Potent Diuretic Research Articles

Na+,2Cl−,K+ cotransport system as a marker of antihypertensive activity of new torasemide derivatives

A series of compounds related to torasemide, a loop diuretic, were synthesized and examined for their diuretic potency and inhibitory activity on the erythrocyte and renal medullary thick ascending limb vesicle Na+,2Cl−,K+ cotransport in Milan hypertensive (MHS) and normotensive (MNS) rat strains, where previous studies had demonstrated an alteration of the cotransport system genetically related to hypertension. From the results of the screening, structure-activity relationships were drawn and two compounds, JDL 961 and C 2921 were selected. Their IC50 on renal vesicle cotransport were similar in the two strains (JDL 961: MHS = 1.8 μM; MNS = 1.2 μM; C 2921: MHS = 4 μM; MNS = 3.8 μM), and were 4–8 times lower than those of torasemide (MHS = 13 μM; MNS = 31 μM, P < 0.01) and 50–60 times lower than those of bumetanide (MHS = 145 μM; MNS = 206 μM, P < 0.05) taken as reference compounds. Their ability to reduce the development rate of hypertension was tested both in MHS and in Okamoto spontaneously hypertensive rats (SHR) strain, in which cotransport alterations are opposite to those of MHS. Both torasemide derivatives (7.5 mg·kg−1 os per day) prevented development of hypertension in the two strains. The time course of this hypotensive activity was faster and the percentage of blood pressure fall greater in MHS (20–25%) than in SHR rats (12–15%), even though the absolute value of blood pressure fall was similar in MHS (JDL 961 = −17 mm Hg; C 2921 = −30 mm Hg) and SHR (JDL 961 = −25 mm Hg; C 2921 = −20 mm Hg). A superimposable effect of bumentanide was observed in the two strains, but at 8 times higher daily dose (60 mg·kg−1). These results suggest that new loop diuretics can be selected for their antihypertensive activity on the basis of their in vitro potency in inhibiting the Na+,2Cl−,K+.

Liver transplantation in the management of bleeding oesophageal varices

The vast majority of patients who require liver transplants have significant portal venous hypertension, and their liver replacement is specifically aimed to treat three major complications of portal hypertension, namely, bleeding oesophageal varices, refractory ascites and encephalopathy (liver failure). Variceal haemorrhage and ascites can be treated effectively by various types of portal decompression surgery, but these procedures invariably decrease hepatic blood flow and hence worsen the function of an already compromised liver. The enthusiasm for treating oesophageal varices and ascites with non-selective portosystemic shunting started to wane more than two decades ago when it became apparent that the price of preventing haemorrhage from oesophageal varices and intractable ascites in this manner was dehumanizing encephalopathy and progressive hepatic dysfunction (Jackson et al, 1971; Resnick et al, 1974). With the development of potent and specific diuretic drugs, truly intractable ascites is extremely uncommon. When it does occur, more appropriate therapy than portosystemic shunt will often be a peritoneojugular shunt. Chronic hepatic encephalopathy can rarely be managed by medical means, and it is effectively treated only with liver transplantation. Thus, the principal problem in portal hypertension for which therapeutic planning must be done is the haemorrhage from oesophageal varices. Prophylactic and therapeutic uses of anti-P-adrenergic agents and endoscopic sclerotherapy play a significant role in the management of oesophageal varices. Various types of portosystemicvenous shunting have been evaluated as to their efficacy in preventing both haemorrhage from varices and accelerated decline of hepatic function. In our centre, where there is a chronic shortage of organs, Child’s A patients who have had variceal bleeding are systemically screened for selective splenorenal shunts, performed electively. The procedure is being used on a trial basis because it is attended by a lower incidence of encephalopathy than is seen after non-selective shunts. Forty patients have been entered with no perioperative deaths but longer follow-up will be necessary to assess the validity of this approach. Five of the 40 have come to successful transplantation during the first 12 months after their Warren

Effect of Inhaled Furosemide and Torasemide on Bronchial Response to Ultrasonically Nebulized Distilled Water in Asthmatic Subjects

