Effect of combined administration of furosemide and aspirin on urinary urate excretion in man

Summary Furosemid (20 mg) was administered intravenously to 7 healthy volunteers, before and after 4 days of oral administration of aspirin in uricosuric dosage (1 g daily). Aspirin prevented the decrease in urinary urate excretion induced by furosemide, without interfering with its natriuretic action. This finding is suggested to be the result of the opposite and independent effects of the two drugs on tubular reabsorption of urate.     

Short lasting increase in urinary specific kallikrein activity during long term administration of furosemide

Furosemide was administered for seven days to normal rats. Urinary kallikrein excretion showed a biphasic response during the seven consecutive days of study. During the initial three days only the kininogenase activity showed a significant increase without any variation in the excretion of the immunoreactive kallikrein. The specific urinary kininogenase activity was therefore enhanced. After three days of furosemide administration, both the urinary kininogenase activity and urinary immunoreactive kallikrein were augmented. The urinary specific kininogenase activity was that time no more different when compared to the basal value. Considering the delay time of three days, this second part of the response could be a mineralocorticoid mediated effect. In this respect, kidney level of immunoreactive and kininogenase activity of kallikrein are also increased after seven days of furosemide administration. However the short lasting increase in urinary specific kininogenase activity observed during the initial three days is due to a change in the ratio active versus inactive kallikrein without any variation of total kallikrein. It is possible that this immediate response results of a direct effect of furosemide acting either on the preferential excretion of the active form or on the activation of the prokallikrein in the urine.     

Salivary kallikrein excretion in hypertension

Summary According to immunohistochemical investigations kallikrein in the majors salivary glands is located predominantly at the apical border of the striated duct cells and as a luminal rim in the main excretory ducts. Comparatively the highest concentrations are observed in the submandibular gland of rats and cats in the cytoplasmic granules of the granular tubules.In normal humans and rats the kallikrein activity of parotid saliva is inversely related to flow rate and sodium concentration. An increased salivary kallikrein concentration is found in human essential hypertension and renoparenchymal hypertension associated with impaired kidney function. Furthermore in rats with various forms of hypertension (genetic hypertension, DOCTMA salt and renovascular hypertension) the salivary kallikrein secretion — as determined by the BAEE-esterase activity — is enhanced. In contrast to the kallikrein secretion the flow dependent sodium concentration of parotid saliva is reduced in human essential and renoparenchymal hypertension as well as in rats with various forms of experimental and genetic hypertension, which indicates an enhanced sodium reabsorption in the glandular duct system. Furthermore in most forms of hypertension, there is a tendency of higher potassium levels in the saliva.The pathogenesis of the enhanced glandular kallikrein secretion in hypertension is discussed with regard to a counterregulatory mechanism in hypertension as well as to a sympathicoadrenergic activation. The enhanced sodium reabsorption in the duct system in the various forms of hypertension could be the cause as well as a consequence of the enhanced kallikrein secretion.Supported by the Deutsche Forschungsgemeinschaft SFB 92, Biomund     

Effect of metabolic alkalosis and metabolic acidosis on urinary kallikrein excretion of anaesthetized rats: evidence for a role of blood pH as regulator of renal kallikrein secretion

The effect of altering the acid-base status on urinary kallikrein excretion of barbiturate-anaesthetized rats was investigated. Alkalosis was induced in a group of rats by intravenous (i.v.) infusion of NaOH at 0.45 mmol ⋅h⁻¹ for 30 min. Acidosis was induced in two groups of rats by i.v. infusion of HCl at 1.5 mmol⋅h⁻¹ for 30 min (uncompensated acidosis) or 0.15 mmol⋅h⁻¹ for 3 h (compensated acidosis), respectively. Time controls received 0.45 mmol⋅h⁻¹ NaCl. Rats with alkalosis excreted less kallikrein than their controls (P < 0.05). Rats with uncompensated acidosis excreted more active kallikrein (P < 0.05), whereas rats with compensated acidosis excreted similar amounts when compared with their respective controls. In rats with uncompensated acid-base derangements, the urinary kallikrein excreted per millilitre of glomerular filtrate was correlated with blood H⁺ activity (r = 0.99, P < 0.01). Arterial blood pressure, haematocrit, glomerular filtration rate, urine flow rate and Na⁺ and K⁺ excretions of experimental and control animals did not differ. Thus, renal kallikrein secretion into the tubular fluid appears to be regulated by blood proton activity. This, along with our previous demonstration that kallikrein inhibits HCO₃ ⁻ secretion into the tubular lumen (Renal Physiol 17:301–306, 1994; J Physiol (Lond) 488:163–170, 1995), indicates that this enzyme is part of a feedback loop regulating acid-base balance. Received: 26 June 1995/Received after revision: 27 December 1995/Accepted: 8 January 1996     

Effects of orally administered glandular kallikrein on urinary kallikrein and prostaglandin excretion,plasma immunoreactive prostanoids and platelet aggregation in essential hypertension

