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PubMed2006

Preconditioning protects endothelium by preventing ET-1-induced activation of NADPH oxidase and xanthine oxidase in post-ischemic heart.

The hypothesis was tested that endothelin-1 (ET-1)-induced superoxide (O(2)(-)) generation mediates post-ischemic coronary endothelial injury, that ischemic preconditioning (IPC) affords endothelial protection by preventing post-ischemic ET-1, and thus O(2)(-), generation, and that opening of the mitochondrial ATP-dependent potassium channel (mK(ATP)) triggers the mechanism of IPC. Furthermore, the study was aimed at identifying the source of O(2)(-) mediating the endothelial injury. Langendorff-perfused guinea-pig hearts were subjected either to 30 min ischemia/35 min reperfusion (IR) or were preconditioned prior to IR with three cycles of either 5 min ischemia/5 min reperfusion or 5 min infusion/5 min washout of mK(ATP) opener diazoxide (0.5 mM). Coronary flow responses to acetylcholine (ACh) served as a measure of endothelium-dependent vascular function. Myocardial outflow of ET-1 and O(2)(-) and functional recoveries were followed during reperfusion. NADPH oxidase and xanthine oxidase (XO) activities were measured in cardiac homogenates. IR augmented ET-1 and O(2)(-) outflow and impaired ACh response. All these effects were attenuated or prevented by IPC and diazoxide, and 5-hydroxydecanoate (a selective mK(ATP) blocker) abolished the effects of IPC and diazoxide. Superoxide dismutase and tezosentan (a mixed ET-1-receptor antagonist) mimicked the effects of IPC, although they had no effect on the ET-1 generation. IR augmented also the activity of NADPH oxidase and XO. Apocynin treatment, that resulted in NADPH oxidase inhibition, prevented XO activation and O(2)(-) generation in IR hearts. The inhibition of XO, either by allopurinol or feeding the animals with tungsten-enriched chow, prevented post-ischemic O(2)(-) generation, although these interventions had no effect on the NADPH activity. In addition, the post-ischemic activation of NADPH oxidase and XO, and O(2)(-) generation were prevented by IPC, tezosentan, thenoyltrifluoroacetone (mitochondrial complex II inhibitor), and tempol (cell-membrane permeable O(2)(-) scavenger). In guinea-pig heart: (i) ET-1-induced O(2)(-) generation mediates post-ischemic endothelial dysfunction; (ii) IPC and diazoxide afford endothelial protection by attenuating the ET-1, and thus O(2)(-) generation, and the mK(ATP) opening triggers the protection; (iii) the NADPH oxidase maintains the activity of XO, and the XO-derived O(2)(-) mediates the endothelial injury, and (iv) ET-1 and O(2)(-) (probably of mitochondrial origin) are upstream activators of the NADPH oxidase-XO cascade, and IPC prevents the cascade activation and the endothelial dysfunction by preventing the ET-1 generation.

Animals↗

PubMed2001

Direct activation of mitochondrial K(ATP) channels mimics preconditioning but protein kinase C activation is less effective in middle-aged rat hearts.

OBJECTIVES: This study is aimed to determine whether loss of preconditioning (IP) effects in the middle-aged hearts (MA) is due to the failure of protein kinase C (PKC) activation and, if so, whether direct activation of mitochondrial ATP-sensitive potassium channels (m-K(ATP)) or PKC mimics IP. BACKGROUND: PKC is a mediator and m-K(ATP) may be its downstream effector of IP in young adult hearts (YA), but we have demonstrated that IP is not effective in MA. METHODS AND RESULTS: Isolated hearts from YA (12-week) and MA (50-week) Fischer 344 rats were preconditioned by three cycles of ischemia and reperfusion (5 min each), and the translocation of PKC isoforms and the effects on reperfusion injury were assessed. In some hearts activation of m-K(ATP) or PKC by diazoxide or 1, 2-dioctanoyl glycerol (DOG) was performed before 25 min of global ischemia/30 min of reperfusion. IP could improve the recovery of LV function and resulted in higher content of ATP after reperfusion in YA but these beneficial effects of IP was not found in MA. The effects of IP in YA were abolished by 5-hydroxydecanoate. In YA but not in MA, immunohistochemical analysis revealed that IP translocated PKC-alpha and delta from the cytosolic or membrane to the perinuclear region but immunoblotting analysis showed translocation of PKC-alpha, delta and epsilon to the membrane fraction. Pretreatment with diazoxide or DOG mimicked IP and decreased the creatine kinase release in YA. Diazoxide was also effective but effects of DOG were less in MA as compared with in YA. CONCLUSIONS: IP is not effective in MA hearts partly due to failure of translocation of PKC isoforms. Moreover, less efficacy of PKC activation by DOG as compared with activities of m-K(ATP) by diazoxide in MA may suggest that defect(s) of cell signaling downstream to PKC may also be involved in the loss of IP effects in MA.