Inhaled furosemide has been shown to reduce the bronchoconstriction induced by several indirect stimuli, including ultrasonically nebulized distilled water (UNDW). Because the protective effect could be due to the inhibition of the Na(+)-2Cl(-)-K+ cotransport system of bronchial epithelium, we have compared the protective effect of inhaled furosemide with that of inhaled torasemide, a new and more potent loop diuretic, on UNDW-induced bronchoconstriction in a group of 12 asthmatic subjects. UNDW challenge was performed by constructing a stimulus-response curve with five increasing volume outputs of distilled water (from 0.5 to 5.2 ml/min) and the bronchial response expressed as the provocative output causing a 20% fall in FEV1 (PO20UNDW). On different days, each subject inhaled an equal dose (28 mg) of furosemide and torasemide in a randomized, double-blind, placebo-controlled study 5 min prior to an UNDW challenge. Furosemide and torasemide had no significant effect on resting lung function. The geometric mean value of PO20UNDW measured after placebo was 1.73 ml/min. This was significantly lower than that recorded after furosemide (4.25 ml/min; p < 0.025), but not after torasemide (3.05 ml/min; p = 0.07). Inhaled furosemide totally blocked bronchial response to UNDW in five subjects. In two of five subjects the response was also blocked by inhaled torasemide. A remarkable increase in diuresis was noted only after torasemide in most subjects. We conclude that inhaled furosemide has a better protective effect than does inhaled torasemide against UNDW-induced bronchoconstriction. However, the protective effect of furosemide is variable, with some asthmatic patients showing no change in bronchial response to UNDW.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine A1 antagonists. 2. Structure-activity relationships on diuretic activities and protective effects against acute renal failure.

Diuretic activities of xanthine or nonxanthine adenosine antagonists and their ameliorative effects against glycerol-induced acute renal failure in rats were investigated in order to clarify the physiological and pathological function of adenosine receptors in the kidney. Diuretic and natriuretic activities of a variety of adenosine antagonists clarified systematically for the first time that the blockade of A1 receptors is more important than that of A2 receptors in sodium and water excretion and support the hypothesis that endogenous intrarenal levels of adenosine directly enhance tubular sodium readsorption. Studies of structure-activity relationships of 8-substituted xanthines in the acute renal failure demonstrated that the activation of adenosine A1 receptor was an important factor in developing such a renal failure. A series of 8-(3-noradamantyl)xanthines exhibited the extremely potent diuretic and natriuretic activities (24; 2.5 micrograms/kg, po, the ratio of urinary excretion value in treated rats to urinary excretion value in control rats = 1.69, the ratio of Na+/K+ in treated rats to Na+/K+ in control rats = 1.76) and potent ameliorative effects against glycerol-induced acute renal failure (24; 10 micrograms/kg, ip, 55% inhibition). From our detailed studies of structure-activity relationships, we can speculate that some tissue differences of the adenosine A1 receptor might exist between kidney and brain and sites of action for adenosine antagonists could be different between two renal pharmacological assays. 1,3-Dipropyl-8-(3-noradamantyl)xanthine, KW-3902 (24), was chosen for further studies and is under development as a drug for treating the acute renal failure.

Atrial natriuretic factor in experimental cirrhosis in rats

Atrial natriuretic factor (ANF) is a cardiac hormone with potent natriuretic, diuretic, and vasorelaxant properties. Although abnormalities in ANF release, plasma level, and renal receptors have been described in humans and/or animals with cirrhosis and ascites, little is known about the ANF hormonal system in cirrhosis without ascites. The aim of this study was to examine the ANF hormonal system in an animal model of cirrhosis to determine whether compensated cirrhosis is associated with changes in the ANF hormonal system. Pair-fed rats were studied 5–7 weeks after either sham surgery or bile duct ligation. Bile duct-ligated (BDL) rats had elevated portal pressure and cirrhosis but did not have ascites. ANF messenger RNA levels were increased onefold in the atria of BDL rats. Sham-operated and BDL rats had similar plasma ANF levels. Competitive binding inhibition studies of isolated glomeruli showed a single class of receptors in sham-operated and BDL rats. The equilibrium dissociation constant was similar in sham-operated (0.51 nmol/L) and BDL (0.63 nmol/L) rats. Glomerular ANF receptor density increased significantly in BDL rats. Cyclic guanosine monophosphate generation in isolated glomeruli in response to 100 nmol/L ANF decreased slightly but not significantly in BDL rats. It was concluded that the ANF hormonal system is altered in cirrhosis without ascites; atrial messenger RNA level and glomerular ANF receptor density are increased.

