Decreased KATP Channel Activity Contributes to the Low Glucose Threshold for Insulin Secretion of Rat Neonatal Islets.

Transitional hypoglycemia in normal newborns occurs in the first 3 days of life and has clinical features consistent with hyperinsulinism. We found a lower threshold for glucose-stimulated insulin secretion from freshly isolated embryonic day (E) 22 rat islets, which persisted into the first postnatal days. The threshold reached the adult level by postnatal day (P) 14. Culturing P14 islets also decreased the glucose threshold. Freshly isolated P1 rat islets had a lower threshold for insulin secretion in response to 2-aminobicyclo-(2, 2, 1)-heptane-2-carboxylic acid, a nonmetabolizable leucine analog, and diminished insulin release in response to tolbutamide, an inhibitor of ß-cell KATP channels. These findings suggested that decreased KATP channel function could be responsible for the lower glucose threshold for insulin secretion. Single-cell transcriptomic analysis did not reveal a lower expression of KATP subunit genes in E22 compared with P14 ß cells. The investigation of electrophysiological characteristics of dispersed ß cells showed that early neonatal and cultured cells had fewer functional KATP channels per unit membrane area. Our findings suggest that decreased surface density of KATP channels may contribute to the observed differences in glucose threshold for insulin release.

KATP Channel Openers Inhibit Lymphatic Contractions and Lymph Flow as a Possible Mechanism of Peripheral Edema.

Pharmacological openers of ATP-sensitive potassium (KATP) channels are effective antihypertensive agents, but off-target effects, including severe peripheral edema, limit their clinical usefulness. It is presumed that the arterial dilation induced by KATP channel openers (KCOs) increases capillary pressure to promote filtration edema. However, KATP channels also are expressed by lymphatic muscle cells (LMCs), raising the possibility that KCOs also attenuate lymph flow to increase interstitial fluid. The present study explored the effect of KCOs on lymphatic contractile function and lymph flow. In isolated rat mesenteric lymph vessels (LVs), the prototypic KATP channel opener cromakalim (0.01-3 µmol/l) progressively inhibited rhythmic contractions and calculated intraluminal flow. Minoxidil sulfate and diazoxide (0.01-100 µmol/l) had similar effects at clinically relevant plasma concentrations. High-speed in vivo imaging of the rat mesenteric lymphatic circulation revealed that superfusion of LVs with cromakalim and minoxidil sulfate (0.01-10 µmol/l) maximally decreased lymph flow in vivo by 38.4% and 27.4%, respectively. Real-time polymerase chain reaction and flow cytometry identified the abundant KATP channel subunits in LMCs as the pore-forming Kir6.1/6.2 and regulatory sulfonylurea receptor 2 subunits. Patch-clamp studies detected cromakalim-elicited unitary K+ currents in cell-attached patches of LMCs with a single-channel conductance of 46.4 pS, which is a property consistent with Kir6.1/6.2 tetrameric channels. Addition of minoxidil sulfate and diazoxide elicited unitary currents of similar amplitude. Collectively, our findings indicate that KCOs attenuate lymph flow at clinically relevant plasma concentrations as a potential contributing mechanism to peripheral edema. SIGNIFICANCE STATEMENT: ATP-sensitive potassium (KATP) channel openers (KCOs) are potent antihypertensive medications, but off-target effects, including severe peripheral edema, limit their clinical use. Here, we demonstrate that KCOs impair the rhythmic contractions of lymph vessels and attenuate lymph flow, which may promote edema formation. Our finding that the KATP channels in lymphatic muscle cells may be unique from their counterparts in arterial muscle implies that designing arterial-selective KCOs may avoid activation of lymphatic KATP channels and peripheral edema.

Latest Insights into the Pathophysiology of Migraine: the ATP-Sensitive Potassium Channels.

PURPOSE OF REVIEW: Migraine remains a challenging condition to treat, thus highlighting the need for a better understanding of its molecular mechanisms. This review intends to unravel a new emerging target in migraine pathophysiology, the adenosine 5'-triphosphate-sensitive K+ (KATP) channel. RECENT FINDINGS: KATP channel is a common denominator in the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) mediated intracellular cascades, both of which are involved in migraine. Intravenous infusion of KATP channel opener, levcromakalim, provoked migraine attack associated with dilation of extracerebral arteries in all persons with migraine. Preclinical and clinical studies implicate KATP channels in migraine initiation. KATP channel is a novel therapeutic target for the acute and preventive treatment of migraine. Future studies are warranted to provide a better understanding of the role of KATP channel subgroups in migraine.

