A Peripheral Action of Sodium Salicylate

Abstract

Sodium salicylate and related compounds are widely used for their antipyretic properties. It has been suggested that the antipyresis is due to an effect on the hypothalamus, leading to increased heat loss (Barbour, 1926;Guerra and Barbour, 1943). This concept, however, does not specify what effects salicylate would be expected to have on metabolic rate.The observation of Reid (1952), when studying the changes in acid-base balance, that sodium salicylate caused a marked increase in the 0°con-sumption of the rabbit, was surprising in view of the antipyretic activity of the drug. The question arose, whether such an increase occurred in man with therapeutic doses of sodium salicylate. Denis and Means (1916) appear to have been the first to observe the effect clinically, but they did not attach any significance to it; Cochran (1952), however, clearly demonstrated that salicylate is a powerful metabolic stimulant in man.The present study was to determine whether metabolic stimulation by sodium salicylate occurs only in the whole animal, or if it is also demonstrable in isolated tissue. METHODSThe 02 consumption of liver slices from CBA mice was determined by the direct method in Warburg respirometers at 370 C., according to the procedure of Dixon (1951). Glucose-phosphate-Ringer of pH 7.40 was used as medium. It was dispensed from double strength stock solutions and finally made up to volume in the Warburg flasks with water for the control tissues, or with a solution of sodium salicylate for the treated tissues.Sufficient slices were obtained from each mouse to determine in duplicate the control rate of 02 consumption, in c.mm. 02 at N.T.P./hr./mg. dry weight of tissue (Qo2), and that in the presence of sodium salicylate.Preliminary observations were made from a concentration of sodium salicylate of 10-5M upwards. Systematic observations were then made at eight concentrations found to affect the Qo2 of the liver slices; at each of these concentrations liver slices from sixteen mice, eight of each sex, were studied.The duration of the runs was 30 min.; readings were taken at 15-min. intervals. RESULTSFor each animal, the difference between the mean control and treated rates of 02 consumption (AQo2) was obtained by subtracting the Qo2 of the salicylate treated tissue from that of the control. Therefore increased rates of 02 uptake appear as positive quantities and decreased rates as negative.

Salsalate (Salicylate) Uncouples Mitochondria, Improves Glucose Homeostasis, and Reduces Liver Lipids Independent of AMPK-β1

“…Classic studies from the 1950s observed that salicylate stimulates mitochondrial uncoupling (53,59), and previous work established that mitochondrial Δψm is reduced by 1.0 mmol/L salicylate (54). Moreover, proton conductance is increased with 1.0 mmol/L salicylate treatment (present data and ref.…”

“…This is the first study to suggest that salicylate-driven mitochondrial uncoupling is the primary mechanism of action to explain the host of beneficial effects associated with salicylate (11,49,50) and salsalate (6)(7)(8)14,51,52). Data from the present study and previous investigations suggest that mitochondrial uncoupling resulting from the protonophoric properties of salicylate explains the consistently observed increases in energy expenditure in murine models and human subjects treated with salicylate-based compounds (6,10,11,14,15,(52)(53)(54)(55)(56)(57)(58).…”

“…This is the first study to suggest that salicylate-driven mitochondrial uncoupling is the primary mechanism of action to explain the host of beneficial effects associated with salicylate (11,49,50) and salsalate (6-8,14,51,52). Data from the present study and previous investigations suggest that mitochondrial uncoupling resulting from the protonophoric properties of salicylate explains the consistently observed increases in energy expenditure in murine models and human subjects treated with salicylate-based compounds (6,10,11,14,15,(52)(53)(54)(55)(56)(57)(58).Classic studies from the 1950s observed that salicylate stimulates mitochondrial uncoupling (53,59), and previous work established that mitochondrial Δψm is reduced by 1.0 mmol/L salicylate (54). Moreover, proton conductance is increased with 1.0 mmol/L salicylate treatment (present data and ref.…”

Salicylates and Thyroid Function. I. Depression of Thyroid Function

“…Decapitated or curarized dogs maintained in a total body respirator to keep ventilation constant showed the same increased oxygen consumption in response to salicylate administration as the intact animal (5). Furthermore, oxygen consumption has been shown to be increased in tissues removed from salicylatetreated animals (7) and in isolated tissue or mitochondrial preparations to which salicylates have been added (8,9). The increase in oxygen consumption is accompanied by a reduction in the esterification of inorganic phosphate, i.e., salicylates uncouple oxidative phosphorylation (7).…”

“…Basal metabolic rate is increased in the intact animal (10)(11)(12), tissue oxygen consumption is stimulated in slices (13), and oxidative phosphorylation is uncoupled in isolated mitochondrial preparations (14,15). Indeed, several authors have commented on the similarity of 2,4-dinitrophenol and salicylate (6,8,16).…”