In VitroInteraction of Nonsteroidal Anti-inflammatory Drugs on Oxidative Phosphorylation of Rat Kidney Mitochondria: Respiration and ATP Synthesis

Mingatto, Fábio Ermínio; Santos, Antônio Carlos dos; Uyemura, Ségio A.; Jordani, Maria Cecília; Curti, Carlos

doi:10.1006/abbi.1996.0459

Cited by 83 publications

(49 citation statements)

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“…cascade underlying this process might involve the uncoupling of the mitochondrial oxidative phosphorylation and a reduction in the intracellular ATP concentration (32)(33)(34). Similar mechanisms appear to underlie shedding of glycoproteins in platelets.…”

Section: Discussionmentioning

confidence: 97%

Aspirin Induces Platelet Receptor Shedding via ADAM17 (TACE)

Aktas¹,

Požgajová²,

Bergmeier

et al. 2005

Journal of Biological Chemistry

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Aspirin is effective in the therapy of cardiovascular diseases, because it causes acetylation of cyclooxygenase 1 (COX-1) leading to irreversible inhibition of platelets. Additional mechanisms can be suspected, because patients treated with other platelet COX inhibitors such as indomethacin do not display an increased bleeding tendency as observed for aspirin-treated patients. Recently, aspirin and other anti-inflammatory drugs were shown to induce shedding of L-selectin in neutrophils in a metalloproteinasedependent manner. Therefore, we investigated the effects of aspirin on the von Willebrand Factor receptor complex glycoprotein (GP) Ib-V-IX, whose lack or dysfunction causes bleeding in patients. As quantified by fluorescence-activated cell sorting analysis in whole blood, aspirin, but not its metabolite salicylic acid, induced dose-dependent shedding of human and murine GPIb␣ and GPV from the platelet surface, whereas other glycoproteins remained unaffected by this treatment. Biotinylated fragments of GPV were detected by immunoprecipitation in the supernatant of washed mouse platelets, and the expression level of GPIb␣ was decreased in these platelets as measured by Western blot analysis. Although shedding occurred normally in COX-1-deficient murine platelets, shedding was completely blocked by a broad-range metalloproteinase inhibitor and, more importantly, in mouse platelets expressing an inactive form of ADAM17. Shed fragments of GPIb␣ and GPV were elevated in the plasma of aspirin-injected mice compared with animals injected with control buffer. These data demonstrate that aspirin at high concentrationsinducessheddingofGPIb␣andGPVbyanADAM17-dependent mechanism and that this process can occur in vivo.The activation of platelets at sites of vascular injury, followed by controlled aggregate formation, is required for normal hemostasis, but can cause thrombosis in pathologically altered arteries leading to myocardial infarction or stroke (1). Under conditions of elevated shear, platelet adhesion is initiated by the von Willebrand Factor receptor glycoprotein (GP) 2 Ib-V-IX, a structurally unique receptor complex expressed in platelets and megakaryocytes. The interaction of GPIb␣ with von Willebrand factor bound to subendothelial collagen or on the surface of activated adherent platelets is essential for platelet adhesion and thrombus formation (1, 2). In patients, a reduced expression or malfunction of GPIb␣ determines the Bernard-Soulier syndrome, a congenital bleeding disorder, which is characterized by a macrothrombocytopenia, an inability of platelets to adhere to subendothelial matrices, and a dramatically prolonged bleeding time (3).The expression levels of GPIb and GPV are physiologically regulated by internalization processes and/or by proteolytic ectodomain cleavage ("shedding"), which might play a role in the clearance of aged platelets from the circulation (4). In contrast to the well known protease activity of the platelet activator thrombin that directly releases a 69-kDa fragment from GPV (GPV...

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Section: Discussionmentioning

confidence: 97%

Aspirin Induces Platelet Receptor Shedding via ADAM17 (TACE)

Aktas¹,

Požgajová²,

Bergmeier

et al. 2005

Journal of Biological Chemistry

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“…NSAIDs are hydrophobic acids that release protons from amino, carboxyl, and hydroxyl groups, which, therefore, can also act as ionophores in the inner mitochondrial membrane, resulting in uncoupling of substrate oxidation from ATP production (21,(25)(26)(27). At high concentrations, NSAIDs interact with mitochondrial membrane phospholipids, resulting in inhibition of mitochondrial electron transport and ATP production and have been shown to exert a negative inotropic effect on cardiac contractility (21,26,27).Studies examining mechanisms of blood flow control have revealed conflicting findings on whether NO increases or decreases V O 2 during contraction. In animals, NOS inhibition has been shown to lower muscle V O 2 during evoked contractions (2,20,22,30,31,41), while other studies show no effect (1, 4) or an increase (35) in muscle V O 2 during voluntary exercise.…”