ATP-Sensitive Potassium Channels Mediate the Cardioprotective Effect of Panax notoginseng Saponins against Myocardial Ischaemia-Reperfusion Injury and Inflammatory Reaction.

Inflammatory response during myocardial ischemia reperfusion injury (MIRI) is essential for cardiac healing, while excessive inflammation extends the infarction and promotes adverse cardiac remodeling. Understanding the mechanism of these uncontrolled inflammatory processes has a significant impact during the MIRI therapy. Here, we found a critical role of ATP-sensitive potassium channels (KATP) in the inflammatory response of MIRI and its potential mechanism and explored the effects of Panax Notoginseng Saponins (PNS) during this possess. Rats underwent 40 min ischemia by occlusion of the left anterior descending (LAD) coronary artery and 60 min of reperfusion. PNS was treated at the corresponding time point before operation; 5-hydroxydecanoate (5-HD) and glybenclamide (Gly) (or Nicorandil (Nic)) were used as pharmacological blocker (or nonselective opener) of KATP. Cardiac function and pathomorphology were evaluated and a set of molecular signaling experiments was tested. KATP current density was measured by patch-clamp. Results revealed that in MIRI, PNS pretreatment restored cardiac function, reduced infarct size, and ameliorated inflammation through KATP. However, inhibiting KATP by 5-HD and Gly significantly reversed the effects, including NLRP3 inflammasome and inflammatory mediators IL-6, MPO, TNF-α, and MCP-1. Moreover, PNS inhibited the phosphorylation and nuclear translocation of NF-κB in I/R myocardium when the KATP was activated. Importantly, PNS promoted the expression of subunits and activation of KATP. The study uncovered KATP served as a new potential mechanism during PNS modulating MIRI-induced inflammation and promoting injured heart recovery. The manipulation of KATP could be a potential therapeutic approach for MIRI and other inflammatory diseases.

Synergistic antiallodynic and antihyperalgesic interaction between L-DOPA and celecoxib in parkinsonian rats is mediated by NO-cGMP-ATP-sensitive K+ channel.

Pain is a usual and troublesome non-motor symptom of Parkinson's disease, with a prevalence of 29-82%. Therefore, it's vital to find pharmacological treatments for managing PD-associated pain symptoms, to improve patients' quality of life. For this reason, we tested the possible synergy between L-DOPA and celecoxib in decreasing allodynia and hyperalgesia induced by unilateral lesioning with 6-OHDA into the SNpc in rats. We also tested whether the antiallodynic and antihyperalgesic effect induced by combination of L-DOPA and celecoxib is mediated by the NO-cGMP-ATP-sensitive K+ channel pathway. Tactile allodynia and mechanical hyperalgesia were evaluated using von Frey filament. Isobolographic analyses were employed to define the nature of the drug interaction using a fixed dose ratio (0.5: 0.5). We found that acute and sub-acute (10-day) treatment with a single dose of L-DOPA (3-25 mg/kg, i. p.) or celecoxib (2.5-20 mg/kg, i. p.) induced a dose-dependent antiallodynic and antihyperalgesic effect in parkinsonian rats. Isobolographic analysis revealed that the ED50 values obtained by L-DOPA + celecoxib combination was significantly less than calculated additive values, indicating that co-administration of L-DOPA with celecoxib produces synergistic interactions in its antiallodynic and antihyperalgesic effect in animals with nigrostriatal lesions. Moreover, the antiallodynic and antihyperalgesic effects induced by L-DOPA + celecoxib combination were blocked by intrathecal pre-treatment with L-NAME, ODQ, and glibenclamide. Taken together, the data suggest that L-DOPA + celecoxib combination produces an antiallodynic and antihyperalgesic synergistic interaction at the systemic level, and these effects are mediated, at the central level, through activation of the NO-cGMP-ATP-sensitive K+ channel pathway.

