Potent Diuretic Research Articles

Discovery and Therapeutic Utility of Vasopressin Antagonists in Rats

Vasopressin is the primary physiological factor regulating renal water reabsorption in mammals. Inhibitors of vasopressin-stimulated water reabsorption have previously been used as water diuretic agents in both experimental animals and man. The present studies describe and characterize the pharmacological effects of the potent vasopressin antagonist desGly d(CH2)5D-Tyr(Et)VAVP (SK&F 101926) and related analogs on renal water and solute excretion in conscious rats. Administration of SK&F 101926 was associated with dose-dependent increases in renal water excretion in conscious hydropenic rats. A selective vasopressin pressor (V1) antagonist (SK&F 100273) was inactive as a diuretic agent in these tests. SK&F 101926 antagonized, in a competitive fashion, exogenous vasopressin-stimulated antidiuresis in conscious water-loaded rats. Only modest increases in renal excretion of Na+, K+, and urea were observed when SK&F 101926 was administered. No changes in endogenous creatinine excretion were associated with the administration of SK&F 101926, suggesting that this drug does not affect glomerular filtration rate. The rank order of bioequivalency of alternative routes of administration of SK&F 101926 was intraperitoneal = intravenous = intramuscular = subcutaneous greater than intranasal much greater than rectal, ocular, and oral. SK&F 101926 (20 micrograms/kg/day) was effective in blocking the development of hyponatremia in a rat model of the syndrome of inappropriate antidiuretic hormone (SIADH). SK&F 100273 (100 micrograms/kg) hastened the onset of endotoxin-associated shock in rats. We conclude that SK&F 101926 is a potent water diuretic (aquaretic) agent in rats. The mechanism of action is most probably antagonism of vasopressin at renal epithelial (V2) receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of potassium canrenoate on kinins and renin in rats

Frusemide (F) is a potent natriuretic and diuretic that acts mainly on the luminal side of the ascending loop of Henle (Schlatter et al. (1983) Pflug. Arch. 396: 210–217). F increases the urinary excretion of prostaglandin (PG) E (Mackay et al. (1984) Contr. Nephrol. 41: 160–162) and its diuretic and natriuretic effects are blunted by indomethacin, suggesting that PGs are involved in the cellular action of this drug (Chennavasin et al. (1980) J. Pharmacol. Exp. Ther. 215: 77–81; Waller et al. (1987) Arch. Pharmacodyn. Ther. 290: 145–150). Several investigators have shown a rapid but short-lived rise in urinary kallikrein (UK) excretion after F administration in man, which could represent a ‘wash-out’ phenomenon rather than indicating a direct involvement of the kallikrein-kinin system (KKS) in mediating the action of F (Zschiedrich et al. (1979) Clin. Sci. 57: 247–250; Waller et al. (1987); Waller et al. (1990) Clin. Sci. 79:117–121). However, using a mouse model, 5 days treatment with F has been shown to stimulate renal cortical tubular messenger RNA for tissue kallikrein (Penchow and Coghlan (1994) J. Hypertension 12 (Suppl. 3): 887). Urinary excretion of the components of the KKS is believed to reflect the intra-renal activity of the system (Bhoola et al. (1992) Am. Soc. Pharmacol. Exp. Ther. 44: 1–80) Therefore, if the KKS is directly involved in the natriuretic action of F, a dose-related release of the active components of the system would be expected. This study was designed to examine the effect of three intravenous (i.v.) doses of F on the urinary excretion of components of the renal KKS and the relationships of these components with the excretion of water, electrolytes and F.

Failure of indomethacin to impair the diuretic and natriuretic effects of the loop diuretic torasemide in healthy volunteers.

