Effect of tobacco smoke on hydrogen sulfide-induced rat thoracic aorta relaxation

Levels of hydrogen sulfide (H2S), a gaseous signaling molecule, are reduced in the serum of individuals who smoke. We hypothesized that tobacco smoke influenced smooth muscle relaxation by decreasing H2S levels and this effect could also influence expression of cystathionine γ-lyase (CSE) and sulfonylurea receptor-2 (SUR-2). The aim of this study was to explore the effect of tobacco smoke on H2S-mediated rat thoracic aorta relaxation and its possible mechanism. Thirty-two Sprague-Dawley rats were divided into four groups: control (C) group, short-term smoker (SS) group, mid-term smoker (MS) group, and long-term smoker (LS) group. H2S concentrations in serum, action of H2S on rat aortic vascular relaxation, and expression of CSE and SUR-2 in thoracic aortic smooth muscle were measured. Although there was no significant difference in H2S between the C and the SS groups, concentration of H2S was significantly reduced in both the LS and MS groups compared to control (P<0.01). Furthermore, H2S was significantly lower in the LS than in the MS group (P<0.05). Rat aortic vascular relaxation was lower in all three treatment groups compared to the control, with the most significant decrease observed in the LS group (P<0.05 compared to the MS group). Expression of CSE and SUR-2 was reduced in the LS and MS groups compared to control (P<0.05), with the lowest levels observed in the LS group (P<0.05). Therefore, tobacco smoke reduced expression of CSE and SUR-2 in rat thoracic aorta, which may inhibit H2S production and vascular dilation.

Association study of the ABCC8 gene variants with type 2 diabetes in south Indians.

BACKGROUND: The ABCC8 gene which encodes the sulfonylurea receptor plays a major role in insulin secretion and is a potential candidate for type 2 diabetes. The ‑3c → t (rs1799854) and Thr759Thr (C → T, rs1801261) single nucleotide polymorphisms (SNPs) of the ABCC8 gene have been associated with type 2 diabetes in many populations. The present study was designed to investigate the association of these two SNPs in an Asian Indian population from south India. MATERIALS AND METHODS: A total of 1,300 subjects, 663 normal glucose tolerant (NGT) and 637 type 2 diabetic subjects were randomly selected from the Chennai Urban Rural Epidemiology Study (CURES). The ‑3c → t and Thr759Thr were genotyped in these subjects using polymerase chain reaction‑restriction fragment length polymorphism (PCR‑RFLP) and a few variants were confirmed by direct sequencing. RESULTS: The frequency of the ‘t’ allele of the ‑3c → t SNP was found to be 0.27 in NGT and 0.29 in type 2 diabetic subjects (P = 0.44). There was no significant difference in the genotypic frequency between the NGT and type 2 diabetic group (P = 0.18). Neither the genotypic frequency nor the allele frequency of the Thr759Thr polymorphism was found to differ significantly between the NGT and type 2 diabetic groups. CONCLUSION: The ‑3c → t and the Thr759Thr polymorphisms of the ABCC8 gene were not associated with type 2 diabetes in this study. However, an effect of these genetic variants on specific unidentified sub groups of type 2 diabetes cannot be excluded.

Sulfony lureas and ischemic stroke / 国际脑血管病杂志

Sulfonylureas are one of the major oral drugs for the treatment of type 2 diabetes mellitus.Studies in recent years have shown that such drugs have the effect of independent of reducing blood sugar on ischemic stroke.This effect is mainly associated with the combination of sulfonylurea receptor 1 (SUR1) to regulate of ATP-sensitive non-selective cation channels.