Summary The effects of orally administered glandular kallikrein on urinary kallikrein, aldosterone and prostaglandin E (PGE) excretion, plasma renin activity (PRA), immunoreactive 6-keto PGF₁ and thromboxane B₂ concentrations and platelet aggregation were studied in 12 patients with essential hypertension (EH). After a 2-week control period, each patient was given orally 450 KU/day of hog glandular kallikrein for 8 weeks. Urinary kallikrein, aldosterone and PGE excretion, and plasma 6-keto PGF₁ and thromboxane B₂ concentrations were measured by radio-immunoassay. Platelet aggregation was measured by the addition of ADP, collagen or ristocetin with an aggregometer. Urinary kallikrein excretion and plasma 6-keto PGF₁ concentration were significantly decreased in patients with EH. There were no significant differences in PRA, urinary aldosterone excretion and plasma thromboxane B₂ concentrations between control subjects and patients with EH. There was a significant decrease in blood pressure in patients with EH coinciding with significant increases of urinary kallikrein and PGE excretion and plasma immunoreactive 6-keto PGF₁ concentration after administration of glandular kallikrein. There was also a significant inhibition of platelet aggregation induced by collagen in these patients. Thus, a suppression of the kallikrein-kinin-prostaglandin system in patients with EH was found, and a decrease in blood pressure with an increment of urinary kallikrein, PGE excretion, plasma immunoreactive 6-keto PGF₁ and inhibition of platelet aggregation in vivo by the administration of glandular kallikrein.Abbreviations BK bradikinin - EH essential hypertension - KU kallikrein unit - PG prostaglandin - PRA plasma renin activity - PRP platelet rich plasma - TX thromboxane Presented at IXth European Congress of Cardiology Düsseldorf, July 8–12, 1984     

The relationship between kallikrein and water excretion and the conditional relationship between kallikrein and sodium excretion.

1. The renal kallikrein-kinin system has previously been linked with renal control of sodium and water excretion. The present investigations were carried out to examine more closely these relationships. 2. In physiological studies with rabbits, urinary kallikrein was measured by a modification of the [3-H]TAME method. 3. With rabbits on free sodium and water intake, urinary kallikrein was positively correlated with both sodium and water excretion. Kallikrein excretion was also negatively correlated with urinary osmolality. 4. In rabbits on chronic high and low sodium diets, urinary kallikrein was positively correlated with urinary volume but not with sodium excretion. 5. In rabbits held to a constant fluid intake but with sodium intake changed, urinary kallikrein was not correlated with sodium excretion. 6. These results indicate that the positive correlation of kallikrein excretion with sodium excretion under conditions of free sodium and water intake may be only secondary to the positive relationship of kallikrein excretion with urinary volume. 7. The results of the present investigations do not support the hypothesis that the renal kallikrein-kinin system is necessarily involved in renal control of sodium excretion under normal conditions but it is where a change in sodium intake leads to a change in fluid intake and consequently of urinary volume. 8. In the above experiments, urinary kallikrein was always positively correlated with urinary volume and negatively correlated with urinary osmolality. This may indicate a functional relationship between renal kallikrein and water excretion.     

Different effects of furosemide on urinary excretion of prostaglandin E2 and F2 alpha in rabbits.

The effect of a constant infusion of furosemide (130 micrograms/min i.v. for 60 min, n = 8) was studied on urinary excretion of water, electrolytes and immunoreactive prostaglandin E2 (iPGE2) and iPGF2alpha in chloralose-urethane anesthetized rabbits. During the furosemide infusion sodium and water excretion increased ten-fold and the excretion of potassium and iPGE2 two to three times. The excretion of iPGF2alpha (0.06 +/- 0.03 micrograms/min/100 g kidney weight) was not significantly changed during the furosemide infusion but increased markedly after the infusion and reached a maximum (1.0 +/- 0.6 microgram/min/100 g) 30 to 45 min later, while the small increase in iPGE2 excretion at this time could be attributed to cross-reaction with PGF2alpha. The results indicate that PGE2 might possibly be involved directly in the action of furosemide, while PGF2alpha might participate in sodium and water conserving mechanisms in the rabbit kidney, activated by the drug induced diuresis.     

Effect of chronic furosemide administration on hydrogen and sodium excretion in the dog.

Studies were performed to evaluate the effects of the chronic administration of furosemide on hydrogen and electrolyte excretion in dogs on a normal electrolyte diet and in the absence of electrolyte or volume depletion. Control daily excretion in five dogs averaged 64 meq for Na, 51 meq for K, 66 meq for Cl, and 17 meq for net H. Furosemide, 40 mg, in the drinking water 3 times daily was given for 4 days. On day 1 Na excretion averaged 128 meq, but thereafter was not significantly different from control levels. Over 4 days cumulative net H excretion increased 63.6 meq and plasma HCO3 rose 6.6 meq/liter. The same dogs were restudied by the same protocol except that, to obviate electrolyte depletion, NaCl and KCl were administered daily in quantities sufficient to replace urinary losses. All dogs remained in positive Na, K, and Cl balance. Body weight, hematocrit, plasma albumin, creatinine, and plasma renin activity were unchanged, indicating the absence of electrolyte or volume depletion. Nonetheless, cumulative net H excretion increased 61.2 meq and plasma HCO3 increased 4.3 meq/liter. Two adrenalectomized dogs receiving steroid replacement showed similar changes in net H excretion and plasma HCO3. These experiments suggest that chronic furosemide administration may enhance H excretion and generate alkalosis even in the absence of volume or electrolyte depletion and without increased aldosterone secretion.     

Orthostatic response of plasma renin activity and urinary kallikrein excretion in children with difficulty awakening in the morning

Twenty-six children, aged 10-15 years, with difficulty awakening in the morning, showed significantly lower plasma renin activity (PRA) before and after standing (15 and 60 min) and significantly greater postural fall in mean blood pressure than the age-matched control children. They also showed high urinary kallikrein excretion, but this was not statistically significant. These results suggest that low PRA and a readily decreasing blood pressure may contribute to difficulty awakening in the morning in teen-aged children.