Atrial natriuretic factor in experimental cirrhosis in rats

Atrial natriuretic factor (ANF) is a cardiac hormone with potent natriuretic, diuretic, and vasorelaxant properties. Although abnormalities in ANF release, plasma level, and renal receptors have been described in humans and/or animals with cirrhosis and ascites, little is known about the ANF hormonal system in cirrhosis without ascites. The aim of this study was to examine the ANF hormonal system in an animal model of cirrhosis to determine whether compensated cirrhosis is associated with changes in the ANF hormonal system. Pair-fed rats were studied 5-7 weeks after either sham surgery or bile duct ligation. Bile duct-ligated (BDL) rats had elevated portal pressure and cirrhosis but did not have ascites. ANF messenger RNA levels were increased onefold in the atria of BDL rats. Sham-operated and BDL rats had similar plasma ANF levels. Competitive binding inhibition studies of isolated glomeruli showed a single class of receptors in sham-operated and BDL rats. The equilibrium dissociation constant was similar in sham-operated (0.51 nmol/L) and BDL (0.63 nmol/L) rats. Glomerular ANF receptor density increased significantly in BDL rats. Cyclic guanosine monophosphate generation in isolated glomeruli in response to 100 nmol/L ANF decreased slightly but not significantly in BDL rats. It was concluded that the ANF hormonal system is altered in cirrhosis without ascites; atrial messenger RNA level and glomerular ANF receptor density are increased. (Gastroenterology 1992 Apr;102(4 Pt 1):1356-62)

Studies on uricosuric diuretics. III. Substituted 1,3-dioxolo[4,5-f]-1,2-benzisoxazole-6-carboxylic acids and 1,3-dioxolo[4,5-g]-1,2-benzisoxazole-7-carboxylic acids.

A series of substituted 1,3-dioxolo[4,5-f]-1,2-benzisoxazole-6-carboxylic acids 13 and 1,3-dioxolo[4,5-g]-1,2-benzisoxazole-7-carboxylic acids 14 were synthesized and evaluated for diuretic and uricosuric activities in rats. Most of the benzisoxazole derivatives 13 and 14 showed potent diuretic activities. Moderate uricosuric activities were also found in 14a, 14b, and 14f.

Diuretic and hypotensive actions of torasemide in hypertensive models of rat

The diuretic and the antihypertensive actions of torasemide were examined in renal and genetic hypertensive rats and compared to the effects of furosemide. Oral administration of torasemide (1 and 3 mg/kg) elicited a dose-dependent increase in the excretion of urine and electrolytes and elevated the urinary Na/K ratio in both renal and genetic hypertensive rats. Torasemide and furosemide had a similar maximum diuretic effect in the normotensive Wistar rat and the spontaneously hypertensive rat (SHR). However, the diuretic activity of furosemide was weaker in the renal hypertensive rat (RHR). Torasemide showed approximately 30 times greater diuretic potency than furosemide. Torasemide and furosemide demonstrated hypotensive action in hypertensive rat models, but not in the normotensive Wistar rat. Especially in the RHR, torasemide exhibited a more potent hypotensive action than furosemide. These results show that the diuretic and antihypertensive activities of torasemide are effective in various rat models of hypertension, while the diuretic activity of furosemide is weak in certain hypertensive rat models. © 1992 Wiley-Liss, Inc.

Engineering the Cardiovascular System

We have generated several lineages of transgenic mice that exhibit chronic elevations in the steady-state concentration of atrial natriuretic factor (ANF) in the peripheral circulation. ANF, a peptide hormone synthesized primarily by atrial cardiomyocytes, is a potent natriuretic and diuretic. ANF also reduces blood pressure transiently when acutely administered. To address the potential role of ANF in chronic cardiovascular regulation, we generated transgenic mice that express the ANF gene in the liver. The fusion genes comprised either the mouse transthyretin (TTR) or rat phosphoenolpyruvate carboxykinase (PEPCK) promoters fused to the mouse ANF structural gene and were designed to target to the liver constitutive and inducible expression of pre-pro-ANF, respectively. Transgenic animals harboring the TTR-ANF fusion gene expressed chimeric ANF transcripts exclusively in the liver. In contrast, mice harboring the PEPCK-ANF fusion gene did not express detectable amounts of ANF mRNA in liver even after induction (24-hour fasting). In the TTR-ANF mice, hepatic and plasma immunoreactive ANF concentrations were proportional to the concentration of hepatic ANF transcripts. Moreover, mean arterial blood pressure recorded in conscious transgenic mice was inversely proportional to hepatic ANF expression. These transgenic models demonstrate that chronically elevated ANF concentration can induce sustained hypotension.