Searching for novel hydrogen sulfide donors: The vascular effects of two thiourea derivatives.

The gasotransmitter hydrogen sulfide (H2S) is involved in the regulation of the vascular tone and an impairment of its endogenous production may play a role in hypertension. Thus, the administration of exogenous H2S may be a possible novel and effective strategy to control blood pressure. Some natural and synthetic sulfur compounds are suitable H2S-donors, exhibiting long-lasting H2S release; however, novel H2S-releasing agents are needed to improve the pharmacological armamentarium for the treatment of cardiovascular diseases. For this purpose, N-phenylthiourea (PTU) and N,N'-diphenylthiourea (DPTU) compounds have been investigated as potential H2S-donors. The thioureas showed long-lasting H2S donation in cell free environment and in human aortic smooth muscle cells (HASMCs). In HASMCs, DPTU caused membrane hyperpolarization, mediated by activation of KATP and Kv7 potassium channels. The thiourea derivatives promoted vasodilation in rat aortic rings, which was abolished by KATP and Kv7 blockers. The vasorelaxing effects were also observed in angiotensin II-constricted coronary vessels. In conclusion, thiourea represents an original H2S-donor functional group, which releases H2S with slow and long lasting kinetic, and promotes typical H2S-mediated vascular effects. Such a moiety will be extremely useful for developing original cardiovascular drugs and new chemical tools for investigating the pharmacological roles of H2S.

The Potential Role of Activating the ATP-Sensitive Potassium Channel in the Treatment of Hyperphagic Obesity.

To evaluate the potential role of ATP-sensitive potassium (KATP) channel activation in the treatment of hyperphagic obesity, a PubMed search was conducted focused on the expression of genes encoding the KATP channel, the response to activating the KATP channel in tissues regulating appetite and the establishment and maintenance of obesity, the evaluation of KATP activators in obese hyperphagic animal models, and clinical studies on syndromic obesity. KATP channel activation is mechanistically involved in the regulation of appetite in the arcuate nucleus; the regulation of hyperinsulinemia, glycemic control, appetite and satiety in the dorsal motor nucleus of vagus; insulin secretion by ß-cells; and the synthesis and ß-oxidation of fatty acids in adipocytes. KATP channel activators have been evaluated in hyperphagic obese animal models and were shown to reduce hyperphagia, induce fat loss and weight loss in older animals, reduce the accumulation of excess body fat in growing animals, reduce circulating and hepatic lipids, and improve glycemic control. Recent experience with a KATP channel activator in Prader-Willi syndrome is consistent with the therapeutic responses observed in animal models. KATP channel activation, given the breadth of impact and animal model and clinical results, is a viable target in hyperphagic obesity.

Nicorandil, a KATP Channel Opener, Attenuates Ischemia-Reperfusion Injury in Isolated Rat Lungs.

PURPOSE: Nicorandil is a hybrid between nitrates and KATP channel opener activators. The aim of this study was to evaluate the nicorandil's effects on ischemia-reperfusion (IR) lung injury and examine the mechanism of its effects. METHODS: Isolated rat lungs were divided into 6 groups. In the sham group, the lungs were perfused and ventilated for 150 min. In the IR group, after perfusion and ventilation for 30 min, they were interrupted (ischemia) for 60 min, and then resumed for 60 min. In the nicorandil (N) + IR group, nicorandil 6 mg was added before ischemia (nicorandil concentration was 75 µg ml-1). In the glibenclamide + N + IR group, the L-NAME (Nω-Nitro-L-arginine methyl ester) + N + IR group and ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) + N + IR group, glibenclamide 3 µM, L-NAME 100 µM, and ODQ 30 µM were added 5 min before nicorandil administration, respectively. We measured the coefficient of filtration (Kfc) of the lungs, total pulmonary vascular resistance, and the wet-to-dry lung weight ratio (WW/DW ratio). RESULTS: Kfc was significantly increased after 60 min reperfusion compared with baseline in the IR group, but no change in the sham group. An increase in Kfc was inhibited in the N + IR group compared with the IR group (0.92 ± 0.28 vs. 2.82 ± 0.68 ml min-1 mmHg-1 100 g-1; P < 0.01). Also, nicorandil attenuated WW/DW ratio was compared with IR group (8.3 ± 0.41 vs. 10.9 ± 2.5; P < 0.05). Nicorandil's inhibitory effect was blocked by glibenclamide and ODQ (P < 0.01), but not by L-NAME. CONCLUSIONS: Nicorandil attenuated IR injury in isolated rat lungs. This protective effect appears to involve its activation as KATP channel opener as well as that of the sGC-cGMP pathway.