Aging↗

PubMed2002

Opening of mitochondrial K+ channels increases ischemic ATP levels by preventing hydrolysis.

Mitochondrial ATP-sensitive K+ channels (mitoK(ATP)) have been proposed to mediate protection against ischemic injury by increasing high-energy intermediate levels. This study was designed to verify if mitochondria are an important factor in the loss of cardiac ATP associated to ischemia, and determine the possible role of mitoK(ATP) in the control of ischemic ATP loss. Langendorff-perfused rat hearts subjected to ischemia were found to have significantly higher ATP contents when pretreated with oligomycin or atractyloside, indicating that mitochondrial ATP hydrolysis contributes toward ischemic ATP depletion. MitoK(ATP) opening induced by diazoxide promoted a similar protection against ATP loss. Diazoxide also inhibited ATP hydrolysis in isolated, nonrespiring mitochondria, an effect accompanied by a drop in the membrane potential and Ca2+ uptake. In hearts subjected to ischemia followed by reperfusion, myocardial injury was prevented by diazoxide, but not atractyloside or oligomycin, which, unlike diazoxide, decreased reperfusion ATP levels. Our results suggest that mitoK(ATP)-mediated protection occurs due to selective inhibition of mitochondrial ATP hydrolysis during ischemia, without affecting ATP synthesis after reperfusion.

Adenosine Triphosphate↗

PubMed1996

Selective effect of thiazides on the human osteoblast-like cell line MG-63.

Thiazide diuretics have been shown to decrease bone-loss rate and to improve bone mineral density in patients using this medication. However, the exact role of thiazides on bone cells is still debated. In the present work, we studied whether thiazides could affect the normal features of osteoblasts using the human model cell line MG-63. Hydrochlorothiazide (HCTZ) did not affect cell growth nor DNA synthesis in these cells, yet slightly increased alkaline phosphatase activity in these cells at pharmacologically relevant concentrations. Under similar conditions, HCTZ dose-dependently inhibited 1,25(OH)2D3-induced osteocalcin secretion by these cells (maximal effect, -40 to 50%, P < 0.005). However, HCTZ did not inhibit the basal production of osteocalcin in MG-63 cells (without 1,25(OH)2D3 induction), which was very low to undectable. Two different thiazide derivatives, chlorothiazide and cyclothiazide, and two structurally related sulfonamides with selective inhibition of carbonic anhydrase (Acetazolamide) or hyperglycemic effects (Diazoxide) were also tested. Chlorothiazide (1000 microM) inhibited osteocalcin secretion (-42 +/- 12.7%) at doses 10-fold higher than HCTZ (100 microM) while cyclothiazide was effective at doses of 1 microM (-27 +/- 3.6%), and hence 100-fold lower than HCTZ, compatible with the relative natriuretic effect in vivo of these compounds. Acetazolamide (10 microM) poorly affected osteocalcin secretion at doses 100-fold higher than those needed in vivo to inhibit carbonic anhydrase. Likewise, Diazoxide (100 microM) poorly affected osteocalcin secretion at doses known to promote its biological effect. Higher doses of acetazolamide and diazoxide induced cell death. Neither Acetazolamide nor Diazoxide affected alkaline phosphatase, whereas chlorothiazide had a weak positive effect on this enzymatic activity. The production of macrophage colony-stimulating factor (M-CSF) was stimulated in the presence of 1,25(OH)2D3 (50 nM), TNF-alpha (2 ng/ml) or both in MG-63 cells. HCTZ (25 microM, 24 hr of preincubation) did not modify basal M-CSF production and did not reduce the response to 1,25(OH)2D3 alone. In contrast, HCTZ inhibited the response to TNF-alpha alone (P < 0.05), and also reduced the response to a combination of 1,25(OH)2D3 and TNF-alpha (P < 0.01). In conclusion, these results indicate that thiazide diuretics show a selective inhibition of osteocalcin secretion and M-CSF production by MG-63 cells unlike structurally related drugs. Therefore, these features may explain, in part, the positive effect of thiazides on bone mineral density.

Alkaline Phosphatase↗

PubMed2001

Methyl pyruvate initiates membrane depolarization and insulin release by metabolic factors other than ATP.