The effects of torasemide, a new potent loop diuretic, on renin release, water and sodium excretion were investigated in young healthy volunteers before and after 3 days of treatment with indomethacin. Torasemide 20 mg i.v. induced a rapid and biphasic increase both in plasma renin activity and plasma angiotensin II levels, which was almost completely abolished by pretreatment with indomethacin. Torasemide also increased urine volume, sodium excretion and, during the first hour after dosing, the creatinine clearance. None of the latter effects was impaired by indomethacin pretreatment. It is concluded that, like other loop diuretics, torasemide stimulates renin release by increasing renal prostaglandin production. However, at variance with what is observed with other loop diuretics, the diuretic and natriuretic effects of torasemide as well as the change in creatinine clearance do not appear to be inhibited by indomethacin.

Sodium and hypertension. Still a controversy in 1986.

Interpopulation studies support the hypothesis of a causal relationship between sodium consumption and arterial hypertension. However, although this association has been contradicted by intrapopulation studies, the correlation between sodium and hypertension appears to be genetically determined, as there are both sodium-sensitive and sodium-resistant individuals. Sodium is essential for the maintenance of extracellular and plasma volume equilibrium. It is controlled metabolically by the interaction of several biological systems such as the renin-angiotensin-aldosterone system, the sympathetic nervous system and the kallikrein-kinin and prostaglandin systems. Thus, sodium has a definite role in the mechanism involved in the pathophysiology of the predominantly volume-dependent forms of arterial hypertension. Recently, different structural substances with natriuretic effects have been identified. Natriuretic hormone is a non-peptide substance which inhibits the Na,K-ATPase in response to extracellular volume increase. This hormone acts on the renal tubular cells reducing sodium reabsorption, and at an arteriolar level elevating peripheral resistance by increasing smooth muscle tension. Mammalian atria contain various precursors of biologically active peptides, with potent natriuretic and diuretic effects. They are released in response to volume loading and atrial stretch. Although some data suggest an important role for these natriuretic substances in fluid volume and blood pressure control, their place in physiology and in abnormal clinical states should be more definitively clarified in the next few years.

Atrial natriuretic factor inhibits vasotocin-induced water reabsorption in the toad urinary bladder.

Peptides recently isolated from atrial extracts possess potent natriuretic and diuretic activities, which are thought to be due to hemodynamic actions, such as increased glomerular filtration or altered medullary blood flow. A direct tubular site of action cannot be ruled out; therefore we have examined the effect of one of these peptides, atriopeptin III on vasotocin-induced water absorption in the toad urinary bladder. Our results indicate that equimolar doses (10(-12) to 10(-11) M) of atriopeptin III can significantly inhibit vasotocin-induced water reabsorption in vitro and suggest a physiologic role for the cardiac peptides to alter water reabsorption directly at the level of the tubules or collecting ducts, independent of any hemodynamic effects they might also exert in vivo.

Main forms of immunoreactive cardionatrin in atrial extracts and in atrial-specific granules