Role of ATP-Sensitive Potassium Channel (KATP) and eNOS in Mediating the Protective Effect of Nicorandil in Cyclophosphamide-Induced Cardiotoxicity.

Cyclophosphamide (CP) is a widely used chemotherapeutic agent but its clinical usefulness is challenged with different forms of toxicities. No studies have evaluated the possible protective effect of nicorandil (NIC) in CP-induced cardiotoxicity. Our study aimed to investigate this effect by using NIC (3 mg/kg/day) orally for 5 days, in the presence or absence of cardiotoxicity induced by intraperitoneal (i.p.) injection of CP (150 mg/kg) on 4th and 5th days. We confirmed the role of ATP-sensitive potassium channel (KATP) by coadministration of glibenclamide (GP) (5 mg/kg/day) 2 h before NIC (3 mg/kg/day) for 5 days. Moreover, the role of endothelial nitric oxide synthase (eNOS) was confirmed by coadministration of nitro-ω-L-arginine (L-NNA) (25 mg/kg/day) for 5 days. Results showed that CP succeeded in induction of cardiotoxicity which manifested by a significant increase in heart weights, creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), troponin I, cardiac tissue malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α), interleukin 1ß (IL1 ß), and caspase-3 levels. Furthermore, CP group showed toxic histopathological changes of marked cardiac damage in addition to a significant decrease in total antioxidant capacity (TAC), superoxide dismutase (SOD), eNOS gene expression, and B cell lymphoma 2 (Bcl2) immunoexpression. NIC succeeded in reversing CP-induced cardiotoxicity by its potassium channel opening effect, stimulating eNOS gene expression, anti-inflammatory, antiapoptotic, and antioxidant properties. Coadministration of GP or L-NNA could diminish the protective effect of NIC. This proves the important role of KATP and eNOS in mediating such protection.

Asteriscus graveolens exhibits Antihypertensive Activity through Activation of Vascular KATP Channels Activation in Rats.

OBJECTIVE: The objective of the study was to evaluate the antihypertensive activity of Asteriscus graveolens. METHODS: L-NAME hypertensive and normotensive rats have received orally the aqueous extract of Asteriscus graveolens aerial parts (AGAPE) (100 mg/kg) during six hours for the acute experiment and during seven days for the sub-chronic treatment. Thereafter, blood pressure parameters were evaluated. Concerning the in vitro investigation, the vasorelaxant effect of AGAPE was tested in isolated thoracic aortic rings. RESULTS: AGAPE extract significantly decreased the blood pressure parameters in hypertensive rats. Moreover, the results revealed that AGAPE exhibited antihypertensive effect through its vasorelaxant properties. More interestingly, this vasorelaxant activity seems to be probably mediated through activation of K+ ATP-sensitive (KATP) channels. CONCLUSION: The study demonstrates the antihypertensive activity of aqueous Asteriscus graveolens extract in hypertensive rats through activation of vascular KATP channels. This finding supports the use of this plant for the management of hypertension in Morocco.

Remote Ischemic Preconditioning and Diazoxide Protect from Hepatic Ischemic Reperfusion Injury by Inhibiting HMGB1-Induced TLR4/MyD88/NF-κB Signaling.

