Triphosphate-sensitive Potassium Research Articles

Expression and influence of KATP in umbilical artery smooth muscle cells of patients with hypertensive disorders of pregnancy

The objective of this study is to investigate the expression and influence of adenosine triphosphate-sensitive potassium channel (KATP) in human umbilical arterial smooth muscle cells (HUASMCs) of patients with hypertensive disorders of pregnancy (HDP). Western blotting was used to detect the protein expression levels of KATP inwardly rectifying potassium channel (Kir)6.1 and sulphonylurea receptor (SUR)2B subunits in HUASMCs from patients with normal parturients (NP), gestational hypertension (GH), chronic hypertension (CH), preeclampsia (PE) and chronic hypertension with superimposed preeclampsia (CHSP), respectively. There was no significant difference in the protein expression of Kir6.1 subunit in NP group, GH group, CH group, PE group and CHSP group (P > 0.05). The protein expression of SUR2B subunit was gradually decreased in NP group, GH group, CH group, PE group and CHSP group, with statistically significant difference among the groups (P < 0.05). The altered expression level of KATP SUR2B subunit may be involved in the pathogenesis of HDP. The severity of HDP may be related to the degree of decrease of SUR2B subunit.

Vascular contraction of umbilical arteries of pregnant women with preeclampsia.

Potassium channels have an important role in the vascular adaptation during pregnancy and a reduction in the expression of adenosine triphosphate-sensitive potassium channels (Katp) has been linked to preeclampsia. Activation of Katp induces vasodilation; however, no previous study has been conducted to evaluate the effects of the inhibition of these channels in the contractility of preeclamptic arteries. Glibenclamide is an oral antihyperglycemic agent that inhibits Katp and has been widely used in vascular studies. To investigate the effects of the inhibition of Katp, umbilical arteries of preeclamptic women and women with healthy pregnancies were assessed by vascular contractility experiments, in the presence or absence of glibenclamide. The umbilical arteries were challenged with cumulative concentrations of potassium chloride (KCl) and serotonin. There were no differences between the groups concerning the maternal age and gestational age of the patients. The percentage of smokers, caucasians and primiparae per group was also similar. On the other hand, blood pressure parameters were elevated in the preeclamptic group. In addition, the preeclamptic group presented a significantly higher body mass index. The newborns of both groups presented similar APGAR scores and weights. In the presence of glibenclamide, there was an increase in the KCl-induced contractions only in vessels from the PE group, showing a possible involvement of these channels in the disorder.

Incretin hormone responses to carbohydrate and protein/fat are preserved in adults with sulfonylurea-treated KCNJ11 neonatal diabetes.

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are thought to be the main drivers of insulin secretion in individuals with sulfonylurea (SU)-treated KCNJ11 permanent neonatal diabetes. The aim of this study was to assess for the first time the incretin hormone response to carbohydrate and protein/fat in adults with sulfonylurea-treated KCNJ11 permanent neonatal diabetes compared with that of controls without diabetes. Participants were given a breakfast high in carbohydrate and an isocaloric breakfast high in protein/fat on two different mornings. Incremental area under the curve and total area under the curve (0-240 minutes)for total GLP-1 and GIP were compared between groups, using non-parametric statistical methods. Post-meal GLP-1 and GIP secretion were similar in cases and controls, suggesting this process is adenosine triphosphate-sensitive potassium channel-independent. Future research will investigate whether treatments targeting the incretin pathway are effective in individuals with KCNJ11 permanent neonatal diabetes who do not have good glycemic control on sulfonylurea alone.