Several laboratories have reported the isolation and amino acid sequence of peptides from mammalian atria which are potent diuretic, natriuretic and vasodilatory agents (Flynn et al., 1983; Seidah et al., 1984; Atlas et a/., 1984; Currie et al., 1984; Kangawa & Matsuo, 1984; Misono et al., 1984). All of the peptides sequenced so far are either extended or truncated versions of a 28 residue disulphide-looped structure (cardionatrin I), whose sequence was reported initially from this laboratory (Flynn et al., 1983). It has now been shown that these biologically active peptides derive from the C-terminal region of a common precursor (procardionatrin or proatrialnatriuretic factor) whose structure was determined by cDNA sequencing (Yamanaka eC al., 1984; Maki et al., 1984; Oikawa et al., 1984; Seidmann et al., 1984; Flynn et al., 1985). It remains to be established which of the various peptides isolated to date are the natural cleavage products of the pro-protein. Using extraction conditions known to inhibit proteolysis (Bennett et al., 1981) we have not found the multitude of different peptides reported by other laboratories (Currie et al., 1984; Seidah et al., 1984). Frozen rat atria were ground with solid COz chips and homogenized in 1Ovol. of 1 .O M-acetic acid/l .O M-HCI/I% (w/v) NaCl. After centrifugation of the extracts the supernatants were passed through pre-wetted Sep-Pak (Waters) cartridges. Each cartridge was washed with 0.1% (v/v) trifluoroacetic acid (TFA) and eluted with 3ml of 80% (v/v) acetonitrile in 0.1% TFA. The combined cartridge eluates were freezedried, dissolved in 5 ml of 1.0111-acetic acid/l% (w/v) NaCl and fractionated on a Biol-Gel P10 column using the same solution. The fraction pools indicated by the bars in Fig. 1 contained diuretic and natriuretic activity when assayed by the procedure of de Bold (1982). These fraction pools were then further processed by reverse-phase h.p.l.c., as recently described (Flynn et al., 1985). This procedure showed that each of the areas of activity denoted in Fig. 1 contained a single peptide. Each of these peptides was then subjected to protein sequencing with an Applied Biosystems Gas Phase Model A70A Sequencer. The sequence of the peptide purified by reverse-phase h.p.1.c. from the area corresponding to CI in Fig. 1 was that of cardionatrin I (residues 123-150 of the pro-protein) sequenced previously by us (Flynn et al., 1983). The sequence of CII could not be determined because insufficient amounts were present. Amino acid sequence determination of CIII located the N-terminus of this peptide at position 73 of the pro-protein. The N-terminal sequence of CIV begins at Asp-25, which is the cleavage point for the removal of the signal sequence. Amino acid compositional analysis of CIII and CIV indicated that these peptides, like cardionatrin I , extend up to and include Tyr-150. Cardionatrin IV, therefore, is procardionatrin (proatrialnatriuretic factor) minus the two terminal arginine residues. Thus, four peptides, CIV and three others all derived from CIV, are the only peptides present in acid extracts of atrial muscle. When the fractions obtained in Fig. 1 were assayed by a

Atrial natriuretic factor inhibits dehydration- and angiotensin II-induced water intake in the conscious, unrestrained rat.

Peptides isolated from atrial extracts possess potent natriuretic and diuretic activities. In general, these peptides, called atrial natriuretic factors (ANFs), oppose the actions of the water-conservatory peptides angiotensin II and vasopressin and are released from the heart in response to atrial stretch as a consequence of increased venous return. The recent description of ANF-like immunoreactivity in brain regions associated with the control of water intake suggested a role for these peptides in the neurogenic mechanisms of thirst. Intracerebroventricular (third ventricle) infusion of 1.0 or 2.0 nmol of ANF in conscious, overnight-dehydrated rats significantly inhibited subsequent water intake over a 2-hr test period. Intravenous infusion of 2.0 nmol, but not 1.0 nmol, of ANF resulted in a similar inhibitory action, suggesting that ANF released from the heart might act centrally to inhibit water intake by an action at one or more of the circumventricular organs. Water intake induced by central infusion of angiotensin II (9.6 and 25 pmol) in normally hydrated rats was significantly inhibited by prior infusion of 2.0 nmol of ANF. Water intake induced by higher doses of angiotensin II was not altered significantly by prior infusion of ANF. These results indicate a possible physiologic role for ANF in the hypothalamic control of water intake and reveal that the cardiac peptides can act centrally, as well as peripherally, to assist in the normalization of extracellular fluid volume.

Lack of effect of synthetic atrial natriuretic factor on rubidium uptake by human erythrocytes

The effect of synthetic atrial natriuretic factor on the ouabain-sensitive and the furosemide-sensitive rubidium uptake by human erythrocytes has been studied. This peptide with potent diuretic and natriuretic effects did not affect any rubidium uptake system at concentrations of 10 −7 and 10 −9 M. These results do not support that the natriuretic effect is based on the inhibition of active transport systems in the renal tubules.

