolemmal IK(ATP) of dissociated ventricular myocytes reperfused with 10 micromol/L GLB, 1 micromol/L GLM, and 1 micromol/L GLC was recorded with single-pipette whole-cell voltage clamp under simulated ischemic condition.

RESULTSThe infarct sizes of rat hearts in IPC (23.7% +/- 1.3%), IPC + GLM (24.6% +/- 1.0%), and IPC + GLC (33.1% +/- 1.3%) groups were all significantly smaller than that in control group (43.3% +/- 1.8%; P < 0.01, n = 6). The infarct size of rat hearts in IPC + GLB group (40.4% +/- 1.4%) was significantly larger than that in IPC group (P < 0.01, n=6). Under simulated ischemic condition, GLB (10 micromol/L) decreased IK(ATP) from 20.65 +/- 7.80 to 9.09 +/- 0.10 pA/pF (P < 0.01, n=6), GLM (1 micromol/L) did not significantly inhibit IK(ATP) (n=6), and GLC (1 micromol/L) decreased IK(ATP) from 16.73 +/- 0.97 to 11. 18 +/- 3.56 pA/pF (P < 0.05, n=6).

CONCLUSIONSGLM has less effect on myocardial protection of IPC than GLB and GLC. Blockage of sarcolemmal ATP-sensitive potassium channels in myocardium might play an important role in diminishing IPC-induced protection of GLM, GLB, and GLC.

Animals ; Gliclazide ; pharmacology ; Glyburide ; pharmacology ; Heart ; drug effects ; Ischemic Preconditioning ; Male ; Rats ; Rats, Sprague-Dawley ; Sulfonylurea Compounds ; pharmacology

Acetohydroxyacid synthase (AHAS) catalyses the first reaction in the pathway for synthesis of the branched-chain amino acids. AHAS is the target for sulfonylurea, imidazolinone and other AHAS-inhibitor herbicides. Herbicides-resistant AHAS genes have potential application in plant transgenetic engineering and development of new generation herbicide. The AHAS isozyme genes ilvBN, ilvGM and ilvIH were cloned from metsulfuron-methyl resistant strain Klebsiella sp. HR11 and metsulfuron-methyl sensitive strain Klebsiella pneumoniae MGH 78578. Homologous sequences comparison indicated that the differences in AHAS isozyme genes at amino acid levels between strain HR11 and strain MGH 78578 were mainly on the large subunits of ilvBN and ilvGM. The three AHAS isozyme genes from HR11 and MGH 78578 were ligated into the expression vector pET29a(+) and expressed in Escherichia coli BL21, respectively. The results of enzyme inhibition assay showed that only ilvBN and ilvGM from strain HR11 showed strong resistance to AHAS-inhibitor herbicides, while ilvIH from strain HR11 and ilvBN, ilvGM and ilvIH from strain MGH78578 were sensitive to AHAS-inhibitor herbicides.
Acetolactate Synthase ; chemistry ; genetics ; Escherichia coli ; genetics ; metabolism ; Gene Expression ; Genes, Bacterial ; drug effects ; Herbicide Resistance ; genetics ; Herbicides ; pharmacology ; Imidazolines ; pharmacology ; Isoenzymes ; genetics ; Klebsiella ; genetics ; Sulfonylurea Compounds ; pharmacology

BACKGROUND: Although insulin resistance and decreased insulin secretion are characteristics of established type 2 DM, which of these metabolic abnormalities is the primary determinant of type 2 DM is controversial. It is also not well known how insulin resistance and beta cell dysfunction influence serum insulin, proinsulin, proinsulin/insulin ratio in type 2 DM. METHODS: We compared serum insulin, proinsulin and proinsulin/insulin ratio in type 2 diabetic patients and control subjects. We also investigated the relationship between serum insulin, proinsulin and proinsulin/insulin ratio and several biochemical markers which represent insulin resistance or beta cell function. RESULTS: Insulin, proinsulin and proinsulin/insulin ratio were significantly higher in type 2 DM than control(p < 0.001). In diabetic patients, total insulin level was correlated with urinary albumin excretion rates(r = 0.224, p = 0.025) and body mass index(r = 0.269, p = 0.014). Proinsulin level was correlated with fasting C-peptide(r = 0.43, p = 0.002), postprandial 2 hour blood glucose(r = 0.213, p = 0.05) and triglyceride(r = 0.28, p = 0.022). Proinsulin/insulin ratio was positively correlated with fasting C-peptide(r = 0.236, p = 0.031), fasting blood glucose (r = 0.264, p = 0.015), postprandial 2 hour blood glucose(r = 0.277, p = 0.001) and triglyceride(r = 0.428, p < 0.001). In control subjects, insulin level was correlated with triglyceride(r = 0.366, p = 0.002). Proinsulin/insulin ratio was correlated with age(r = 0.241, p = 0.044). CONCLUSION: The serum levels of insulin and proinsulin seem to be associated with several markers of insulin resistance. Whereas proinsulin/insulin ratio might represent beta cell function rather than insulin resistance. But more studies are needed to clarify the mechanisms of elevated proinsulin/insulin ratio in type 2 DM.
Aged ; Diabetes Mellitus, Non-Insulin-Dependent/etiology ; Diabetes Mellitus, Non-Insulin-Dependent/blood* ; Female ; Human ; Insulin/blood* ; Insulin Resistance* ; Islets of Langerhans/physiopathology* ; Male ; Middle Age ; Proinsulin/blood* ; Sulfonylurea Compounds/pharmacology