The role of mitochondria in stimulus-secretion coupling of pancreatic beta-cells was examined using methyl pyruvate (MP). MP stimulated insulin secretion in the absence of glucose, with maximal effect at 5 mM. K+ (30 mM) alone, or in combination with diazoxide (100 microM), failed to enhance MP-induced secretion. Diazoxide (100 microM) inhibited MP-induced insulin secretion. MP depolarized the beta-cell in a concentration-dependent manner (5-20 mM). The sustained depolarization induced by 20 mM MP was not influenced by 100 microM diazoxide, but the continuous spiking activity was suppressed by 500 microM diazoxide. Pyruvate failed to initiate insulin release (5-20 mM) or to depolarize the membrane potential. ATP production in isolated beta-cell mitochondria was detected as accumulation of ATP in the medium during incubation in the presence of malate or glutamate in combination with pyruvate or MP. There was no difference in ATP production induced by pyruvate/malate or MP/malate in isolated beta-cell mitochondria. ATP production by MP/glutamate was higher than that induced by pyruvate/glutamate, but it was much lower than that induced by alpha-ketoisocaproate/glutamate. Pyruvate (5 mM) or MP (5 mM) had no effect on the ATP/ADP ratio in whole islets, whereas glucose (20 mM) significantly increased the whole islet ATP/ADP ratio. It is concluded that MP-induced beta-cell membrane depolarization or insulin release does not relate directly to mitochondrial ATP production. Instead MP may exert a direct extramitochondrial effect, or it may stimulate beta-cell mitochondria to produce coupling factors different from ATP to initiate insulin release.

Adenosine Diphosphate↗

PubMed2002

Nicorandil and leukocyte activation.

Nicorandil, a hybrid compound of an ATP-sensitive potassium (KATP ) channel opener and a nitric oxide donor, has been reported to preserve microvascular integrity in patients with reperfused myocardial infarction. The aim of the current study was to test the hypothesis that nicorandil suppresses activation of polymorphonuclear leukocytes (PMNLs), resulting in reduction of PMNL migration into tissue upon ischemia/reperfusion. Nicorandil, along with the mitochondrial KATP channel opener diazoxide and the nitric oxide donors nitroglycerin and isosorbide dinitrate, suppressed pseudopod projection in human PMNLs treated with 10(-9)-formyl-methionyl-leucyl-phenylalanine (FMLP) and subjected to shear stress (5 dyn/cm(2)) with a cone-and-plate shear device. Suppression by nicorandil and diazoxide was reversed by KATP channel blockers, 5 hydroxydecanoate and glibenclamide. FMLP-induced increase of [Ca2+] in PMNLs was suppressed by nicorandil and diazoxide, and 5 hydroxy-decanoate and glibenclamide reversed this suppression. Results of reverse transcription polymerase chain reaction with rat PMNL mRNA indicated the presence of mRNAs of Kir6.2 and Kir6.1 but not mRNAs of sulfonylurea receptor 1 or 2. Isosorbide dinitrate, diazoxide, and nicorandil reduced leukocyte migration and microvascular obstruction in reperfused ischemic tissue of rat mesenteric microcirculation. In conclusion, nicorandil attenuates ischemia/reperfusion-induced PMNL activation via donation of nitric oxide and K channel-related cascade.

Animals↗

PubMed1992

Potassium channel conductance: a mechanism affecting hair growth both in vitro and in vivo.

The opening of intracellular potassium channels has been suggested as a mechanism regulating hair growth. Enhancing the flux of potassium ions is a mechanism shared by several structurally diverse antihypertensive agents including minoxidil sulfate (the active metabolite of minoxidil), pinacidil, P-1075 (a potent pinacidil analog), RP-49,356, diazoxide, cromakalim, and nicorandil. Of these drugs, minoxidil, pinacidil, and diazoxide have been reported to elicit hypertrichosis in humans. This potassium channel hypothesis was examined by testing these drugs for effects on hair growth both in vitro and in vivo. For the in vitro studies, mouse vibrissae follicles were cultured for 3 d with drug and the effects on hair growth were measured by metabolic labeling. All drugs, except diazoxide, enhanced cysteine incorporation into the hair shafts of the cultured vibrissae. Diazoxide was poorly soluble and thus was tested only at low doses. Minoxidil, P-1075, cromakalim, and RP-49,356 were also evaluated in vivo by measuring hair growth effects in balding stumptail macaque monkeys. The drugs were administered topically to defined sites on balding scalps once per day for 4-5 months and the amount of hair grown was determined by monthly measurements of shaved hair weight. Three of the drugs produced significant increases in hair weight whereas, the RP-49,356 had no effect. These studies provide correlative evidence that the opening of potassium channels is an important regulatory mechanism for hair growth. This provides the impetus for further studies on this potentially important mechanism affecting hair biology.