Kir1.1 and SUR1 are not implicated as subunits of an adenosine triphosphate-sensitive potassium channel involved in diazoxide cardioprotection

ObjectiveThe adenosine triphosphate-sensitive potassium channel opener diazoxide mimics ischemic preconditioning and is cardioprotective. Clarification of diazoxide's site and mechanism of action could lead to targeted pharmacologic therapies for patients undergoing cardiac surgery. Several mitochondrial candidate proteins have been investigated as potential adenosine triphosphate-sensitive potassium channel components. Renal outer medullary potassium (Kir1.1) and sulfonylurea sensitive regulatory subunit 1 have been suggested as subunits of a mitochondrial adenosine triphosphate-sensitive potassium channel. We hypothesized that pharmacologic blockade or genetic deletion (knockout) of renal outer medullary potassium and sensitive regulatory subunit 1 would result in loss of diazoxide cardioprotection in models of global ischemia with cardioplegia. MethodsMyocyte volume and contractility were compared after Tyrode's physiologic solution (20 minutes), stress (hyperkalemic cardioplegia ± diazoxide, ± VU591 (Kir1.1 inhibitor), N = 9 to 23 each, 20 min), and Tyrode's (20 minutes). Isolated mouse (wild-type, sensitive regulatory subunit 1 [−/−], and cardiac knockout renal outer medullary potassium) hearts were given cardioplegia ± diazoxide (N = 9-16 each) before global ischemia (90 minutes) and 30 minutes reperfusion. Left ventricular pressures were compared before and after ischemia. ResultsStress (cardioplegia) was associated with reduced myocyte contractility that was prevented by diazoxide. Isolated myocytes were not responsive to diazoxide in the presence of VU591. In isolated hearts, diazoxide improved left ventricular function after prolonged ischemia compared with cardioplegia alone in wild-type and knockout (sensitive regulatory subunit 1 [−/−] and cardiac knockout renal outer medullary potassium) mice. ConclusionsIsolated myocyte and heart models may measure independent and separate actions of diazoxide. By definitive genetic deletion, these data indicate that sensitive regulatory subunit 1 and renal outer medullary potassium are not implicated in cardioprotection by diazoxide.

Direct and indirect activation of the adenosine triphosphate-sensitive potassium channel to induce spinal cord ischemic metabolic tolerance.

The mitochondrial adenosine triphosphate-sensitive potassium channel is central to pharmacologically induced tolerance to spinal cord injury. We hypothesized that both direct and nitric oxide-dependent indirect activation of the adenosine triphosphate-sensitive potassium channel contribute to the induction of ischemic metabolic tolerance. Spinal cord injury was induced in adult male C57BL/6 mice through 7minutes of thoracic aortic crossclamping. Pretreatment consisted of intraperitoneal injection 3 consecutive days before injury. Experimental groups were sham (no pretreatment or ischemia, n=10), spinal cord injury control (pretreatment with normal saline, n=27), Nicorandil 1.0mg/kg (direct and indirect adenosine triphosphate-sensitive potassium channel opener, n=20), Nicorandil 1mg/kg+carboxy-PTIO 1mg/kg (nitric oxide scavenger, n=21), carboxy-PTIO (n=12), diazoxide 5mg/kg (selective direct adenosine triphosphate-sensitive potassium channel opener, n=25), and DZ 5mg/kg+carboxy-PTIO 1mg/kg, carboxy-PTIO (n=23). Limb motor function was assessed using the Basso Mouse Score (0-9) at 12-hour intervals for 48hours after ischemia. Motor function was significantly preserved at all time points after ischemia in the Nicorandil pretreatment group compared with ischemic control. The addition of carboxy-PTIO partially attenuated Nicorandil's motor-preserving effect. Motor function in the Nicorandil+carboxy-PTIO group was significantly preserved compared with the spinal cord injury control group (P<.001), but worse than in the Nicorandil group (P=.078). Motor preservation in the diazoxide group was similar to the Nicorandil+carboxy-PTIO group. There was no significant difference between the diazoxide and diazoxide+carboxy-PTIO groups. Both direct and nitric oxide-dependent indirect activation of the mitochondrial adenosine triphosphate-sensitive potassium channel play an important role in pharmacologically induced motor function preservation.

Targeted gene panel analysis of Japanese patients with maturity-onset diabetes of the young-like diabetes mellitus: Roles of inactivating variants in the ABCC8 and insulin resistance genes.