Effects of three sodium-potassium adenosine triphosphatase inhibitors.

Reports from several laboratories suggest the presence of an ouabainlike compound in plasma and various animal tissues, particularly during acute volume expansion and in low-renin hypertension. It has been hypothesized that this compound, through inhibition of the Na(+)-K+ pump, can constrict blood vessels, enhance vasoconstriction in response to agonists, increase cardiac contractility, raise blood pressure, and cause natriuresis/diuresis and therefore is implicated in the pathophysiology of the low-renin, volume-expanded type of hypertension. However, so far, only two steroid Na(+)-K+ pump inhibitors (namely, a bufodienolide derivative [resibufogenin], obtained from toad skin and plasma and a factor with the same carbon, oxygen, and hydrogen content as ouabain obtained from the plasma of volume-expanded humans) have been purified and structurally characterized. To determine whether such endogenous Na(+)-K+ pump inhibitors can in fact produce the above effects on the cardiovascular and renal systems, we infused commercially available bufalin (aglycone, identical to resibufogenin except for one H+), ouabain, and ouabagenin (aglycone) at equimolar doses in normotensive rats. Relative to ouabain, bufalin produced significantly greater dose-dependent increases in blood pressure, left ventricular rate of pressure change, heart rate, and excretion of urinary volume and sodium. Ouabagenin was without effect on any of these parameters. These data indicate that a Na(+)-K+ pump inhibitor can cause an increase in blood pressure despite potent diuretic and natriuretic effects and that, in rats, bufalin is much more potent in this respect than ouabain or ouabagenin.

Atrial regulation of intravascular volume: Observations on the tachycardia-polyuria syndrome

The atria, strategically located at the junction of the venous and arterial circulation, contain a network of neural and humoral structures by which they sense and regulate intravascular volume. Atrial receptors, most commonly consisting of complex unencapsulated nerve endings discharging into myelinated vagal fibers, are located in the intrapericardial portions of the caval and pulmonary veins and the adjacent atrial walls. Receptor activation by atrial distension results in increased afferent vagal fiber discharge, which in turn leads to tachycardia (Bainbridge's reflex) and decreased renal sympathetic nerve activity, renal vasomotor tone, and antidiuretic hormone activity. In addition, atrial distension also releases ANF, a peptide with potent diuretic, natriuretic, and vasorelaxant actions. The combined effect of these neurohumoral changes is the production of a large hypotonic diuresis. In the clinical setting the volume-regulating role of the atria is demonstrated by the tachycardia-polyuria syndrome. Laboratory and clinical evidence points to the activation of atrial neurohumoral mechanisms in response to atrial distension as the mediators of the polyuria that often accompanies paroxysmal tachycardias. The involvement of these mechanisms in other forms of cardiac congestion and the capability to easily measure in the blood an index of atrial distension, namely ANF, provide the opportunity to elucidate the pathophysiology and hence to open new therapeutic avenues in many cardiac disorders.

Increased Plasma Levels and Blunted Effects of Brain Natriuretic Peptide in Rats With Congestive Heart Failure

The hemodynamic and renal effects of brain natriuretic peptide (BNP) were studied in conscious rats with experimental congestive heart failure (CHF) produced by an aortocaval fistula. The peptide had potent hypotensive, diuretic, and natriuretic effects in control rats, all of which were abolished in CHF. Plasma levels of BNP increased time-dependently during the development of CHF, and were more than four-fold higher in sodium retaining rats than in control rats. The data suggest that BNP secretion from the atria is increased in CHF, and that resistance to BNP, in addition to the relative resistance to atrial natriuretic factor, may contribute to sodium retention in CHF.