Pharmacology and Pharmacokinetics of Drugs Used to Treat Cardiac Disease in Horses

The rational therapy of cardiovascular disease in horses requires a thorough knowledge of the pharmacology and pharmacokinetics of several specific drugs (digitalis, digoxin). Calcium solutions, dopamine, and dobutamine are frequently used to treat congestive heart failure in horses. Quinidine, procainamide, lidocaine, and propranolol are used to treat a variety of supraventricular and ventricular arrhythmias. Furosemide, a highly potent loop diuretic, is used to eliminate edema and promote diuresis. A thorough understanding of the applied pharmacology, dosage recommendations, toxicity, and practical considerations must be attained before these drugs can be used effectively.

Nonoliguric acute renal failure.

Oliguria has been considered a cardinal feature of acute renal failure. However, many recent reports indicate that acute renal failure usually occurs in the setting of well-maintained urine output. Moreover, the nonoliguric state may accompany acute renal failure due to pre- and post-renal azotemia and a variety of renal parenchymal disorders, as well as acute tubular necrosis. Most studies indicate that nonoliguric forms of acute renal failure are associated with less morbidity and mortality than oliguric acute renal failure. Uncontrolled studies also suggest that volume expansion, potent diuretic agents, and renal vasodilators can convert oliguric to nonoliguric acute tubular necrosis if administered early in the course of acute renal failure. However, prospective studies of early intervention in oliguric patients are needed.

STUDY TO DETERMINE RELATIVE HYPERURICAEMIC EFFECTS OF THE DIURETIC DRUGS BUMETANIDE AND FRUSEMIDE: 46

The aim of this study was to see whether bumetanide had less hyperuricaemic effect that frusemide, using doses of equal diuretic potency.Thirty adult patients who required diuretic therapy had plasma and urinary urate estimations and plasma sodium and potassium measurements performed on a low purine diet.They were then given either bumetanide or frusemide in doses of equal diuretic potency and urate, sodium and potassium levels were measured over the months that followed.Both drugs caused hyperuricaemia and there was no significant difference between bumetanide and frusemide in their hyperuricaemic effects (p>0.05).

Piretanide. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy.

Piretanide is a potent 'loop' diuretic whose principal site of action is in the thick ascending limb of the loop of Henle. When administered orally or intravenously to healthy volunteers it rapidly increases diuresis and electrolyte excretion, and the effects are short-lived. In comparative studies, piretanide has generally been found to be 5 to 7 times more potent than frusemide (furosemide) but only one-tenth as potent as bumetanide, on a weight-for-weight basis. Piretanide 6 to 12 mg/day, in conventional or sustained release formulations, has been shown to significantly lower elevated blood pressure in a large proportion of patients with mild to moderate hypertension. Comparative trials of up to 3 months duration indicate that at this dosage piretanide is of comparable antihypertensive efficacy as hydrochlorothiazide 50 to 100 mg/day, but has significantly less effect on serum potassium levels. Short term studies in patients with oedema caused by renal, hepatic or cardiac failure demonstrated that piretanide 6 to 9 mg is of similar diuretic potency as frusemide 40 mg and bumetanide 1 mg. In medium term trials in patients with congestive heart failure piretanide 6 mg/day produced equivalent symptomatic improvement as frusemide 40 mg/day. When used to treat oedema caused by liver disease, piretanide 12 to 24 mg/day was successful in only about 50% of patients, but spironolactone added to the treatment regimen greatly increased the response rate. Generally, piretanide has been well-tolerated in clinical trials, although the conventional tablet formulation has caused a relatively high incidence of acute adverse effects--these were greatly reduced with the introduction of the sustained release formulation. Serum concentrations of most electrolytes have not shown any consistent adverse trends and hyperuricaemia and hypokalaemia have been encountered infrequently. Thus, piretanide appears to offer an effective alternative to other 'loop' diuretics for the treatment of oedematous diseases and to hydrochlorothiazide for the management of mild to moderate hypertension. However, its relative place in therapy remains to be clarified with wider clinical experience.