Animals↗

PubMed1993

Stimulation of insulin secretion by imidazoline compounds is not due to interaction with non-adrenoceptor idazoxan binding sites.

1. The potency of interaction of several imidazoline compounds with non-adrenoceptor idazoxan binding sites (NAIBS) in rat liver membranes was compared with their ability to alter insulin secretion from rat pancreatic islets. 2. NAIBS could be labelled specifically with [3H]-idazoxan in both rat liver membranes and in rat islet homogenates. Liver binding sites exhibited a KD for [3H]-idazoxan of 24 nM and a Bmax of 264 fmol mg-1 protein. 3. Binding of [3H]-idazoxan to NAIBS in rat liver membranes was displaced effectively by unlabelled idazoxan (IC50 0.1 microM) and by UK14304 (IC50 0.5 microM). However, two other imidazoline compounds efaroxan and RX821002, which are related in structure to idazoxan, were much less effective as displacers. 4. In insulin secretion experiments, the ATP-sensitive potassium channel agonist diazoxide (250 microM) was able to suppress the rise in insulin secretion induced by 20 mM glucose. Both efaroxan and RX821002 (100 microM) antagonized the inhibitory effect of diazoxide on glucose-induced insulin secretion. By contrast, neither idazoxan (100 microM) nor UK14304 (50 microM), was able to overcome significantly the inhibitory effect of diazoxide. 5. The ability of 100 microM efaroxan to antagonize the suppression of insulin secretion mediated by diazoxide, was not prevented by idazoxan (up to 100 microM) or by UK14304 (up to 50 microM). 6. The results indicate that the stimulatory effects of imidazoline compounds on insulin secretion are not due to interaction with NAIBS similar to those present in rat liver.

Adrenergic alpha-Agonists↗

PubMed1993

Antagonism of the stimulatory effects of efaroxan and glibenclamide in rat pancreatic islets by the imidazoline, RX801080.

1. The imidazoline alpha 2-adrenoceptor antagonist, efaroxan, stimulates insulin secretion from rat isolated islets and antagonizes the ability of diazoxide to inhibit glucose-induced insulin secretion. These effects result from closure of ATP-sensitive potassium channels although the mechanisms involved have not been elucidated. 2. In the present work, we have examined the effects of a close structural analogue of efaroxan, RX801080, in rat isolated islets of Langerhans. RX801080 was found to be ineffective as a stimulator of insulin secretion and did not prevent the inhibition of insulin secretion mediated by diazoxide. 3. RX801080 acted as an antagonist of the actions of several imidazolines (efaroxan, phentolamine and midaglizole) in rat islets. It dose-dependently inhibited the ability of efaroxan to antagonize the effects of diazoxide in islets and also completely inhibited the direct stimulation of insulin secretion mediated by efaroxan. 4. RX801080 also antagonized the effects of the non-imidazoline, ATP-sensitive potassium channel blocker, glibenclamide, in rat islets. It inhibited both the capacity of glibenclamide to stimulate insulin secretion and the ability of glibenclamide to overcome the inhibitory effects of diazoxide in rat islets. 5. Antagonism of glibenclamide responses by RX801080 was not due to inhibition of binding of the sulphonylurea to its receptor on the pancreatic beta-cell. 6. The results suggest that imidazoline compounds and sulphonylureas interact with distinct binding sites on islet cells, but that these sites can interact functionally to control islet cell ATP-sensitive potassium channel activity and insulin secretion.

Adrenergic alpha-Antagonists↗

PubMed2003

Antiangiogenic effect of KR-31372 by apoptosis via mediation of mitochondrial KATP channel opening and the phosphatase and tensin homolog deleted from chromosome 10 phosphorylation.

Antiangiogenic action of (2R,3R,4S)-N"-cyano-N-(6-nitro-3,4-dihydro-hydroxy-2-methyl-2-dimethoxymethyl-2H-1-benzopyran-4yl)-N'-benzyl guanidine (KR-31372) was examined with its proapoptotic action in human umbilical vein endothelial cells (HUVECs) compared with diazoxide. KR-31372 as well as diazoxide significantly suppressed the neovascularization in mice induced by the Matrigel-containing recombinant human vascular endothelial growth factor (VEGF)165 in vivo and the basal tube formation of HUVECs in vitro with suppression of proliferation of HUVECs stimulated by VEGF165. KR-31372 and diazoxide enhanced DNA fragmentation associated with increase in phosphatase and tensin homolog deleted from chromosome 10 (PTEN) and decrease in serine/threonine kinase phosphorylation, which were accompanied by augmented Bax and cytochrome c release, and suppressed Bcl-2 in HUVECs. In the U87-MG cells, when transfected with expression vectors for sense PTEN, KR-31372 enhanced DNA fragmentation, but not in naive U87-MG cells. The suppression by KR-31372 and diazoxide of these variables was significantly antagonized by 5-hydroxydecanoic acid, a mitochondrial KATP channel blocker. Taken together, KR-31372 strongly inhibited angiogenesis in HUVECs by proapoptotic mechanism via mediation of 5-hydroxydecanoic acid-inhibitable mitochondrial KATP channel opening and PTEN phosphorylation.