Allicin, a SUR2 opener: possible mechanism for the treatment of diabetic hypertension in rats

The garlic (Allium sativum L., Amaryllidaceae) has been popularly used in the treatment of diabetes and cardiac complications. In the present work, we have studied the possible mechanisms, sulfonylurea receptor (SUR) selectivity of allicin in diabetic hypertensive rats. Diabetic hypertension was induced by intraperitoneal injection of streptozotocin (50 mg/kg) followed by daily administration of dexamethasone (10 µg/kg, s.c.). Different parameters, blood pressure and blood glucose levels were studied in the rats weekly up to eight weeks. Allicin (8 mg/kg, p.o.) shows potent antidiabetic (*p<0.001) as well as antihypertensive effect (**p<0.001, *p<0.01). It may act as a vasodilator by hyperpolarizing the membrane of normal vascular smooth muscle cells. The hyperpolarization in vascular smooth muscle occurs due to K+ channel opener activity. Antihypertensive effect of allicin is inhibited by glibenclamide, nonselective SUR blocker while combination of allicin with nateglinide, selective SUR1 blocker exerted synergistic antihypertensive effect. The results indicates that allicin is effective in the treatment of diabetic hypertension; through a mechanism that might involve selective opening of SUR2.

Transient neonatal diabetes mellitus caused by a de novo ABCC8 gene mutation / 소아과

Transient neonatal diabetes mellitus (TNDM) is a rare form of diabetes mellitus that presents within the first 6 months of life with remission in infancy or early childhood. TNDM is mainly caused by anomalies in the imprinted region on chromosome 6q24; however, recently, mutations in the ABCC8 gene, which encodes sulfonylurea receptor 1 (SUR1), have also been implicated in TNDM. Herein, we present the case of a male child with TNDM whose mutational analysis revealed a heterozygous c.3547C>T substitution in the ABCC8 gene, leading to an Arg1183Trp mutation in the SUR1 protein. The parents were clinically unaffected and did not show a mutation in the ABCC8 gene. This is the first case of a de novo ABCC8 gene mutation in a Korean patient with TNDM. The patient was initially treated with insulin and successfully switched to sulfonylurea therapy at 14 months of age. Remission of diabetes had occurred at the age of 16 months. Currently, the patient is 21 months old and is euglycemic without any insulin or oral hypoglycemic agents. His growth and physical development are normal, and there are no delays in achieving neurological and developmental milestones.

Association between SUR1 Ser1369Ala polymorphism and the efficacy of sulfonylurea / 基础医学与临床

Objective To investigate the association between a missense mutation (T/G, Ser 1369 Ala) in exon 33 of sulfonylurea receptor 1(SUR1) gene in type 2 diabetes patients and the glucose-lowering effect of Gliclazide. Methods One hundred and four type 2 diabetes patients were selected and orally administered with Gliclazide for 56 days. Venous fasting plasma glucose levels (FPG), plasma glucose levels half an hour after taking 75 g glucose (OGH) and two hours (OGT) after taking Gliclazide were measured. Ser1369Ala polymorphism genotypes(TT, TG, GG) of SUR1 gene were determined by Taqman method. The glucose-lowering effect of Gliclazide was compared among different groups. If FPG was reduced more than 20%, we define it as effective. People whose blood sugar level was effectively reduced and not significantly reduced were compared to find whether their genotype groups were different.Results The change of FPG,OGH and OGT on day 1 and day 57 among TT,TG and GG genotype groups had no statistically significant difference. There was no statistically significant difference of the efficacy of Gliclazide in recessive model (TT+TG vs GG). The combination of TG and GG was more effective in reducing blood sugar level than TT. Conclusion Patients carrying one or two copies of the G allele were more sensitive to Gliclazide than patients carrying T allele.

Study of relationship between sulfonylurea receptor gene polymorphism and type 2 diabetes / 医学研究生学报

Objective: To explore relationship between sulfonylurea receptor gene polymorphism and type 2 diabetes mellitus in Chinese subjects. Methods: Polymorphism of exon 16-3T→C in SUR gene 1 in 155 type 2 diabetic subjects and 132 controls were assessed by restriction fragment length polymorphism. Results: Frequency of “C” allele and “CC” homozygous phenotype in type 2 diabetic subjects was higher than that in control group. Conclusion:Allele “C” stands for hereditary susceptibility to diabetes.