Remote ischemic preconditioning (RIPC) is known to have a protective effect against hepatic ischemia-reperfusion (IR) injury in animal models. However, the underlying mechanism of action is not clearly understood. This study examined the effectiveness of RIPC in a mouse model of hepatic IR and aimed to clarify the mechanism and relationship of the ATP-sensitive potassium channel (KATP) and HMGB1-induced TLR4/MyD88/NF-κB signaling. C57BL/6 male mice were separated into six groups: (i) sham-operated control, (ii) IR, (iii) RIPC+IR, (iv) RIPC+IR+glyburide (KATP blocker), (v) RIPC+IR+diazoxide (KATP opener), and (vi) RIPC+IR+diazoxide+glyburide groups. Histological changes, including hepatic ischemia injury, were assessed. The levels of circulating liver enzymes and inflammatory cytokines were measured. Levels of apoptotic proteins, proinflammatory factors (TLR4, HMGB1, MyD88, and NF-κB), and IκBα were measured by Western blot and mRNA levels of proinflammatory cytokine factors were determined by RT-PCR. RIPC significantly decreased hepatic ischemic injury, inflammatory cytokine levels, and liver enzymes compared to the corresponding values observed in the IR mouse model. The KATP opener diazoxide + RIPC significantly reduced hepatic IR injury demonstrating an additive effect on protection against hepatic IR injury. The protective effect appeared to be related to the opening of KATP, which inhibited HMGB1-induced TRL4/MyD88/NF-kB signaling.

Extracranial activation of ATP-sensitive potassium channels induces vasodilation without nociceptive effects.

INTRODUCTION: Levcromakalim opens ATP-sensitive potassium channels (KATP channel) and induces head pain in healthy volunteers and migraine headache in migraine patients, but no pain in other parts of the body. KATP channels are expressed in C- and Aδ-fibers, and these channels might directly activate nociceptors and thereby evoke pain in humans. METHODS: To assess the local effect of KATP channel opening in trigeminal and extra-trigeminal regions, we performed a crossover, double-blind, placebo-controlled study in healthy volunteers. Participants received intradermal and intramuscular injections of levcromakalim and placebo in the forehead and the forearms. RESULTS: Intradermal and intramuscular injections of levcromakalim did not evoke more pain compared to placebo in the forehead (p > 0.05) and the forearms (p > 0.05). Intradermal injection of levcromakalim caused more flare (p < 0.001), skin temperature increase (p < 0.001), and skin blood flow increase (p < 0.001) compared to placebo in the forehead and the forearms. CONCLUSION: These findings suggest that it is unlikely that levcromakalim induces head pain by direct activation of peripheral neurons.

Dexmedetomidine attenuates the induction and reverses the progress of 6-hydroxydopamine- induced parkinsonism; involvement of KATP channels, alpha 2 adrenoceptors and anti-inflammatory mechanisms.

BACKGROUND: Studies have shown that dexmedetomidine (DEX), a potent α2-adrenoceptors agonist provides neuroprotection through suppression of inflammatory response. In present study, we examined effect of DEX and its underlying mechanisms on the induction and progress of 6-OHDA- induced Parkinsonism in rat. MATERIAL AND METHODS: The 6-OHDA was injected into the medial forebrain bundle of right hemisphere by stereotaxic surgery and then, behavioral tests carried out within second, fourth, sixth and eighth weeks post-surgery. All treatments were started before the toxin and continued to eight weeks afterwards. Striatal levels of dopamine, TNF-α and IL-6 were measured within the eighth week after the toxin by enzyme-linked immunosorbent assay kits. RESULTS: DEX at dose of 50 µg/kg attenuated significantly the intensity of 6-OHDA- induced behavioral symptoms in the second week post-surgery. DEX also attenuated remarkably 6-OHDA- induced reduction in striatal dopamine level. These effects were also observed in rats treated by both DEX and yohimbine (YOH), a selective α2-adrenoceptors antagonist but were not observed in rats treated by both of DEX and glibenclamide (Glib), an ATP-sensitive potassium (KATP) channels blocker. DEX also reversed the progressive increase in intensity of the behavioral symptoms and reversed 6-OHDA- induced overproduction of TNF-α and IL-6. These effects were reversed by YOH but not Glib. CONCLUSION: Our findings indicate that DEX attenuates the induction and reverses the progress of 6-OHDA- induced Parkinsonism through activation of KATP channels and α2-adrenoceptors, respectively. Through activation of α2-adrenoceptors, DEX also exerts anti-inflammatory effect which is possibly another mechanism underlying the DEX's antiparkinsonism effect.