ChemInform Abstract: ((AMINOMETHYL)ARYLOXY)ACETIC ACID ESTERS. A NEW CLASS OF HIGH‐CEILING DIURETICS. 3. VARIATION IN THE BRIDGE BETWEEN THE AROMATIC RINGS TO COMPLETE MAPPING OF THE RECEPTOR

AbstractSynthetisiert und auf saluretische Eigenschaften untersucht werden die Verbindungen (IV) und (V).

Atrial natriuretic factor

Mammalian atria contain different peptides with potent diuretic, natriuretic, smooth muscle relaxing and blood pressure lowering properties. A preprohormone of these peptides is synthetized and stored in specific granules in atrial myocytes. Different peptides have been isolated, analyzed and in vitro synthetized. Their biological activity indicates a potential role in the regulation of volume and sodium homeostasis as well as in blood pressure regulation.

(Aminomethyl)arloxy]acetic acid esters. A new class of high-ceiling diuretics. 3. Variation in the bridge between the aromatic rings to complete mapping of the receptor.

Continued structural evaluation of the [(aminomethyl)aryloxy]acetic ester diuretics has produced a series of compounds in which the functional group that bridges the two aromatic rings has been varied. Diuretic screening of these analogues in rats indicates that the keto group can be effectively replaced with an ether or thio ether function with a slight increase in potency, whereas the methylene and sulfoxide linking groups lead to diminished saluretic potency. Replacement with either -SO2-, -COCO-, -CH2O-, -CONH- or direct bond results in a loss of activity. Although the series was designed according to QSAR criteria, the traditional linear free-energy properties of these compounds do not correlate with diuretic potency. However, conformational analysis of the series by potential energy calculations indicates that all active compounds have an accessible conformation that matches the bridge atom-carboxylate distance of the very potent dihydrobenzofuran analogue 56. Conformational calculations of several compounds in which the aminomethyl group was varied suggests that the active conformation is probably a low-energy conformation. Consideration of rotation about the bridge could not distinguish between two possible orientations of the aminomethyl ring in the active conformation. However, there is a quantitative negative linear correlation between diuretic potency and the protrusion into space of the group that bridges the two aromatic rings.

Protection by magnesium of renal calcinosis in furosemide-treated weanling rats with moderate magnesium deficiency.

Prolonged treatment of premature infants with the potent diuretic furosemide has resulted in hypercalciuria, sometimes with renal calcinosis and other complications. Furosemide was administered to weanling rats to explore its effect on magnesium and calcium metabolism. The animals were fed purified diets providing 40 mg magnesium/100 g diet or 10 mg magnesium/100 g. Half of each dietary group (40-F or 10-F) received 18 doses of furosemide, 20 mg/kg body weight, intraperitoneally between days 7 and 35, and half received normal saline intraperitoneally (40-O or 10-O). Furosemide had little effect on the magnesium-sufficient animals (40-F), but comparison of 10-O and 10-F data showed that it aggravated the magnesium-deficiency syndrome. Comparison of data from 40-F and 10-F animals showed the protective effect of magnesium in preserving calcium homeostasis in furosemide-treated animals: the elevation of calcium values in 10-F rats was greater in plasma (p less than 0.0005), heart (p less than 0.0025), and kidney (p less than 0.0005). Stated another way, furosemide was associated with severely disordered calcium metabolism only in animals fed suboptimal magnesium. Studies exploring the role of magnesium in furosemide-treated infants can be recommended.

L'échangeur Na +/H + des cellules eucaryotes : Propriétés biochimiques et pharmacologiques, rôle physiologique

A membrane mechanism that catalyses the electroneutral exchange of Na+ for H+ has recently been characterized in a variety of eukaryotic cells. This exchanger is inhibited by amiloride, a potent diuretic drug. It has been implicated in a number of important physiological processes such as the regulation of the intracellular pH, the reabsorption of Na+ by the renal proximal tubule, the regulation of the cell volume and the fertilization of the sea urchin egg. The Na+/H+ exchanger seems able to mediate the action of growth factors. The biochemical and pharmacological properties of the Na+/H+ exchange system are reviewed. They are very similar in the different cell types that have been studied. Yet the Na+/H+ exchange system can fulfil different functions in different cell types depending i) on its properties of interaction with intracellular H+, ii) on the presence of other membrane structures that are involved in the maintenance of transmembrane Na+ and H+ gradients and iii) on the presence of extracellular messages that modify its catalytic properties and, among them, its interaction with internal H+.