To investigate the genetic background of Japanese patients with suspected maturity-onset diabetes of the young (MODY). On 340 proband patients referred from across Japan, genomic variants were analyzed using a targeted multigene panel analysis combined with the multiplex ligation probe amplification (MLPA) analysis, mitochondrial m.3243A > G analysis and methylation-specific polymerase chain reaction of the imprinted 6q24 locus. Pathogenic/likely pathogenic variants were listed according to the 2015 American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria. Additionally, variants with a population frequency <0.001 and Combined Annotation Dependent Depletion score >20 (CS >20) were listed as rare variants of uncertain significance-CS >20. A total of 157 pathogenic/likely pathogenic variants and 44 rare variants of uncertain significance-CS >20 were identified. In the pathogenic/likely pathogenic variants, alterations in the GCK gene were the most common (82, 52.2%) followed by HNF1A (29,18.5%), HNF4A (13, 8.3%) and HNF1B (13, 8.3%). One patient was a 29.5% mosaic with a truncating INSR variant. In the rare variants of uncertain significance-CS >20, 20 (45.5%) were in the genes coding for the adenosine triphosphate-sensitive potassium channel, KCNJ11 or ABCC8, and four were in the genes of the insulin-signaling pathway, INSR and PIK3R1. Four variants in ABCC8 were previously reported in patients with congenital hyperinsulinism, suggesting the inactivating nature of these variants, and at least two of our patients had a history of congenital hyperinsulinism evolving into diabetes. In two patients with INSR or PIK3R1 variants, insulin resistance was evident at diagnosis. Causative genomic variants could be identified in at least 46.2% of clinically suspected MODY patients. ABCC8-MODY with inactivating variants could represent a distinct category of MODY. Genes of insulin resistance should be included in the sequencing panel for MODY.

Abstract 15530: Renal Outer Medullary Potassium (Kir 1.1) is not the Kir Subunit of a Cardioprotective, Diazoxide - Mediated Mitochondrial Adenosine Triphosphate - Sensitive Potassium Channel

Objective: The adenosine triphosphate-sensitive potassium (K ATP ) channel opener diazoxide (DZX) mimics ischemic preconditioning and is cardioprotective. The molecular mechanism of action is unknown, although several mitochondrial candidate protein targets have been proposed. We suggested that cardioprotection occurs at a non-sarcolemmal channel, requires the inhibition of succinate dehydrogenase, and involves K ATP channel subunit SUR1. The renal outer medullary potassium channel (ROMK, or Kir1.1) subunit was proposed as the Kir subunit of a mitochondrial (m)K ATP channel. We tested the hypothesis that genetic deletion of ROMK will result in loss of DZX cardioprotection in a model of prolonged ischemia with cardioplegia. Methods: Mice lacking ROMK in cardiac myocytes (cKO) and wild-type (WT) litter mates were randomly assigned to 90 min. global ischemia in a Langendorff model following hypothermic hyperkalemic cardioplegia (CPG) or CPG + DZX (100 μM/L) (N=6-9 per group). Left ventricular developed pressure (LVDP), end diastolic pressure (EDP), and coronary flow were compared before and after global ischemia. Data acquisition and interpretation were blinded to group. Results: Similar to previous results, prolonged global ischemia was associated with a reduction in LVDP and an increase in EDP with CPG that was prevented by DZX in WT. Unexpectedly, ROMK (cKO) mice were equally responsive to DZX (Figure), indicating that DZX protection is not mediated by ROMK channels. Conclusions: Genetic deletion of ROMK in cardiac myocytes does not negate cardioprotection provided by DZX, indicating ROMK is not a subunit of a cardioprotective mK ATP channel. Alternate proposed DZX-sensitive target channels or mechanisms of action remain to be tested. Identification of the specific subunits of a mK ATP channel would allow for targeted pharmacologic therapy to reduce myocardial stunning following prolonged ischemia, similar to that seen following cardiac surgery.