Hypoxia augments NaHS-induced ANP secretion via KATP channel, HIF-1α and PPAR-γ pathway.

It has been reported that sodium hydrosulfide (NaHS) stimulated high stretch induced-atrial natriuretic peptide (ANP) secretion via ATP sensitive potassium (KATP) channel. KATP channel is activated during hypoxic condition as a compensatory mechanism. However, whether NaHS affects ANP secretion during hypoxia remains obscure. The purpose of the present study is to discover the impact of NaHS on ANP secretion during hypoxia and to unravel its signaling pathway. Isolated beating rat atria were perfused with buffer exposed to different O2 tension (to 100% O2, normoxia; to 20% O2, hypoxia). The ANP secretion increased negatively correlated with O2 tension. NaHS (50 µM) did not show any significant effect on low stretch induced-ANP secretion in normoxic condition but augmented low stretch induced-ANP secretion in hypoxic condition. The augmentation of NaHS-induced ANP secretion during hypoxia was blocked by the pretreatment with KATP channel blocker (glibenclamide) and was enhanced by the pretreatment with KATP channel activator (pinacidil). Hypoxia increased the expression of PPAR-γ protein but did not change the expression of HIF-1α protein and eNOS phosphorylation. The NaHS-induced ANP secretion during hypoxia was also blocked by the pretreatment with HIF-1α inhibitor (2-methoxy- estradiol), PPAR-γ inhibitor (GW9662) but not by NOS inhibitor (L-NAME) and endothelin receptor inhibitor (bosentan). The intravenous infusion of NaHS increased plasma ANP level in monocrotaline-treated rats but not in sham rats. These results suggest that hypoxia augmented NaHS-induced ANP secretion partly through KATP channel, HIF-1α, and PPAR-γ pathway.

Opening of ATP-sensitive potassium channels causes migraine attacks: a new target for the treatment of migraine.

Migraine is one of the most disabling and prevalent of all disorders. To improve understanding of migraine mechanisms and to suggest a new therapeutic target, we investigated whether opening of ATP-sensitive potassium channels (KATP) would cause migraine attacks. In this randomized, double-blind, placebo-controlled, crossover study, 16 patients aged 18-49 years with one to five migraine attacks a month were randomly allocated to receive an infusion of 0.05 mg/min KATP channel opener levcromakalim and placebo on two different days (ClinicalTrials.gov number, NCT03228355). The primary endpoints were the difference in incidence of migraine attacks, headaches and the difference in area under the curve (AUC) for headache intensity scores (0-12 h) and for middle cerebral artery blood flow velocity (0-2 h) between levcromakalim and placebo. Between 24 May 2017 and 23 November 2017, 16 patients randomly received levcromakalim and placebo on two different days. Sixteen patients (100%) developed migraine attacks after levcromakalim compared with one patient (6%) after placebo (P = 0.0001); the difference of incidence is 94% [95% confidence interval (CI) 78-100%]. The incidence of headache over the 12 h observation period was higher but not significant after levcromakalim (n = 16) than after placebo (n = 7) (P = 0.016) (95% CI 16-71%). The AUC for headache intensity was significantly larger after levcromakalim compared to placebo (AUC0-12h, P < 0.0001). There was no change in mean middle cerebral artery blood flow velocity after levcromakalim compared to placebo (AUC0-2hP = 0.46). Opening of KATP channels caused migraine attacks in all patients. This suggests a crucial role of these channels in migraine pathophysiology and that KATP channel blockers could be potential targets for novel drugs for migraine.

Pinacidil, a KATP channel opener, stimulates cardiac Na+/Ca2+ exchanger function through the NO/cGMP/PKG signaling pathway in guinea pig cardiac ventricular myocytes.