Angiogenesis Inhibitors↗

PubMed2004

PKC-epsilon is upstream and PKC-alpha is downstream of mitoKATP channels in the signal transduction pathway of ischemic preconditioning of human myocardium.

Protein kinase C (PKC) is involved in the process of ischemic preconditioning (IPC), although the precise mechanism is still a subject of debate. Using specific PKC inhibitors, we investigated which PKC isoforms were involved in IPC of the human atrial myocardium sections and to determine their temporal relationship to the opening of mitochondrial potassium-sensitive ATP (mitoKATP) channels. Right atrial muscles obtained from patients undergoing elective cardiac surgery were equilibrated and then randomized to receive any of the following protocols: aerobic control, 90-min simulated ischemia/120-min reoxygenation, IPC using 5-min simulated ischemia/5-min reoxygenation followed by 90-min simulated ischemia/120-min reoxygenation and finally, PKC inhibitors were added 10 min before and 10 min during IPC followed by 90-min simulated ischemia/120-min reoxygenation. The PKC isoforms inhibitors investigated were V1-2 peptide, GO-6976, rottlerin, and LY-333531 for PKC-epsilon, -alpha, -delta and -beta, respectively. To investigate the relation of PKC isoforms to mitoKATP channels, PKC inhibitors found to be involved in IPC were added 10 min before and 10 min during preconditioning by diazoxide followed by 90-min simulated ischemia/120-min reoxygenation in a second experiment. Creatine kinase leakage and methylthiazoletetrazolium cell viability were measured. Phosphorylation of PKC isoforms after activation of the sample by either diazoxide or IPC was detected by using Western blot analysis and then analyzed by using Scion image software. PKC-alpha and -epsilon inhibitors blocked IPC, whereas PKC-delta and -beta inhibitors did not. The protection elicited by diazoxide, believed to be via mitoKATP channels opening, was blocked by the inhibition of PKC-alpha but not -epsilon isoforms. In addition, diazoxide caused increased phosphorylation of PKC-alpha to the same extent as IPC but did not affect the phosphorylation of PKC-epsilon, a process believed to be critical in PKC activation. The results demonstrate that PKC-alpha and -epsilon are involved in IPC of the human myocardium with PKC-epsilon being upstream and PKC-alpha being downstream of mitoKATP channels.

Dose-Response Relationship, Drug↗

PubMed1999

Preconditioning by mitochondrial ATP-sensitive potassium channel openers: An effective approach for improving the preservation of heart transplants.

BACKGROUND: Recent studies have implicated mitochondrial ATP-sensitive potassium (K(ATP)) channels in the cardioprotective effects of ischemic preconditioning. The present study used a model of prolonged cold heart storage to assess whether the mitochondrial K(ATP) opener diazoxide could reproduce the protection conferred by ischemic preconditioning. METHODS AND RESULTS: Fifty-four isolated rat hearts were arrested with and stored in Celsior at 4 degrees C for 10 hours before a 2-hour reperfusion. They were divided into 5 groups. Group 1 hearts served as controls. In group 2, hearts were preconditioned by two 5-minute episodes of global ischemia, each separated by 5 minutes of reperfusion before arrest. In group 3, hearts received a 15-minute infusion of the mitochondrial K(ATP) opener diazoxide (30 micromol/L) followed by 5 minutes of washout before arrest. In groups 4 and 5, hearts underwent a protocol similar to that used in groups 2 and 3, respectively, except that the preconditioning was preceded by a 10-minute infusion of the mitochondrial K(ATP) blocker 5-hydroxydecanoate (5-HD, 100 micromol/L). Both ischemic and diazoxide preconditioning provided a similar degree of cardioprotection demonstrated by a significantly better preservation of left ventricular compliance, reduced leakage of creatine kinase, and smaller degree of myocardial edema compared with control hearts. These beneficial effects were abolished by 5-HD pretreatment. Postischemic left ventricular contractility and endothelium-dependent coronary response to 5-hydroxytryptamine and acetylcholine were not different among groups. However, the endothelium-independent vasodilatory postischemic response to papaverine was better preserved after ischemic and diazoxide preconditioning than in the other groups. CONCLUSION: These data support the concept that the cardioprotective effects of ischemic preconditioning can be duplicated by a mitochondrial K(ATP) opener and suggest that activation of these channels could be an effective means of improving the preservation of globally ischemic cold-stored hearts, as occurs during cardiac transplantation.

