Carbenoxolone is a derivative of glycyrrhetinic acid used for the treatment of peptic ulcer and gastritis, with salt and water retention a very common side-effect. To investigate this drug-induced pseudohyperaldosteronism we have studied 6 male volunteers before, during and after treatment with carbenoxolone for 7 days. Serum, urinary and sweat electrolytes values were consistent with a mineralocorticoid-like effect of drug administration. PRA was suppressed, and plasma cortisol and aldosterone progressively decreased over treatment. We have also determined by radioreceptor assay the plasma levels of factors which bind to mineralocorticoid receptors in rat kidney cytosol. The levels of these factors were decreased significantly at day 3 of treatment, suggesting a local renal effect of carbenoxolone to amplify endogenous steroid action. At day 7 the radioreceptor assay values were still decreased but significantly higher than at day 3, suggesting in addition a direct mineralocorticoid effect of the drug. We conclude that the drug is initially effective by amplifying the effect of endogenous steroids, and then when the plasma concentrations of the drug or its metabolites reach a higher plasma concentration, there may also be in addition a direct mineralocorticoid-like effect.
1 The effects ofenalapril, an angiotensin converting enzyme (ACE) inhibitor, on maternal and foetal blood pressure, heart rate and components ofthe renin-angiotensin-aldosterone system were studied in 9 chronically-cannulated pregnant ewes and their foetuses.2 Six ewes received 1 mg kg-' enalapril i.v. while 3 were given 2mg kg-'.Although the initial fall in blood pressure was slightly greater in the higher dose group, there was substantial overlap of data. The pressor response to angiotensin I, assessing ACE activity, was abolished within 10 min of administration, and did not recover during 3 h of observation. Maternal systolic and diastolic pressures reached a nadir 90min after administration (P<0.001, P<0.002 respectively). The maximum tachycardia was seen at 60 min (P<0.05). 3 The foetuses of the ewes given 1 mg kg-enalapril showed no change in systolic or diastolic blood pressure or heart rate. Those of the ewes given the higher dose showed late-onset hypotension, coincident with the lowest maternal blood pressures. 4 Maternal plasma renin concentration (PRC) had risen significantly by 30 min (P < 0.02), reaching a maximum at approximately 90 min. Maternal plasma angiotensin II and aldosterone concentrations both fell initially (P <0.05) but were almost at basal levels by the end of the experiment. 5 Foetal plasma renin, angiotensin II and aldosterone concentrations were unchanged throughout the experiment. 6 Peak values of enaprilic acid, the active principle, were recorded in maternal plasma 65-90 min after administration of I mg kg-', and 25-30 min after the administration of 2mg kg-'. A trace amount of the active principle was recorded in the foetal plasma of one lamb, whose mother had been given the higher dose. None was recorded in the plasma from three other lambs. 7 Maternal plasma ACE concentrations fell by an average of 84%; in 4 of the 6 ewes in which concentrations were measured they were undetectable after treatment. Foetal plasma ACE concentrations were unchanged throughout. 8 Enalapril at I mg kg-' thus exerts a depressor effect on the pregnant ewe which is probably related to its blockade of the renin-angiotensin system. Both direct measurement of the drug and foetal observation suggest that it does not cross the sheep placenta at this dose. This is consistent with its failure to cross the blood-brain barrier. Foetal effects were noted at 2 mg kg-', and there was an unexpected foetal death in this group.
Summary Plasma renin substrate concentration was measured in 18, four‐day‐old pony foals after the administration of the natriuretic agent frusemide. Thirteen foals had been delivered spontaneously; labour had been induced in the remaining five mares. Plasma aldosterone concentration was measured in 12 of the spontaneously delivered foals. Renin substrate concentration had risen sharply within 15 mins (P<0.005) and peaked at 1 h. The response was consistently greater in the induced foals. Serum sodium concentration fell rapidly in the induced foals (P<0.002 by 60 mins) but was better maintained in the spontaneous group. Individual serum potassium concentrations varied widely and were higher in both the induced group and smaller (30 kg or less) spontaneous foals. Plasma renin substrate concentration was positively correlated with plasma potassium in both groups (P<0.05, P<0.001 respectively). Plasma aldosterone rose significantly within 30 mins (P<0.025) and did not stabilise during the experiment. Plasma aldosterone was significantly correlated with renin substrate concentration in both lighter (P<0.005) and heavier (P<0.05) spontaneously delivered foals. It is suggested that maturation of renal sodium and potassium handling occurs late in gestation in the foal and is in part related to body mass. ‘Premature’ delivery following induced labour is associated with a more rapid loss of sodium when challenged with frusemide, even though the response of the renin‐angiotensin system may be exaggerated.
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