Nicorandil attenuates ventricular dysfunction and organ injury after cardiopulmonary bypass

BackgroundNicorandil, an adenosine triphosphate-sensitive potassium channel agonist and nitric oxide donor, is a coronary vasodilator used to treat ischemia-induced chest pain, but it's potential cardioprotective benefits during open heart surgery have not been thoroughly investigated. The study objective was to assess the impact of nicorandil on postoperative ventricular dysfunction and end-organ injury in an established experimental model of open-heart surgery with cardiopulmonary bypass (CPB) and cardioplegic arrest. We hypothesized that nicorandil would attenuate myocardial ischemia-reperfusion (IR) injury, preserve ventricular function, and reduce end-organ injury. MethodsRabbits were cannulated for CPB, followed by 60 min of aortic cross-clamp (ACC) with cold cardioplegic arrest, and 120 min of recovery after ACC removal. Nicorandil (or normal saline vehicle) was given intravenously 5 min before ACC and continued throughout the recovery period. Left ventricular developed pressure (LVDP), systolic contractility (LV + dP/dt), and diastolic relaxation (LV -dP/dt) were continuously recorded, and blood and tissue samples were collected for measurement of oxidant stress (OS), inflammation, apoptosis, and organ injury. ResultsNicorandil significantly attenuated IR-induced LV dysfunction compared to saline control (R-120: LV + dP/dt: 1596 ± 397 vs. 514 ± 269 mmHg/s, p = 0.010; LV -dP/dt: −1524 ± 432 vs. -432 ± 243 mmHg/s, p < 0.001; LVDP: 55 ± 11 vs. 22 ± 5 mmHg, p = 0.046). Furthermore, nicorandil inhibited IR-induced increases in OS, inflammation, apoptosis, and organ injury. ConclusionsNicorandil exhibits myocardial protection by attenuation of IR-induced LV dysfunction associated with OS, inflammation, apoptosis, and organ injury. Nicorandil should be explored further as a potential therapeutic strategy for limiting global IR injury during open-heart surgery in humans.

Novel Serum Biomarkers of Neurovascular Unit Associated with Cortical Amyloid Deposition.

Whether blood biomarkers of neurovascular unit are associated with cortical amyloid deposition on positron emission tomography (PET) imaging remains unclear. To investigate the association between novel serum biomarkers of neurovascular unit, such as protein tyrosine phosphatase receptor type B (PTPRB), gap junction protein alpha-5 (GJA5), adenosine triphosphate-sensitive inward rectifier potassium channel-8 (KCNJ8), and von Willebrand factor (vWF), and cortical amyloid deposition. Between 2012 and 2018, 68 elderly individuals with amnestic mild cognitive impairment (32 men and 36 women; mean age 75.2 years) were enrolled. All participants underwent 11C-Pittsburgh compound-B (PiB)-PET, 18F-fluorodeoxyglucose-PET, and measurement of serum PTPRB, GJA5, KCNJ8, and vWF levels using commercially available human enzyme-linked immunosorbent assay kits. Based on the mean cortical standardized uptake value ratio, the participants were divided into two groups: PiB-negative group and PiB-positive group. Serum levels of PTPRB, GJA5, KCNJ8, and vWF were compared between the two groups. Multiple linear regression analysis was performed to investigate the relationship between serum PTPRB, GJA5, KCNJ8, and vWF levels and cortical amyloid deposition. PTPRB and GJA5 levels were significantly lower and KCNJ8 and vWF levels were significantly higher in the PiB-positive group than in the PiB-negative group. PTPRB and GJA5 levels inversely correlated with mean PiB uptake, whereas KCNJ8 and vWF levels positively correlated with mean PiB uptake. Serum levels of PTPRB, GJA5, KCNJ8, and vWF correlate with cortical amyloid deposition. These novel blood biomarkers of neurovascular unit are useful for identifying elderly individuals at risk of developing Alzheimer's disease.