An investigation on the relationship between sulfonylurea receptor 1 gene intron 24-3t/c polymorphism and blood lipids in Chinese population / 中国糖尿病杂志

Obeject To study the association of sulfonylurea receptor (SUR) 1 gene and blood lipids level.Method We investigated the SUR1 gene intron 24 3t/c polymorphism by polymerase chain reaction (PCR) and appropriate restriction enzyme (PCR RFLP) in 132 couples of type 2 diabetic case control and 282 type 2 diabetic pedigrees. The statistical methods were t test, multiple line regression and family based association test (FBAT).Result In the control group, the level of total cholesterol (TC), low density lipoprotein (LDL) and Apo B were higher in the cc genotype than that in the tt and the tc genotype. FBAT showed that sulfonylurea receptor 1 gene intron 24 3t/c polymorphism was significantly associated with TC, ApoB and BMI.Conclusion Sulfonylurea receptor 1 gene intron 24 3t/c polymorphism is associated with blood lipid level in north Chinese population.

Molecular characterisation of pancreatic zymogen granule ion channel and regulator proteins involved in exocytosis

In pancreatic acinar cells Ca(2+)-dependent secretagogues promote the fusion of zymogen granules (ZG) with the apical plasma membrane (PM) and exocytosis of digestive enzymes. In addition to exocytotic fusion complexes between SNARE proteins in the ZG membrane (ZGM) and the apical PM, enzyme secretion elicited by Ca(2+)-dependent secretagogues requires cytosolic Cl and K+ and is inhibited by blockers of Cl- and K+-channels. We have identified a Cl-conductance activated by ATP, and a K+-conductance (with properties similar to ATP-sensitive K+-channels), regulated by the granule matrix protein Zg-16p in the ZGM. Both conductances are inversely regulated by a 65-kD mdr1 gene product. We have also identified a novel Ca(2+)-activated anion conductance in ZGM, the Ca(2+)-sensitivity of which increases 50-fold when Cl is replaced by 1. This conductance is blocked by micromolar H2-DIDS or DTT, reminiscent of a family of epithelial Ca(2+)-activated Cl -channels (CaCC). Expression of a CaCC in exocrine pancreas has been confirmed by RT-PCR analysis, and by immunoblotting and immunogold labeling of ZG membranes. These data suggest that ion channels in the ZGM are essential elements in pancreatic exocytosis.

Stydy of relationship of sulfonylurea receptor-1 gene polymorphism with high insulin secretion levels in non-diabetes Chinese / 中国糖尿病杂志

Objective A recent study has shown the association between a sulfonylurea receptor gene 1 (SUR1) variant and hyperinsulinemia in normal individuals from a high diabetes risk ethnic group,supporting the hypothesis that the primary insulin hypersecretion may be an antecedent of type 2 diabetes.Methods To test this hypothesis in Chinese population,we studied the allele and genotype distribution of the polymorphism at -3 position of intron 24 in SUR1 by PCR RFLP technique in 206 unrelated normal glucose tolerant subjects with strong family history of type 2 diabetes (group A) and 110 normal individuals without family history of diabetes (group B).Results The frequency of “-3c” allele and “-3cc” genotype of intron 24 in group A was significantly higher than that in group B (64% vs 54%, P =0 004 and 38% vs 24%, P =0.002 respectively).Moreover,in group A, those carrying “cc” genetype had a higher BMI (27 27?6 37 vs 24.99?3.43kg/m 2, P

Effects of iptakalim hydrochloride on myocardial ATP-sensitive potassium channels / 中国药理学通报