Pinacidil, a nonselective ATP-sensitive K+ (KATP) channel opener, has cardioprotective effects for hypertension, ischemia/reperfusion injury, and arrhythmia. This agent abolishes early afterdepolarizations, delayed afterdepolarizations (DADs), and abnormal automaticity in canine cardiac ventricular myocytes. DADs are well known to be caused by the Na+/Ca2+ exchange current (INCX). In this study, we used the whole-cell patch-clamp technique and Fura-2/AM (Ca2+-indicator) method to investigate the effect of pinacidil on INCX in isolated guinea pig cardiac ventricular myocytes. In the patch-clamp study, pinacidil enhanced INCX in a concentration-dependent manner. The half-maximal effective concentration values were 23.5 and 23.0 µM for the Ca2+ entry (outward) and Ca2+ exit (inward) components of INCX, respectively. The pinacidil-induced INCX increase was blocked by L-NAME, a nitric oxide (NO) synthase inhibitor, by ODQ, a soluble guanylate cyclase inhibitor, and by KT5823, a cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG) inhibitor, but not by N-2-mercaptopropyonyl glycine (MPG), a reactive oxygen species (ROS) scavenger. Glibenclamide, a nonselective KATP channel inhibitor, blocked the pinacidil-induced INCX increase, while 5-HD, a selective mitochondria KATP channel inhibitor, did not. In the Fura-2/AM study pinacidil also enhanced intracellular Ca2+ concentration, which was inhibited by L-NAME, ODQ, KT5823, and glibenclamide, but not by MPG and 5-HD. Sildenafil, a phosphodiesterase 5 inhibitor, increased further the pinacidil-induced INCX increase. Sodium nitroprusside, a NO donor, also increased INCX. In conclusion, pinacidil may stimulate cardiac Na+/Ca2+ exchanger (NCX1) by opening plasma membrane KATP channels and activating the NO/cGMP/PKG signaling pathway.

Effects of mitochondrial ATP-sensitive potassium channel activation (nicorandil) in patients with angina pectoris undergoing elective percutaneous coronary interventions: A meta-analysis of randomized controlled trials.

AIMS: Nicorandil, which is a mitochondrial ATP-sensitive potassium channel opener, is believed to improve perioperative myocardial injury (PMI) in patients undergoing percutaneous coronary intervention (PCI), but recent studies have shown that nicorandil treatment did not improve functional and clinical outcomes in patients with angina pectoris who underwent elective PCI. We performed a meta-analysis to investigate the protective effect of nicorandil on perioperative injury in patients with angina pectoris who underwent elective PCI. METHODS: The Medline, EMBASE, and Cochrane databases were searched for randomized clinical trials examining the effects of nicorandil. Two investigators independently selected suitable trials, extracted data, and assessed trial quality. RESULTS: Seven studies of patients undergoing elective PCI, comprising a total of 979 patients, were included in this review. The results showed that nicorandil did not reduce the levels of markers of myocardial injury (standardized mean difference [SMD] 0.31 [95%CI -0.6, 1.22] for creatine kinase-MB [CK-MB] and 1.29 [95%CI -2.18, 4.76] for troponin I [TNI]), perioperative complications (relative risk [RR] 0.91 [95%CI 0.46-1.81]), target vessel revascularization (RR 0.79 [95%CI 0.50-1.25]) or major adverse cardiac events (MACE) (RR 0.83 [95%CI 0.49-1.43]). Nicorandil did reduce the corrected TIMI frame count (SMD-0.30 [95%CI -0.52, -0.09]). CONCLUSION: Although nicorandil did not reduce the overall incidence of perioperative complications and the incidence of major adverse cardiac events (MACE) in patients with angina pectoris who underwent elective PCI, it could still improve no reflow and slow coronary flow.

SUR2B/Kir6.1 channel openers correct endothelial dysfunction in chronic heart failure via the miR-1-3p/ET-1 pathway.