mentioning

confidence: 99%

“…Indomethacin is a nonsteroidal anti-inflammatory drug (NSAID) that inhibits cyclooxygenase-mediated formation of PG from arachidonic acid and PG-mediated vasodilation. NSAIDs are hydrophobic acids that release protons from amino, carboxyl, and hydroxyl groups, which, therefore, can also act as ionophores in the inner mitochondrial membrane, resulting in uncoupling of substrate oxidation from ATP production (21,(25)(26)(27). At high concentrations, NSAIDs interact with mitochondrial membrane phospholipids, resulting in inhibition of mitochondrial electron transport and ATP production and have been shown to exert a negative inotropic effect on cardiac contractility (21,26,27).…”

mentioning

confidence: 99%

Opposing effects of nitric oxide and prostaglandin inhibition on muscle mitochondrial V̇o₂ during exercise

Boushel

Fuentes

Hellsten

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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Indomethacin uncouples and inhibits the electron transport chain in a concentration-dependent manner, and thus, inhibition of NO and PG synthesis may regulate both muscle oxygen delivery and utilization. The purpose of this study was to examine the independent and combined effects of NO and PG synthesis blockade (L-NMMA and indomethacin, respectively) on mitochondrial respiration in human muscle following knee extension exercise (KEE). Specifically, this study examined the physiological effect of NO, and the pharmacological effect of indomethacin, on muscle mitochondrial function. Consistent with their mechanism of action, we hypothesized that inhibition of nitric oxide synthase (NOS) and PG synthesis would have opposite effects on muscle mitochondrial respiration. Mitochondrial respiration was measured ex vivo by high-resolution respirometry in saponin-permeabilized fibers following 6 min KEE in control (CON; n ϭ 8), arterial infusion of N G -monomethyl-L-arginine (L-NMMA; n ϭ 4) and Indo (n ϭ 4) followed by combined inhibition of NOS and PG synthesis (L-NMMA ϩ Indo, n ϭ 8). ADP-stimulated state 3 respiration (OXPHOS) with substrates for complex I (glutamate, malate) was reduced 50% by Indo. State 3 O2 flux with complex I and II substrates was reduced less with both Indo (20%) and L-NMMA ϩ Indo (15%) compared with CON. The results indicate that indomethacin reduces state 3 mitochondrial respiration primarily at complex I of the respiratory chain, while blockade of NOS by L-NMMA counteracts the inhibition by Indo. This effect on muscle mitochondria, in concert with a reduction of blood flow accounts for in vivo changes in muscle O2 consumption during combined blockade of NOS and PG synthesis. NG -monomethyl-L-arginine; indomethacin; contraction; OXPHOS; oxygen uptake NITRIC OXIDE (NO) AND PROSTAGLANDINS (PG) contribute synergistically to regulate skeletal muscle blood flow during exercise in humans (5,14,15,28,32,33) through endothelium-dependent relaxation of vascular smooth muscle. Some studies employing dual inhibition of NO and PG synthesis have reported an effect on muscle oxidative metabolism and energy cost of contraction (14,15,28), suggesting overlapping regulation of oxygen delivery and utilization.NO is an endogenous, short-lived free radical that mediates vascular smooth muscle relaxation. At low physiological concentrations (nanomolar range), NO also reversibly inhibits mitochondrial oxygen consumption by competitive binding to the heme a 3 site of cytochrome oxidase in competition with oxygen. Higher (mM) concentrations of NO leads to peroxinitrite production that, in turn, irreversibly inhibits complexes I and II of the electron transport chain (6 -9, 34, 37, 43). Indomethacin is a nonsteroidal anti-inflammatory drug (NSAID) that inhibits cyclooxygenase-mediated formation of PG from arachidonic acid and PG-mediated vasodilation. NSAIDs are hydrophobic acids that release protons from amino, carboxyl, and hydroxyl groups, which, therefore, can also act as ionophores in the inner mitochondrial membra...