Meglitinide (repaglinide) therapy in permanent neonatal diabetes mellitus: two\xa0case reports

BackgroundPermanent neonatal diabetes mellitus (PNDM) presents with dehydration and hyperglycemia, which usually occurs during the first 12 months of life. Activating mutations of beta-cell adenosine triphosphate-sensitive potassium [KATP] channel subunits that cause opening of the channel are associated with PNDM. Some patients with PNDM respond to administration of a sulfonylurea derivative, which has long action on blood glucose even during hypoglycemia and has an apoptotic effect on beta cells. However, there have been no reports regarding treatment with meglitinide (repaglinide), which has rapid and short duration of action during the rise in blood glucose after meals that is more similar to beta cell function. It has no effects during hypoglycemia, so it does not cause neurological damage, and has no apoptotic effect on beta cells. We report herein the effects of repaglinide administration in the management and clinical outcome of two patients with PNDM during 9 and 10 years of follow-up.Case presentationTwo Iranian infants were brought to our institution with poor general condition, dehydration, lethargy, and poor feeding. They had diabetic ketoacidosis at 52 days and 3.5 months of age, respectively. Their genetic analysis revealed mutations in the KCNJ11 gene encoding KIR6.2, so they both had PNDM. After treatment of diabetic ketoacidosis with insulin, they responded to sulfonylurea (glibenclamide) treatment, but were switched to repaglinide because of blood sugar fluctuations in terms of hyper- and hypoglycemia. Repaglinide was administered with the dosage of 0.04 mg/kg/day divided before every meal.ResultsThe patients were 10 and 9 years old at the last visit, with normal growth parameters. The values of self-monitored blood glucose were well-controlled, and the hemoglobin A1C (HbA1C) levels ranged from 3.6 to 6.4% during the follow-up period. There was no complication of diabetes, neurological disorder, or adverse effects related to repaglinide.ConclusionIn every neonate or infant < 6 months of age with diabetes mellitus, PNDM should be considered. A trial of oral repaglinide can be performed and substituted for glibenclamide for prevention of hypoglycemia, neurological damage, and apoptosis of beta cells during long-term administration.

Cardioprotective mechanisms of mitochondria-targeted S-nitrosating agent and adenosine triphosphate-sensitive potassium channel opener are mutually exclusive

BackgroundMyocytes exposed to stress exhibit significant swelling and reduced contractility. These consequences are ameliorated by adenosine triphosphate–sensitive potassium (KATP) channel opener diazoxide (DZX) via an unknown mechanism. KATP channel openers also provide cardioprotection in multiple animal models. Nitric oxide donors are similarly cardioprotective, and their combination with KATP activation may provide synergistic benefit. We hypothesized that mitochondria-targeted S-nitrosating agent (MitoSNO) would provide synergistic cardioprotection with DZX. MethodsMyocyte volume and contractility were compared following Tyrode's physiologic solution (20 minutes) and stress (hyperkalemic cardioplegia [CPG] ± DZX; n = 5-20 each; 20 minutes) with or without MitoSNO (n = 5-11 each) at the end of stress, followed by Tyrode's solution (20 minutes). Isolated mouse hearts received CPG ± DZX (n = 8-10 each) before global ischemia (90 minutes) with or without MitoSNO (n = 8 each) at the end of ischemia, followed by reperfusion (30 minutes). Left ventricular (LV) pressures were compared using a linear mixed model to assess the impact of treatment on the outcome, adjusting for baseline and balloon volume. ResultsStress (CPG) was associated with reduced myocyte contractility that was prevented by DZX and MitoSNO individually; however, their combination was associated with loss of cardioprotection. Similarly, DZX and MitoSNO improved LV function after prolonged ischemia compared with CPG alone, and cardioprotection was lost with their combination. ConclusionsMitoSNO and DZX provide cardioprotection that is lost with their combination, suggesting mutually exclusive mechanisms of action. The lack of a synergistic beneficial effect informs the current knowledge of the cardioprotective mechanisms of DZX and will aid planning of future clinical trials.

Alterations in pore-forming subunits of adenosine triphosphate-sensitive potassium channels in pressure overload rat cardiomyocytes.