AIM To investigate the effects of iptakalim hydrochloride(Ipt) on potassium currents in cardiomyocytes derived from guinea pig and on the specific binding of glibenclamide (Gli) with sulfonylurea receptor(SUR_ 2A ) of ATP-sensitive potassium channel (K_ ATP ) in cardiac membranes derived from Wistar rats. The effects of Ipt on the association and dissociation kinetic processes of Gli binding with SUR_ 2A of K_ ATP in cardiac preparations were also determined. METHODS The effects of Ipt on potassium currents in cardiomyocytes were observed by using patch clamp technique(whole cell recording) after application of the drug in the bath. The experiments of the ass ociation and dissociation kinetic processes of K_ ATP blocker [ 3H]Gli binding with cardiac membranes were used. RESULTS (1)The potassium current-voltage curves (I-U curves) of cardiomyocytes derived from guinea pig were upward shifted by Ipt at the concentrations of 1 and 100 ?mol?L -1 . Within 5 minutes after application of the drug, the current amplitude increased to 124.9%?9.5%(n=5)and 151.6%?11.2%(n=7)of initial current amplitude respectively(P

Tissue specificity in structure and function of ATP-sensitive potassium channel / 中国药理学通报

ATP-sensitive potassium channels (KATP channels) play important roles in various tissues tinder physiological and pathophysiological condi- conditions by coupling cell metabolic status to electrical activity. The KATP channel is a tetrameric complex of inwardly rectified potassium (Kir) and ATP binding protein (ABP). The Kir subunits form the channel pore, whereas ABP is required for activation and regulation. Both Kir and ABP are divided into different subunits and the various Kir and ABP subunits "mix and match" to form KATP channels with different pharmacological and nucleotide sensitivities. This review focuses on the molecular structure, physiological roles, pathophysiological and pharmacological proper ties of KATP channels in different tissues.

Effects of iptakalim hydrochloride on the association and dissociation kinetic processes of [~3H] glibenclamide binding with ATP-sensitive potassium channels in artery smooth muscles and its crosstalk with nucleotides / 中国药理学通报

AIM To investigate the effects of iptakalim hydrochloride(Ipt) on the association and dissociation kinetic processes of [ 3H]glibenclamide(Gli) binding with sulfonylurea receptor(SUR 2B ) of ATP sensitive potassium channel (K ATP ) in vascular smooth muscles derived from Wistar rats,and to compare the properties of Ipt with those of nucleotides. The interactions between Ipt and nucleotides were also determined. METHODS The experiments of the association and dissociation kinetic processes of K ATP blocker[ 3H]Gli binding with endothelium denuded aorta smooth muscles were used. RESRLTS (1)The specific bindings of[ 3H]Gli with SUR 2B were not displaced by Ipt at the concentrations of 10 pmol?L -1 ～ 0 5 mmol?L 1 . Ipt 100 ?mol?L -1 retarded the association kinetic process and accelerated the dissociation kinetic process of [ 3H]Gli binding with SUR 2B . (2)Opposite to Ipt, ATP 1 mmol?L -1 accelerated the association kinetic process and retarded the dissociation kinetic process of [ 3H]Gli binding with SUR 2B There was an interaction between ATP and Ipt in the modulation of [ 3H]Gli binding with SUR 2B . (3) Similar with Ipt, ADP 1 mmol?L -1 retarded the association kinetic process and accelerated the dissociation kinetic process of [ 3H]Gli binding with SUR 2B , there was an interaction between ADP and Ipt in the modulation of [ 3H]Gli binding with SUR 2B . (4)Different from ATP and ADP, UDP had no effect on the association and dissociation kinetic process of [ 3H]Gli binding with SUR 2B . And there was not interaction between UDP and Ipt. CONCLUSION Ipt had no affinity with the binding sites of K ATP blocker in SUR 2B , but had negative allosterical modulation on it. The modulatory properties of Ipt were opposite to those of ATP, similar with those of ADP and different from those of UDP. There were interactions between ATP, ADP and Ipt in the modulation of [ 3H]Gli binding with SUR 2B , but there was not interaction between UDP and Ipt.