Adenosine Triphosphate↗

PubMed2004

Autosomal-dominant hypertension with type E brachydactyly is caused by rearrangement on the short arm of chromosome 12.

We are studying a Turkish family with autosomal-dominant hypertension and brachydactyly; affected persons die of stroke before 50 years of age. With interphase fluorescence in situ hybridization, we found a chromosome 12p deletion, reinsertion, and inversion in affected persons. This finding suggested that the hypertension could be caused by one or more of 3 genes, the ATP-dependent potassium channel Kir6.1, its regulator the sulfonyl urea receptor SUR2, and the phosphodiesterase PDE3A. We further studied 6 affected and 4 nonaffected persons. Buttocks biopsies were done, small vessels were tested on a myograph, and mRNA was extracted. We performed forearm blood flow studies with intrabrachial artery diazoxide, isoproterenol, and milrinone infusions. Systemic pharmacological testing was done with intravenous diazoxide, nitroprusside, and isoproterenol. PDE3A mRNA was high in vessels from 3 affected subjects, but not high in 3 others. The vessels responded similarly to forskolin, with or without glibenclamide, and to cromakalim. However, there was a suggestion that the dilatation after milrinone might be exaggerated. The forearm infusion studies showed no differences in the responses to diazoxide, isoproterenol, or milrinone. Systemically, affected persons showed a greater blood pressure response to diazoxide and nitroprusside, and a greater heart rate response to isoproterenol than nonaffected persons. The results shed doubt on Kir6.1 and SUR2. The differences in PDE3A expression and responses may be the result of hypertension rather than the cause. Although our 3 candidate genes are no longer likely, the rearrangement we describe greatly enhances the perspectives of this project.

Arteries↗

PubMed2004

Myocardial impairment in chronic hypoxia is abolished by short aeration episodes: involvement of K+ATP channels.

In vivo exposure to chronic hypoxia is considered to be a cause of myocardial dysfunction, thereby representing a deleterious condition, but repeated aeration episodes may exert some cardioprotection. We investigated the possible role of ATP-sensitive potassium channels in these mechanisms. First, rats (n = 8/group) were exposed for 14 days to either chronic hypoxia (CH; 10% O(2)) or chronic hypoxia with one episode/day of 1-hr normoxic aeration (CH+A), with normoxia (N) as the control. Second, isolated hearts were Langendorff perfused under hypoxia (10% O(2), 30 min) and reoxygenated (94% O(2), 30 min) with or without 3 microM glibenclamide (nonselective K(+)(ATP) channel-blocker) or 100 microM diazoxide (selective mitochondrial K(+)(ATP) channel-opener). Blood gasses, hemoglobin concentration, and plasma malondialdehyde were similar in CH and CH+A and in both different from normoxic (P < 0.01), body weight gain and plasma nitrate/nitrite were higher in CH+A than CH (P < 0.01), whereas apoptosis (number of TUNEL-positive nuclei) was less in CH+A than CH (P < 0.05). During in vitro hypoxia, the efficiency (ratio of ATP production/pressure x rate product) was the same in all groups and diazoxide had no measurable effects on myocardial performance, whereas glibenclamide increased end-diastolic pressure more in N and CH than in CH+A hearts (P < 0.05). During reoxgenation, efficiency was markedly less in CH with respect to N and CH+A (P < 0.0001), and ratex pressure product remained lower in CH than N and CH+A hearts (P < 0.001), but glibenclamide or diazoxide abolished this difference. Glibenclamide, but not diazoxide, decreased vascular resistance in N and CH (P < 0.005 and < 0.001) without changes in CH+A. We hypothesize that cardioprotection in chronically hypoxic hearts derive from cell depolarization by sarcolemmal K(+)(ATP) blockade or from preservation of oxidative phosphorylation efficiency (ATP turnover/myocardial performance) by mitochondrial K(+)(ATP) opening. Therefore K(+)(ATP) channels are involved in the deleterious effects of chronic hypoxia and in the cardioprotection elicited when chronic hypoxia is interrupted with short normoxic aeration episodes.