Adenosine triphosphate (ATP)-sensitive potassium channels (KATP) link cellular metabolic state and electrical activity of cardiomyocytes. Pharmacological studies indicated the involvement of KATP in pressure overload-induced left ventricular hypertrophy, but the alteration of pore-forming subunits, Kir6.1 and Kir6.2, at membranes and subcellular fractions is unclear. The objective of this study was to investigate the changes in the distribution and levels of Kir6.1 and Kir6.2 in rat cardiomyocytes responding to chronic pressure overload. Male Wistar rats were separated into a sham-operated group (sham) and a pressure overload or transverse aortic constriction (TAC) group. Echocardiography was performed to assess cardiac structure and functions at the 4th month after operation. Ventricular cardiomyocytes in both groups were isolated and then subjected to extract protein into cytoplasm, organelle membrane, and plasma membrane fractions. Immunoblotting and immunohistochemistry techniques were performed to detect and measure Kir6.1 and Kir6.2 protein levels. Echocardiographic parameters showed left ventricular hypertrophy with hypercontractility in TAC rats. The immunoblotting showed the presence of Kir6.1 and Kir6.2 at plasma membranes and only Kir6.1 at organelle membranes. Significantly, Kir6.1 and Kir6.2 levels were decreased in the plasma membrane fraction of the TAC group (n = 8 and 6 for Kir6.1 and Kir6.2, respectively), whereas Kir6.1 in the organelle membrane fraction tended to be higher in TAC but did not reach statistical significance (n = 7). These results seemed to relate to a left ventricular immunohistochemistry study, which showed the trend of decreased staining of Kir6.1 and Kir6.2 in pressure overload left ventricular tissue. In conclusion, both Kir6.1 and Kir6.2 plasma membrane subunits were decreased significantly in pressure overload-induced left ventricular hypertrophy.

Abstract 15316: Paradoxical Reduction in Myocardial Performance When Combining Two Independently Cardioprotective Agents: Mitochondrial-targeted Antioxidant MitoSNO and Adenosine Triphosphate-sensitive Potassium Channel Opener Diazoxide

Introduction: Adenosine triphosphate-sensitive potassium (K ATP ) channel opener diazoxide (DZX) and Antioxidant MitoSNO are both independently cardioprotective in animal models. The cardioprotective mechanism of diazoxide is unknown, and involves a non-sarcolemmal location, requires the inhibition of succinate dehydrogenase, and the K ATP channel subunit SUR1. Mitochondrial - targeted Antioxidant MitoSNO is a S-nitrosylating agent that stalls complex 1, reduces ROS production and succinate accumulation. In an isolated myocyte model of stress due to hyperkalemic cardioplegia (CPG), that the combination of DZX and MitoSNO negated the beneficial effects of each alone. Hypothesis: We hypothesized that the combination of DZX and MitoSNO would negate the beneficial effects of each alone in an isolated heart model of global ischemia. Methods: Isolated mouse hearts underwent assessment of end diastolic pressure (EDP) and left ventricular developed pressure (LVDP) utilizing an LV balloon in a Langendorff model before and after 90 min of global ischemia. Hearts received test solution (CPG (9°C) or CPG±DZX (100μM) at onset of ischemia +/- MitoSNO (1μM/L) at end of ischemia), followed by 30 min reperfusion. LVDP and EDP were compared between groups utilizing a linear mixed model to assess the impact of treatment on the outcome, adjusting for baseline and balloon volume. Results: Similar to previous results, DZX improved LVDP and reduced EDP after ischemia compared to CPG (Figure). Similarly, MitoSNO improved LVDP and reduced EDP compared to CPG (Figure). The addition of MitoSNO with DZX was associated with the loss of cardioprotection observed with MitoSNO or DZX alone. Conclusions: Similar to data in a myocyte model, both MitoSNO and DZX provide cardioprotection that is lost with the combination of both, suggesting mutually exclusive mechanisms of action and that DZX’s mechanism requires a functional complex 1, ROS production, or succinate accumulation.