Furosemide inhibits glucose transport in isolated rat adipocytes via direct inactivation of carrier proteins.

Furosemide inhibits 3-O-methyl-D-glucose equilibrium flux in isolated adipocytes. The inhibition is saturable with an increasing concentration of furosemide and shows a noncompetitive type of kinetics. Both basal and insulin-stimulated fluxes are equally affected by the inhibition. Hydrochlorothiazide and piretanide also inhibit the flux with a similar potency, whereas bumetanide, a more potent diuretic, is much less potent. To understand the molecular basis of this inhibition, effects of furosemide on the glucose-sensitive cytochaslasin B binding activities of adipocytes were studied. Furosemide inhibits the glucose-sensitive cytochalasin B binding of both microsomal and plasma membrane preparations. For both preparations, the inhibition is time dependent and only slowly reversible, is saturable with an increasing concentration of furosemide, shows a noncompetitive type of kinetics with apparent Ki (the inhibitor concentration that gives the half-maximum effect) of 3.5 and 0.7 mM after 2 and 18 h incubation, respectively, and is essentially identical between the basal and insulin-stimulated adipocytes. The inhibition develops with a first-order rate constant of approximately 0.12/h at 4 degrees C. These results indicate that furosemide inhibits glucose transport in adipocytes by directly inactivating transport carriers of both plasma membranes and microsomal reserve pool. This inactivation of glucose carrier may play a part in the diuretic-induced glucose intolerance frequently observed during diuretic therapy.

Synthesis and renal activity of rat atrial granules depend on extracellular volume.

Extracellular fluid volume (by 22Na) and extent of 4-h [3H]fucose incorporation into atrial-specific granules were measured in deoxycorticosterone acetate (DOCA)/salt-loaded or Na-deficient rats. The natriuretic potency of extracts from their atria was also measured in assay rats. DOCA/salt-treated animals had a significantly greater extracellular volume, a significantly greater degree of fucose uptake, and a significantly more potent diuretic and natriuretic effect than did Na-deficient rats. These observations, together with the known decrease in atrial granularity with DOCA treatment, suggest that a chronic increase in extracellular fluid volume is associated with increased synthesis and metabolism of atrial natriuretic factor. They also confirm the finding reported by others that granularity and natriuretic potency are not always directly related. It may be that visible granules represent a peptide storage form that requires further processing to become natriuretic.

Effect of native and synthetic atrial natriuretic factor on cyclic GMP

Mammalian atrial cardiocyte granules contain a potent natriuretic and diuretic peptide. Since cGMP appears to be involved in the modulation of cholinergic and toxin-induced sodium transport, we examined the effect of atrial natriuretic factor (ANF) on this nucleotide. Atrial but not ventricular extracts elicited approximately a 28-fold increase of urinary cGMP excretion parallel to the natriuresis and diuresis. The atrial extracts also elevated cGMP levels in kidney slices and primary cultures of renal tubular cells. The effect of ANF on cGMP appeared to be specific since antibodies which were capable of inhibiting the ANF-induced diuresis also suppressed cGMP excretion. Furthermore, during the course of ANF purification, the ANF-induced increase of cGMP production by kidney cells paralleled the heightened specific natriuretic activity of the atrial factor. A synthetic peptide (8–33)-ANF similarly increased urinary plasma and kidney tubular cGMP levels. The exact mechanism of action of ANF on cGMP remains to be elucidated, but indirect inhibition of cGMP phosphodiesterase appears to participate in its effect.