Animals↗

PubMedDate not supplied

Ischemic and pharmacological induction of delayed cellular protection in iNOS gene-disrupted mice myocytes.

Inducible nitric oxide synthase (iNOS) has been implicated as a mediator in myocardial protection, but this property of iNOS is still conflicting. Therefore, the present study was designed to assess whether iNOS really contributes to the ischemically and pharmacologically induced delayed cellular protection (DCP) in mice myocytes. The following groups of cultured iNOS gene-knockout (iNOS-/-), and its respective wild-type (wt) mice myocytes subjected to simulated ischemia (SI) at 20 h were studied: (a) wt + SI: with ischemia alone; (b) iNOS-/- + SI: with ischemia alone; (c) iNOS-/- + heat shock (HS): iNOS-/- and HS; (d) iNOS-/- + sub-lethal simulated ischemia (SSI): iNOS-/- and SSI; (e) iNOS-/- + A1AR agonist 2-chloro-N6-cyclopentyladenosine (CCPA): iNOS-/- and 1 microM CCPA; (f) iNOS-/- + A1AR agonist (2S)-N6-[2-endo-norbomyl]adenosine (S-ENBA): iNOS-/- and 1 nM S-ENBA; (g) iNOS-/- + K(ATP) channel opener pinacidil (Pin): iNOS-/- and 0.05 microM Pin, and (h) iNOS-/- + mitochondrial K(ATP) channel opener diazoxide (Diazo): iNOS-/- and 100 microM Diazo. The release of LDH into the medium as well as the amount of LDH remaining in the cells was used as a marker of cellular injury and cell viability. The cellular resistance was acquired by iNOS-/- mice myocytes due to HS, SSI, CCPA, S-ENBA, pinacidil and diazoxide treatment, which was evidenced by reduction of LDH (U/L) release from 51.14 +/- 1.35 (iNOS-/-) to 42.20 +/- 1.01 (iNOS-/- + HS); 45.57 +/- 0.75 (iNOS-/- + SSI); 42.87 +/- 0.87 (iNOS-/- + CCPA); 43.21 +/- 0.70 (iNOS-/- + S-ENBA); 37.81 +/- 0.99 (iNOS-/- + Pin) and 36.79 +/- 0.68 (iNOS-/- + Diazo), p < 0.01. Our data suggest that heat shock (HS), sub-lethal simulated ischemia (SSI), A1 adenosine agonists CCPA, S-ENBA and K(ATP) channel openers pinacidil (membrane K(ATP) channel), diazoxide (mitochondrial K(ATP) channel) induce delayed cellular protection in mice myocytes against subsequent sustained simulated ischemia without the involvement of iNOS. Further, our data also suggest that pinacidil and diazoxide are more potent inducers of delayed cellular protection among others in iNOS-/- mice myocytes against sustained simulated ischemia.

Adrenergic Agonists↗

PubMed2006

Ischemic preconditioning prevents endothelial dysfunction, P-selectin expression, and neutrophil adhesion by preventing endothelin and O2- generation in the post-ischemic guinea-pig heart.

Evidence indicates that ischemia/reperfusion (IR) results in endothelial dysfunction and neutrophil adhesion in the post-ischemic myocardium and that ischemic preconditioning (IPC), superoxide dismutase (SOD), and anti-endothelin-1 (ET-1) interventions prevent these effects. We tested the hypothesis that ET-1-induced superoxide (O(2)(-)) generation mediates endothelial injury and neutrophil accumulation in the IR heart, that IPC protects the endothelium and prevents the adhesion by attenuating post-ischemic ET-1, and thus O(2)(-), generation, and that the mitochondrial ATP-dependent potassium channel (mK(ATP)) triggers the IPC-induced protection. Langendorff-perfused guinea-pig hearts were subjected either to 30 min ischemia/35 min reperfusion (IR) or were preconditioned prior to IR with three cycles of either 5 min ischemia/5 min reperfusion or 5 min infusion/5 min wash-out of mK(ATP) opener diazoxide (0.5 microM). Neutrophils were infused to the hearts at 15-25 min of the reperfusion. Coronary flow responses to acetylcholine (ACh) and nitroprusside (SNP) served as measures of endothelium-dependent and -independent vascular function, respectively. Myocardial outflow of ET-1 and O(2)(-), P-selectin expression, neutrophil adhesion and functional recoveries were followed during reperfusion. IR augmented ET-1 and O(2)(-) outflow, P-selectin expression, and neutrophil adhesion, and impaired ACh response. These effects were attenuated or prevented by IPC and diazoxide, and 5-hydroxydecanoate (a selective mK(ATP) blocker) abolished the effects of IPC and diazoxide. SOD (150 U/ml) and tezosentan (5 nM, a mixed ET-1-receptor antagonist) mimicked the effects of IPC, although they had no effect on the ET-1 generation. The preventive effect of IPC, SOD and tezosentan on P-selectin expression preceded their effect on neutrophil adhesion. These data suggest that in guinea-pig heart: (i) ET-1-induced O(2)(-) generation mediates the post-ischemic endothelial dysfunction, P-selectin expression and neutrophil adhesion; (ii) IPC and diazoxide afford protection by attenuating the ET-1, and thus O(2)(-) generation; (iii) the mK(ATP) opening triggers the IPC protection; (iv) endothelial injury promotes post-ischemic neutrophil adhesion, but not vice versa.