Reactive Oxygen Species Mediate Nicorandil-induced Metabolic Tolerance to Spinal Cord Injury

Spinal cord injury remains a devastating complication of thoracoabdominal aortic surgery. We previously demonstrated that pretreatment with nicorandil preserved motor function in a murine spinal cord injury model through mitochondrial adenosine triphosphate-sensitive potassium channel activation. We hypothesized that the neuroprotective effect of nicorandil is mediated by downstream generation of reactive oxygen species. Spinal cord injury was induced by 7 minutes of thoracic aortic cross-clamping in adult male C57BL/6 mice. Five groups were evaluated: ischemic control (n= 19); nicorandil 1.0 mg/kg (n= 17); nicorandil 1.0 mg/kg plus N acetyl L-cysteine (NAC [reactive oxygen species scavenger, n= 18)]) 150 mg/kg; NAC 150 mg/kg (n= 13); and sham (n= 10). Limb motor function and the number of viable neurons within the anterior horn of the spinal cord were evaluated. Mice in the sham group showed no functional deficits after surgery. Compared with ischemic control, motor function was significantly preserved in the nicorandil pretreatment group at every timepoint after ischemia. In the nicorandil plus NAC group, the motor-preserving effect of nicorandil was completely abolished (P < .001). Viable neuron quantification showed significant neuron preservation in the nicorandil group (29.± 2.6) compared with the ischemic control group (18.5 ± 2.1, P= .024) and nicorandil plus NAC group (14 ± 8.3, P= .001); no significant difference was observed between the ischemic control group and nicorandil plus NAC group (P= 0.768). Reactive oxygen species generation plays a key role in the nicorandil-induced metabolic tolerance to spinal cord injury. Manipulation of mitochondrial adenosine triphosphate-sensitive potassium channels may lead to improvement in preventing spinal cord injury after thoracoabdominal aortic interventions.

Effects of nicorandil on p120 expression in the spinal cord and dorsal root ganglion of rats with chronic postsurgical pain.

Chronic postsurgical pain (CPSP) has a high incidence, but the underlying mechanism is not well understood. Accumulating evidence has suggested that central sensitization is the main mechanism of pain. To study the role of p120 in CPSP, a skin/muscle incision and retraction (SMIR) model was established, and immunofluorescence staining and western blotting were performed to analyze the expression of p120 in the spinal cord and dorsal root ganglion (DRG). The results demonstrated that SMIR increased the expression of p120 in the DRG and the spinal cord compared with the naive group. Furthermore, it was demonstrated that p120 was mainly distributed in the glial fibrillary acidic protein-positive astrocytes in the spinal cord, and in the neurofilament 200-positive medium and large neurons in the DRG. Our previous studies have shown that adenosine triphosphate-sensitive potassium channel (KATP) agonists can reduce postoperative pain in rats. Therefore, the changes in p120 were observed in the DRG and spinal cord of rats following the intraperitoneal injection of nicorandil, a KATP agonist. It was demonstrated that nicorandil administration could relieve mechanical pain experienced following SMIR in rats, and decrease the expression of p120 in the DRG and spinal cord. The results revealed that p120 may contribute to the prophylactic analgesic effect of nicorandil, thus providing a novel insight into the mechanism of CPSP prevention.

Regulation of the KATP-JNK gap junction signaling pathway by immunomodulator astragaloside IV attenuates neuropathic pain

Background and objectivesGap junctions play a pivotal role in contributing to the formation of astroglial networks and in chronic pain. However, the mechanisms underlying the dysfunction of astroglial gap junctions...

Diazoxide Protects against Myocardial Ischemia/Reperfusion Injury by Moderating ERS via Regulation of the miR-10a/IRE1 Pathway.

Nowadays, reperfusion is still the most effective treatment for ischemic heart disease. However, cardiac reperfusion therapy would lead to reperfusion injury, which may have resulted from endoplasmic reticulum stress (ERS) during reperfusion. Diazoxide (DZ) is a highly selective mitochondrial adenosine triphosphate-sensitive potassium channel opener. Its protective effect on I/R injury has been confirmed in many organs such as the heart and brain. However, the mechanism of its protective effect has not been fully elucidated. MicroRNAs (miRNAs) are widely involved in pathologies of heart disease. In this study, we found that miR-10a expression was highly upregulated in the myocardial I/R groups, and DZ treatment significantly reduced the expression of miR-10a. More importantly, we found that DZ treatment can moderate ERS via regulation of the miR-10a/IRE1 pathway in the I/R and H/R models, thereby protecting myocardial H/R injury.