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“…Multiple animal studies have demonstrated that very high concentrations of acetaminophen and its metabolite N-acetyl-p-benzoquinoneimine (NAPQI) can inhibit mitochondrial oxidative phosphorylation [117][118][119][120][121][122][123][124]. This mechanism results in diminished oxygen utilization and is likely responsible for both the coma and lactic acidosis that manifest in massive acetaminophen overdoses.…”

Section: Could Acetaminophen Toxicity Explain the Patient's Elevated mentioning

confidence: 99%

Case Files from the University of California San Diego Health System Fellowship Coma and Severe Acidosis: Remember to Consider Acetaminophen

Villano

O'Connell

et al. 2015

J. Med. Toxicol.

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A 28-year-old man was brought to the Emergency Department (ED) for evaluation of a depressed level of consciousness that developed while in jail. Sixteen hours previously, he had been arrested on charges of murder. The patient's mental status was reported as normal at the time of arrest, and it had remained so during several hours of interrogation and during the booking process at jail. Following interrogation, the patient was placed into a cell with no other inmates. During the jail intake process, the patient had not reported any history of medical problems nor was he prescribed with any medications. Paramedics arrived to find him unresponsive, but maintaining airway reflexes and hemodynamically stable. They measured a blood glucose of 300 mg/dL and noted one episode of blood-tinged emesis during transport to the ED. No seizure activity was witnessed.On arrival to the ED, vital signs were: heart rate 132/min, blood pressure 129/74 mmHg, temperature 35.3°C (95.5°F), respiratory rate 24/min, and 100 % oxygen saturation on 15 l/ min of oxygen delivered by non-rebreather face mask.Physical examination was notable for a depressed level of consciousness. His eyes remained closed to pain, he withdrew all extremities equally to pain, and he was non-verbal. He had no signs of trauma, and his pupils were normal in size and reactive. Rapid sequence tracheal intubation was performed for airway protection. An electrocardiogram was normal except for sinus tachycardia at a rate of 111/min. An initial peripherally drawn arterial blood gas obtained immediately after intubation revealed: pH 6.97, pCO 2 40 mmHg, pO 2 215 mmHg. A computed tomography scan of the brain was normal. Initial blood chemistry panel was significant for a serum bicarbonate of 7 mEq/L, glucose of 362 mg/dL, and a normal potassium, blood urea nitrogen (BUN), creatinine, and calcium. The initial serum anion gap was 34 mEq/L. Measured serum osmolality was 320 mOsm/kg, yielding an osmol gap of 9 mOsm/kg (using formula of [2(Na)+BUN/2.8+glu-cose/18] for calculated serum osmolarity). Initial lactate was 156.5 mg/dL (normal reference range 4.5-19.8 mg/dL) and beta-hydroxybutyrate (βHB) 2.9 mg/dL (normal reference range 0.0-2.8 mg/dL). Initial liver panel included an aspartate aminotransferase (AST) of 64 U/L, alanine aminotransferase (ALT) of 27 U/L, and bilirubin of 0.4 mg/dL. Prothrombin time was 13.1 s (reference range 9.7-12.5), and lipase was normal at 25 U/L. Initial creatinine phosphokinase (CK) was slightly elevated at 373 U/L (0-175). Urinalysis was positive for small ketones and crystals were not present. Measurements of acetone and acetoacetate were not performed. Serum ethanol and salicylate levels were undetectable, and a urine drug of abuse panel by immunoassay was negative for amphetamines as a class, barbiturates as a class, benzodiazepines as a class, benzoylecgonine (cocaine metabolite), methadone, opiates as class, oxycodone, phencyclidine, and tetrahydrocannabinoids. Iron concentration was normal at 87 mcg/dL.Over the first hour of management,...

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In VitroInteraction of Nonsteroidal Anti-inflammatory Drugs on Oxidative Phosphorylation of Rat Kidney Mitochondria: Respiration and ATP Synthesis

Cited by 83 publications

References 0 publications

Aspirin Induces Platelet Receptor Shedding via ADAM17 (TACE)

Aspirin Induces Platelet Receptor Shedding via ADAM17 (TACE)

Opposing effects of nitric oxide and prostaglandin inhibition on muscle mitochondrial V̇o₂ during exercise

Case Files from the University of California San Diego Health System Fellowship Coma and Severe Acidosis: Remember to Consider Acetaminophen

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In VitroInteraction of Nonsteroidal Anti-inflammatory Drugs on Oxidative Phosphorylation of Rat Kidney Mitochondria: Respiration and ATP Synthesis

Cited by 83 publications

References 0 publications

Aspirin Induces Platelet Receptor Shedding via ADAM17 (TACE)

Aspirin Induces Platelet Receptor Shedding via ADAM17 (TACE)

Opposing effects of nitric oxide and prostaglandin inhibition on muscle mitochondrial V̇o2 during exercise

Case Files from the University of California San Diego Health System Fellowship Coma and Severe Acidosis: Remember to Consider Acetaminophen

Contact Info

Product

Resources

About

Opposing effects of nitric oxide and prostaglandin inhibition on muscle mitochondrial V̇o₂ during exercise