Animals↗

PubMed1981

[3-Amino-2H-1,2,4-benzothiadiazine-1,1-dioxides with antihypertensive and possibly diabetogenic activity (author's transl)].

By reaction of dialkylaminoalkylamines or omega-amino-alkylethers with 2H-1,2,4-benzothiadiazine-1,1-dioxides bearing a group in the 3-position labile towards nucleophilic substitution (Cl, CH3S, CH3CO2), the corresponding 3-substituted amino-2H-1,2,4-benzothiadiazine-1,1-dioxides are obtained. A series of these compounds exerts an antihypertensive effect in the renally hypertonic rat after oral administration and in the "two-kidney hypertensive dog" after parenteral administration. Two compounds (1 and 4) were studied thoroughly in comparison to diazoxide (16) and the known piperazino compound (17). At 10 mg/kg in the rat, diazoxide causes a marked reduction of water and electrolyte excretion but at this dosage 1 and 4 are neither diuretic nor antidiuretic. In the hyperglycaemia test on normal rats at a dosage 30--100 times that required for an antihypertensive effect, 1 and 4 show after 300 mg/kg no hyperglycaemic effect and after 1000 mg/kg p.o. a very weak one. 17 has a weak hyperglycaemic effect at 300 mg/kg diazoxide a strong one. However, intensive glucose loading studies on diabetic rats (reduced glucose-tolerance) and on metabolically healthy rats with glucose loading showed that compounds 1 and 4 as well as the piperazine derivative 17 inhibit insulin release, albeit in higher doses than does diazoxide. In animals with insulin resistance a diabetic metabolic condition occurs with high blood-sugar levels. Owing to this possible diabetogenic activity, testing and application of 1, 4 and the known 7-chloro-3-(4-methyl-1-piperazinyl)-2H-1,2,4-benzothiadiazine-1,1-dioxide for blood-sugar lowering activity to human volunteers is not considered appropriate.

Animals↗

PubMed1993

Antinociceptive activity of intrathecally administered potassium channel openers and opioid agonists: a common mechanism of action?

The potassium channel openers could share a common mechanism of action with the opiates in the production of antinociception because both classes of drugs have been shown to enhance potassium efflux. The i.t. administration of the potassium channel openers diazoxide, minoxidil, and lemakalim (BRL38227) produced antinociception as measured in the tail-flick test. The ED50's were 122, 184 and 35 micrograms/mouse, respectively. Minoxidil and lemakalim (BRL 38227) were full agonists, whereas diazoxide was a partial agonist. Diazoxide-induced antinociception was blocked by the potassium channel blockers glyburide, apamin and charybdotoxin. Minoxidil- and lemakalim (i.t.)-induced antinociception was blocked totally by only glyburide. The antinociception produced by the potassium channel openers (i.t.) was blocked differentially by opiate antagonists (i.t.). The antinociceptive effects of diazoxide were blocked by nor binaltorphimine, ICI 174,864 and naloxone. Minoxidil- and lemakalim-induced antinociception was blocked by naloxone and ICI 174,864, but not by nor-binaltorphimine. Naloxone (s.c.) shifted the dose-effect curve for minoxidil to the right in a parallel manner. Morphine-induced antinociception was partially blocked by glyburide and apamin, whereas that produced by DPDPE was blocked totally by apamin. U50, 488H-induced antinociception was blocked partially by apamin. The potassium channel openers (i.t.) were not cross tolerant to morphine when measured in the tail-flick test. Apamin and glyburide precipitated "withdrawal-like" symptoms in morphine-tolerant mice. The interaction of potassium channel openers and opioids probably does not represent a direct interaction of these two classes of drugs at a similar receptor, but rather may occur via an interaction with a common second messenger system such as calcium.

Analgesics↗