Ionic mechanisms of ST segment elevation in electrocardiogram during acute myocardial infarction

ST elevation on an electrocardiogram is a hallmark of acute transmural ischemia. However, the underlying mechanism remains unclear. We hypothesized that high ischemic sensitivities of epicardial adenosine triphosphate-sensitive potassium (IKATP) and sodium (INa) currents play key roles in the genesis of ST elevation. Using a multi-scale heart simulation under moderately ischemic conditions, transmural heterogeneities of IKATP and INa created a transmural gradient, opposite to that observed in subendocardial injury, leading to ST elevation. These heterogeneities also contributed to the genesis of hyper-acute T waves under mildly ischemic conditions. By contrast, under severely ischemic conditions, although action potentials were suppressed transmurally, the potential gradient at the boundary between the ischemic and normal regions caused ST elevation without a contribution from transmural heterogeneity. Thus, transmural heterogeneities of ion channel properties may contribute to the genesis of ST–T changes during mild or moderate transmural ischemia, while ST elevation may be induced without the contribution of heterogeneity under severe ischemic conditions.

The Possible Role of the Nitroso-Sulfide Signaling Pathway in the Vasomotoric Effect of Garlic Juice.

The beneficial cardiovascular effects of garlic have been reported in numerous studies. The major bioactive properties of garlic are related to organic sulfides. This study aimed to investigate whether garlic juice works exclusively due to its sulfur compounds or rather via the formation of new products of the nitroso-sulfide signaling pathway. Changes in isometric tension were measured on the precontracted aortic rings of adult normotensive Wistar rats. We evaluated NO-donor (S-nitrosoglutathione, GSNO)-induced vasorelaxation and compare it with effects of hydrogen sulfide (H2S)/GSNO and garlic/GSNO. Incubation with garlic juice increased the maximal GSNO-induced relaxation and markedly changed the character of the relaxant response. Although incubation with an H2S donor enhanced the maximal vasorelaxant response of GSNO, neither the absolute nor the relative relaxation changed over time. The mixture of GSNO with an H2S donor evoked a response similar to GSNO-induced relaxation after incubation with garlic juice. This relaxation of the H2S and GSNO mixture was soluble guanylyl cyclase (sGC) dependent, partially reduced by HNO scavenger and it was adenosine triphosphate-sensitive potassium channels (KATP) independent. In this study, we demonstrate for the first time the suggestion that H2S itself is probably not the crucial bioactive compound of garlic juice but rather potentiates the production of new signaling molecules during the GSNO-H2S interaction.

Gastroprotective effects of irsogladine maleate on ethanol/hydrochloric acid induced gastric ulcers in mice.

Background/AimsThis study was conducted to investigate the inhibitory effect of irsogladine maleate (IM) on gastric ulcers induced by ethanol and hydrochloric acid (HCl).MethodsMice were pretreated with IM for 1 hours before ulcer induction. Gastric ulcers were induced by oral administration of an ethanol/HCl mixture. To clarify the action mechanism of IM, the roles of 3ʹ5ʹ-cyclic adenosine monophosphate (cAMP), nitric oxide (NO), adenosine triphosphate-sensitive potassium (KATP) channels, prostaglandins and transient receptor potential cation channel subfamily V member 1 (TRPV1) were investigated, and lipid peroxidation in the stomach of IM-treated and -untreated animals was also measured.ResultsIM significantly reduced the extent of ethanol/HCl mixture-induced gastric ulceration. It exhibited dose-related gastroprotection against the ethanol/HCl-induced lesions, while pretreatment with glibenclamide but not N(ω)-nitro- L-arginine methyl ester, reversed this action. While pretreatment with the TRPV1 antagonist capsazepine failed to effectively block the gastroprotective effect of IM, the non-selective cyclooxygenase inhibitor indomethacin almost abolished it. IM also decreased the level of thiobarbituric acid reactive substances.ConclusionsWe concluded that IM exhibited significant gastroprotective effects in an ethanol/HCl-induced ulcer model, which appear to be mediated, at least in part, by NO, cAMP, endogenous prostaglandins, KATP channel opening, activation of TRPV1 channels, and antioxidant properties