Uncoupling of Oxidative Phosphorylation by some Arylacetic Acids (Anti-inflammatory or Hypocholesterolemic Drugs)

Mw, Whitehouse

doi:10.1038/201629a0

Cited by 66 publications

(17 citation statements)

References 7 publications

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“…These effects of indomethacin are probably due to specific inhibition of prostaglandin biosynthesis, for much higher concentrations are needed to inhibit agonist-induced smooth muscle contractions (Northover, 1971;Sorrentino, Capasso & Di Rosa, 1972) or to uncouple oxidative phosphorylation (Whitehouse, 1964). Dinitrophenol, a much more powerful uncoupler of oxidative phosphorylation, also relaxes smooth muscle but we have shown that output of prostaglandins is not affected.…”

Section: Discussionmentioning

confidence: 84%

Prostaglandin Production by Rabbit Isolated Jejunum and Its Relationship to the Inherent Tone of the Preparation

Ferreira

Herman

Vane

1976

British J Pharmacology

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I Pieces of rabbit jejunum were bathed in Krebs solution at 37°C in an isolated organ bath bubbled with 02 and 5% CO2. The bathing fluid was collected regularly and assayed for prostaglandins. 2 The preparations maintained a continuous sub-maximal muscle contraction, referred to as inherent 'tone'. Prostaglandins E2 and FM were continuously generated by the intestine and released into the bathing fluid. The amounts released first declined over 2 h and then steadily increased. The release was also greater after 48 h storage in the refrigerator and after mechanical damage. 3 There was no change in prostaglandin release when the rabbit jejunum was contracted by acetylcholine or physostigmine or relaxed by adrenaline, hyoscine, papaverine, dinitrophenol, or calcium-free Krebs solution. 4 Addition to the bathing fluid of the prostaglandin precursor, arachidonic acid, did not increase the release of prostaglandins although it contracted the tissue. Thus, output of prostaglandins from the tissue was not limited by substrate concentration but more probably by the capacity of the prostaglandin synthetase. 5Prostaglandin output was decreased by bubbling the bathing fluid with N2 rather than 02; at the same time the preparation relaxed. 6 Aspirin-like drugs such as indomethacin also decreased or abolished prostaglandin formation and this, too, was accompanied by loss of tone of the isolated preparation. 7 Pieces of rabbit jejunum stored in Krebs solution containing indomethacin initially released little or no prostaglandin into the bathing fluid. However, prostaglandin release increased with repeated washing of the preparation. 8 The results suggest that intra-mural prostaglandin production contributes to the inherent tone of the rabbit jejunum, that trauma increases prostaglandin production and that the inhibitory effects of anoxia are linked with the lack of prostaglandin production and activity. The relevance of these findings to intestinal activity in vivo is discussed.

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Section: Discussionmentioning

confidence: 84%

Prostaglandin Production by Rabbit Isolated Jejunum and Its Relationship to the Inherent Tone of the Preparation

Ferreira

Herman

Vane

1976

British J Pharmacology

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“…Possibly, these differences result from the fact that proadifen binds to P-450 at a different site than metyrapone or CO. 18 It also is possible, however, that the effects of proadifen were not related to cytochrome P-450. This drug has been found to inhibit autoregulation of renal blood flow, 31 uncouple oxidative phosphorylation, 32 stabilize red blood cell membranes, 33 and block transmembrane ion transport in both nerve and muscle. 34 " 36 The mechanisms for these effects have not been elucidated.…”

Section: Discussionmentioning

confidence: 99%

The effects of agents that bind to cytochrome P-450 on hypoxic pulmonary vasoconstriction.

Sylvester¹,

McGowan

1978

Circulation Research

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SUMMARY The relationship between pulmonary arterial pressure (Ppa) and blood flow (Q) was determined during normoxia and hypoxia in ventilated pig lungs perfused in situ with the animal's own blood. Hypoxia shifted the Ppa-Q relationship to the right and decreased its slope, indicating pulmonary vasoconstriction. Carbon monoxide (11.5% in the inspired gas) and metyrapone ditartrate (10 mg/min into the perfusate) caused vasodilation when oxygenation was normal and reduced the vasoconstriction caused by hypoxia. Since the only pharmacological property CO and metyrapone are thought to have in common at the concentrations employed is the ability to bind to the heme iron of cytochrome P-450, these results are consistent with the hypothesis that desaturation of this cytochrome leads to pulmonary vasoconstriction. Prostaglandin F 2a , infused into the pulmonary artery at 0.01 mg/min, when oxygenation was normal, had effects on the Ppa-Q relationship similar to those of hypoxia. The F 2o response was also reduced by CO and metyrapone, suggesting either that P-450 was involved in the F 2o response or that CO and metyrapone were toxic to pulmonary vascular smooth muscle. Proadifen hydrochloride (1 mg/min), which is thought to bind to the protein moiety of P-450, also reduced the hypoxic response, but was a vasoconstrictor during normoxia and did not affect the F 2 ,, response.

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“…As for some of these drugs such as salicylates, the uncoupling activity parallels the anti-inflammatory activity (2). There are some observations indicating that non-steroidal anti-inflammatory drugs and 2,4-dinitro phenol uncouple oxidative phosphorylation in connective tissues, in vitro (3,4,24) as well as in vivo (25). From these findings, Whitehouse (6) has proposed a hypothesis that the anti-inflammatory activity may be related to the uncoupling of oxidative phosphorylation.…”

Section: Discussionmentioning

confidence: 96%

“…It has been known that a variety of non-steroidal anti-inflammatory drugs uncouple oxidative phosphorylation in mitochondria (1)(2)(3)(4)(5). Adams and Cobb (2) have studied whether or not the inhibition of inflammation by non-steroidal drugs was related to their in vitro capacity to uncouple oxidative phosphorylation.…”

mentioning

confidence: 99%

Anti-Inflammatory Properties of N-Phenylanthranilic Acid Derivatives in Relation to Uncoupling of Oxidative Phosphorylation

1972

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Uncoupling of Oxidative Phosphorylation by some Arylacetic Acids (Anti-inflammatory or Hypocholesterolemic Drugs)

Cited by 66 publications

References 7 publications

Prostaglandin Production by Rabbit Isolated Jejunum and Its Relationship to the Inherent Tone of the Preparation

Prostaglandin Production by Rabbit Isolated Jejunum and Its Relationship to the Inherent Tone of the Preparation

The effects of agents that bind to cytochrome P-450 on hypoxic pulmonary vasoconstriction.

Anti-Inflammatory Properties of N-Phenylanthranilic Acid Derivatives in Relation to Uncoupling of Oxidative Phosphorylation

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