The SUR2B/Kir6.1 channel openers iptakalim and natakalim reverse cardiac remodeling and ameliorate endothelial dysfunction by re-establishing the balance between the nitric oxide and endothelin systems. In this study, we investigated the microRNAs (miRs) involved in the molecular mechanisms of SUR2B/Kir6.1 channel opening in chronic heart failure. Both iptakalim and natakalim significantly upregulated the expression of miR-1-3p, suggesting that this miR is closely associated with the therapeutic effects against chronic heart failure. Bioinformatic analysis showed that many of the 183 target genes of miR-1-3p are involved in cardiovascular diseases, suggesting that miR-1-3p plays a vital role in such diseases and vascular remodeling. Target gene prediction showed that miR-1-3p combines with the 3' untranslated region (UTR) of endothelin-1 (ET-1) mRNA. Iptakalim and natakalim upregulated miR-1-3p expression and downregulated ET-1 mRNA expression in vitro. The dual luciferase assay confirmed that there is a complementary binding sequence between miR-1-3p and the 3' UTR 158-165 sequence of ET-1 mRNA. To verify the effect of miR-1-3p on ET-1, lentiviral vectors overexpressing or inhibiting miR-1-3p were constructed for the transduction of rat primary cardiac microvascular endothelial cells. The results showed that natakalim enhanced the miR-1-3p level. miR-1-3p overexpression downregulated the expression of ET-1, whereas miR-1-3p inhibition had the opposite effect. Therefore, we verified that SUR2B/Kir6.1 channel openers could correct endothelial imbalance and ameliorate chronic heart failure through the miR-1-3p/ET-1 pathway in endothelial cells. Our study provides comprehensive insights into the molecular mechanisms behind the SUR2B/Kir6.1 channel's activity against chronic heart failure.

Participation of ATP-sensitive K+ channels and µ-opioid receptors in the antinociceptive synergism of the paracetamol-tapentadol co-administration in the formalin-induced pain assay in mice.

Preclinical Research & Development The purpose of this study was to assess the interaction and mechanisms of action of the paracetamol-tapentadol combination in the formalin-induced pain model in mice. Paracetamol (56.23-562.3 mg/kg, i.p.) or tapentadol (1-10 mg/kg, i.p.) were administered 15 min prior the intraplantar injection of formalin. The ED50 value of each drug was determined through the dose-response curves. The ED50 values were used to calculate the combinations in three fixed proportions (1:1, 1:3, and 3:1). Naloxone (1 and 5 mg/kg, i.p.), L-NAME (3 mg/kg, i.p.), or glibenclamide (10 mg/kg, i.p.) were administered before the combination of drugs to evaluate the antinociceptive mechanisms of action. The results showed that the combination 1:1 and paracetamol3-tapenadol1 ratios produced additive effects, whereas the paracetamol1-tapentadol3 proportion showed an antinociceptive synergistic interaction. Moreover, naloxone and glibenclamide reversed the antinociceptive activity of the paracetamol-tapentadol mixture. Our results indicate that the paracetamol-tapentadol combination produces an antinociceptive synergistic interaction with the possible participation of ATP-sensitive K+ channels and µ-opioid receptors in the second phase of the formalin-induced pain model in mice.

Prevalence of Adverse Events in Children With Congenital Hyperinsulinism Treated With Diazoxide.

Context: Diazoxide, the only U.S. Food and Drug Administration-approved drug to treat hyperinsulinemic hypoglycemia, has been associated with several adverse events, which has raised concerns about the safety of this drug. Existing reports are limited to small studies and case reports. Objective: To determine prevalence of and clinical factors associated with adverse events in infants and children treated with diazoxide. Design: Retrospective cohort study of children with hyperinsulinism (HI) treated with diazoxide between 2003 and 2014. Setting: The Congenital Hyperinsulinism Center at the Children's Hospital of Philadelphia. Patients: Children and infants with laboratory-confirmed diagnosis of HI. Main Outcome Measures: Prevalence of pulmonary hypertension (PH), edema, neutropenia, thrombocytopenia, and hyperuricemia was determined. Tests of association and logistic regression were used to identify potential risk factors. Results: A total of 295 patients (129 female) met inclusion criteria. The median age at diazoxide initiation was 29 days (interquartile range, 10 to 142 days; n = 226 available start dates); 2.4% of patients were diagnosed with PH after diazoxide initiation. Children with PH (P = 0.003) or edema (P = 0.002) were born at earlier gestational age and more frequently had potential PH risk factors, including respiratory failure and structural heart disease (P < 0.0001 and P = 0.005). Other adverse events included neutropenia (15.6%), thrombocytopenia (4.7%), and hyperuricemia (5.0%). Conclusion: In this large cohort, PH occurred in infants with underlying risk factors, but no identifiable risk profile emerged for other adverse events. The relatively high prevalence of neutropenia, thrombocytopenia, and hyperuricemia suggests the value in proactively screening for these side effects in children treated with diazoxide.