Effects of DuP 753 on Proximal Nephron and Renal Transport

We used the nonpeptide angiotensin II receptor antagonist DuP 753, which lacks the agonist and kinin/prostaglandin-inducing properties of saralasin and captopril, respectively, to examine the role of endogenous angiotensin II in regulating transport in the proximal convoluted tubule (PCT) and whole kidney. During in vivo microperfusion in the Munich-Wistar rat, a maximally effective dose of DuP 753 (10 mg/kg, intravenously) powerfully inhibited absorption of bicarbonate (370 +/- 3 to 200 +/- 9 pEq/mm.min, P less than .001), chloride (214 +/- 3 to 105 +/- 9 pEq/mm.min, P less than .001), and water 5.2 +/- 0.1 to 2.8 +/- 0.2 nL/mm.min, P less than .001) in the S1 subsegment of the PCT. DuP 753 was significantly more effective than captopril (3 mg/kg, intravenously) in inhibiting sodium chloride transport and is the most potent diuretic ever described in this segment. Consistent with the axial decline of angiotensin II receptor density in the PCT, DuP 753 was a less effective transport inhibitor in the S2 subsegment of the PCT, similar to captopril. Using free-flow micropuncture and clearance techniques, though inhibition in the earliest segment of the nephron is partially compensated by downstream reabsorption, DuP 753 induces a substantial diuresis, natriuresis, and chloruresis. In conclusion, DuP 753 markedly decreases S1 PCT fluid and electrolyte absorption, indicating that endogenous angiotensin II exerts significant tonic support of proximal transport in vivo.

Effect of S-8666 on Cl- Transport in the Rabbit Connecting Tubule Perfused in Vitro.

S-8666, [6, 7-dichloro-5-(N, N-dimethylsulfamoyl)-2, 3-dihydrobenzofurancarboxylic acid] is a potent diuretic with uricosuric action. Although the major site of action of S-8666 has been proven by the in vitro microperfusion study to be the thick ascending limb of Henle's loop, clearance studies in the rat suggested that this drug has an additional thiazide-like action. To provide direct evidence that S-8666 acts also on distal nephron segments, we examined effect of S-8666 on Cl- flux across the rabbit connecting tubule perfused in vitro. The drug suppressed the lumen-to-bath Cl- flux by 96 +/- 41 (S.E.)pmol.mm-1.min-1 (n = 9) without affecting transmural voltage. To demonstrate that S-8666 acts on the connecting tubule cell, the target of thiazide diuretics, we compared effects of S-8666 and trichlormethiazide on the basolateral membrane voltage of the connecting tubule cell. Both drugs added to the lumen caused a small but significant hyperpolarization of the basolateral membrane without affecting transmural voltage. We conclude that S-8666 is a unique uricosuric diuretic having actions on both thick ascending limb of Henle's loop and connecting tubule.

Origin and characterization of atrial natriuretic peptide in the rat parotid gland

The heart atria represent the major site of synthesis for atrial natriuretic peptide (ANP) which exerts potent natriuretic, diuretic and vasoactive functions. Recently, ANP-immunoreactivity has been detected in extracardial organs involved in water and electrolyte homeostasis, such as the intestine and certain exocrine glands. The present study investigates ANP in the parotid gland. It was found by immunohistochemical techniques that the peptide is localized in ductal cells of the gland. An analysis of the immunoreactive material by high-pressure liquid chromatography and radioimmunoassay revealed the prohormone of ANP (ANP 1-126) and the biologically active fragment (ANP 99-126). Furthermore, Northern blot hybridization disclosed the presence of mRNA coding for ANP. It is suggested that ANP is synthesized and released from the parotid gland and functions in the control of saliva production.

Atrial Natriuretic Peptide in the Central Nervous System

Atrial natriuretic peptide (ANP), first isolated from rat atrial cardiocytes, is a potent natriuretic, diuretic and vasorelaxant hormone when given intravenously. In keeping with increasing evidence that many bioactive peptides that were first discovered in peripheral organs, are often present in the central nervous system, ANP and its binding sites have been localized on neurons in different regions of the brain. Further, ANP binding sites have been found on primary astrocyte and glial cell lines and ligand binding results in cyclic GMP production. In this review, we shall discuss the possible role of ANP as a neuromodulator and its effects on astrocytes, the most numerous cell type in mammalian brain.

Effects of Diuretics on Outputs and Flows of Urine and Urinary Solutes in Healthy Subjects

The effects of single oral doses of common formulations of diuretics (i.e. formulations on the market or designed to be marketed) on 24-hour diuresis and natriuresis in healthy subjects are considered as a measure of the renal excretory potency of diuretics. Common formulations of distal tubular diuretics (e.g. hydrochlorothiazide 25mg, xipamide 10mg and 20mg) are more potent diuretics and natriuretics than common formulations of loop diuretics [e.g. furosemide (frusemide) 40mg, torasemide 2.5, 5 and 10mg]. Indeed, some common formulations of loop diuretics, such as torasemide 2.5, do not increase 24-hour diuresis or natriuresis in healthy subjects. 24-hour kaliuresis and magnesiuresis are elevated by common formulations of distal tubular diuretics, but they are only slightly increased or (more usually) not affected by common formulations of loop diuretics, when single doses are administered to healthy individuals. Common formulations of loop diuretics have lower diuretic and natriuretic potency and lower kaliuretic and magnesiuretic effects than common formulations of distal tubular diuretics, because the pronounced elevations in urinary excretions caused by loop diuretics during the first 6 hours after dosing are followed by rebounds, with respect to post-placebo excretions, between 6 and 24 hours after dosing. These rebounds, which affect the urinary flows of fluid, chloride, sodium, potassium and magnesium, do not occur after administration of common formulations of distal tubular diuretics, at least during the first 24 hours after administration of single doses to healthy subjects. The time courses of urinary excretions after loop diuretics are dose dependent. Higher doses produce more rapid changes in the urinary flows of fluid, chloride, sodium, potassium and magnesium than lower doses, to the extent that single administration of torasemide 2.5 or 5mg to healthy subjects is followed by urinary fluid and solute flows whose time courses resemble those after administration of hydrochlorothiazide 25mg.

The influence of diuretics on the excretion and metabolism of doping agents — V. Dimefline

A sensitive method for the quantitative determination of the respiratory stimulant dimefline in 5 ml urine using capillary gas chromatography with nitrogen specific detection is presented. After the oral administration of a therapeutical amount of 16 mg dimefline to five subjects only 0.26 +/- 0.16% of the dose is excreted as the conjugated drug in 24 h. The maximum excretion rate occurred 3 h after dosing, the peak concentration being 154 +/- 60 ng ml-1. The influence of diuretics taken 2 h after the administration of dimefline was studied in three subjects. From these results it appeared that the use of acetazolamide and hydrochlorthiazide in order to circumvent a positive dimefline doping case is questionable. Due to the potent diuretic effect of furosemide, the intake of this diuretic could result in a suppression of the dimefline concentration below the detection limit of 10 ng ml-1.

Aryloxy Acetic Acid Diuretics with Uricosuric Activity. I. Polycyclic Aryloxy Acetic Acids.

In order to obtain lead compounds for uricosuric diuretics, various polycyclic aryloxy acetic acids [isoindole derivative (7), quinazoline derivative (15), benzopyran derivative (20), xanthone derivative (24), benzofuran derivative (30) and indene derivative (36)] were prepared. These compounds were evaluated for diuretic activity in rats, uricosuric activity in rats and antihypertensive activity in 11-deoxycorticosterone acetate (DOCA)/salt hypertensive rats. Among the compounds, 20 showed potent diuretic, uricosuric and moderate antihypertensive activities. Therefore, we selected 20 as a lead compound for development of new uricosuric diuretics.

Studies on Uricosuric Diuretics. II. Substituted 7,8-Dihydrofuro(2,3-g)-1,2-benzisoxazole-7-carboxylic acids and 7,8-Dihydrofuro(2,3-g)benzoxazole-7-carboxylic acids.

A series of substituted 7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acids 9 and 7,8-dihydrofuro[2,3-g]benzoxazole-7-carboxylic acids 12 were synthesized and evaluated for uricosuric and diuretic activities in rats. Many of the benzisoxazole derivatives 9 showed uricosuric and only weak diuretic activities, whereas the benzoxazoles 12 exhibited potent diuretic activities with little affecting urate excretion. Among these compounds, 5-chloro-7,8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-carbo xylic acid (9b, AA-193) was found to be a potent uricosuric agent without diuretic activity and was selected for further development.