Potent Diuretic Research Articles

Expression of biologically active atrial natriuretic factor following intrahepatic injection of a replication-defective adenoviral vector in dogs.

Atrial natriuretic factor (ANF) is a potent natriuretic, diuretic, and vasoactive hormone produced and released by atrial cardiomyocytes. We investigated whether adenovirus-mediated ANF gene delivery to dogs leads to a sustained increase in circulating ANF levels resulting in long-lasting biological effects. An adenoviral vector containing the canine ANF cDNA under the control of the Rous sarcoma virus 3' long terminal repeat (AdRSV-ANF) was injected via the intrahepatic route to nonvaccinated 2-month-old dogs. In the first group of four dogs injected with AdRSV-ANF (10(10.2) TCID50), a short-lived increase in plasma ANF concentrations not associated with biological effects occurred 8-10 days after the injection, as compared with four control dogs injected with an adenovirus encoding a luciferase reporter gene (AdRSV-luc). In a second series of experiments, six dogs received AdRSV-ANF at a dose of 10(10) TCID50 and a replication-defective type 5 adenovirus harboring a modified VAI gene (Ad-VAr) at the same dose. Sustained increases in plasma ANF concentrations and urinary cGMP excretion starting on day 2 and persisting until day 20 were seen, as well as concomitant elevations in natriuresis and diuresis, a transient increase in cardiac output, and a delay in body weight gain, as compared with control dogs injected with AdRSV-luc/Ad-VAr. These results show that adenovirus-mediated ANF gene expression can lead to systemic biological effects in dogs, a finding of potential relevance for the treatment of cardiovascular diseases and sodium-retaining disorders.

Natriuretic peptides in assessment of left-ventricular dysfunction

The heart secrets two different natriuretic peptides, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), which have potent vasorelaxant, diuretic, and natriuretic actions. They are main tools in the body's defense against volume overload and hypertension. The natriuretic peptides (NP) are synthetized as prohormones. The C-terminal endocrinological active peptides and their N-terminal prohormone fragments are found in plasma. The NP system is maximally activated in ventricular dysfunction. However, NP:s are also increased in patients with renal failure or pulmonary hypertension, and increases may be found in arterial hypertension or liver cirrhosis. Among all NP and prohormone fragments currently BNP is the most promising candidate analyte for routine diagnosis. BNP is also superior to other neurohormones for diagnosis of left-ventricular dysfunction (LVD) or estimating prognosis in LVD or during the subacute phase of myocardial infarction. For primary care physicians BNP measurement is useful to decide which patient with suspected heart failure warrants further investigation, particularly when assessment of left ventricular function is not readily available. BNP has an excellent negative predictive value particularly in high risk patients. For the cardiologists the NP:s are helpful for monitoring therapy and disease course in LVD patients and for estimating prognosis in LVD and myocardial infarction patients. There is now sufficient evidence to encourage physicians to gain experience with NP as a supplement in the diagnosis of patients suspected of having heart failure. An increase in BNP is serious enough to warrant follow-up examinations.

Natriuretic peptides--relevance in cardiovascular disease.

4In contrast, the increase in intravascular volume from dietary salt loading results in the expected increase in BNP. 4 Similarly, a change in a patient’s pacemaker mode from atrial to ventricular pacing leading to uncoordinated atrial contractions and high pressure waves causes a greater acute increase in plasma ANP than BNP. 5 It therefore appears that BNP level reflects long-term intravascular volume status rather than momentary volume. Moreover, BNP is more stable than ANP in plasma and has a longer half-life, 6 which may be attributable to its lesser affinity for clearance receptors. CNP is synthesized in the endothelium and has vasodilatory and antiproliferative effects on vascular smooth muscle. It has a local action in the blood vessels or within the organ where it is produced. The natriuretic peptides are cleared from the circulation by at least 2 mechanisms. They bind to widely distributed natriuretic peptide clearance receptors (NPR-Cs) on endothelial cells and are then internalized and degraded. 7 They are also metabolized by neutral endopeptidases that are widely distributed on cells of various tissues. 2 Actions Intravenous infusion of ANP or BNP has a potent natriuretic and diuretic effect in healthy subjects, and infusions of supraphysiological concentrations of these peptides also show some hypotensive effect and suppression of the reninangiotensin-aldosterone system. 6,8,9 The effects of ANP and BNP seem to be additive, which may be because ANP and BNP share a common receptor (NPR-A). 6 Activation of this receptor leads to formation of cyclic guanosine monophosphate (cGMP), the second messenger mediating the effects of the natriuretic peptides. Plasma ANP and BNP levels are markedly increased in congestive heart failure, the magnitude of increase being related to the degree of heart failure. 2 Because their actions include vasodilation, natriuresis, and suppression of the renin-angiotensin-aldosterone system, ANP and BNP may be endogenous hormones counteracting the development of heart failure. The physiological effects of exogenous ANP are blunted in patients with congestive heart failure compared with its effects in normal subjects. 9 Proposed explanations for this resistance include receptor down-regulation and increased cGMP phosphodiesterase activity. 2 In contrast, BNP infused intravenously in patients with chronic congestive heart failure leads to a dose-dependent natriuretic response, a decrease in pulmonary capillary wedge pressure, and an increase in cardiac output. 10

Transport of Monoamine Transmitters by the Organic Cation Transporter Type 2, OCT2

The recently cloned apical renal transport system for organic cations (OCT2) exists in dopamine-rich tissues such as kidney and some brain areas (Gründemann, D., Babin-Ebell, J., Martel, F., Ording, N., Schmidt, A., and Schömig, E. (1997) J. Biol. Chem. 272, 10408-10413). The study at hand was performed to answer the question of whether OCT2 accepts dopamine and other monoamine transmitters as substrate. 293 cells were stably transfected with the OCT2r cDNA resulting in the 293OCT2r cell line. Expression of OCT2r in 293 cells induces specific transport of tritiated dopamine, noradrenaline, adrenaline, and 5-hydroxytryptamine (5-HT). Initial rates of specific 3H-dopamine, 3H-noradrenaline, 3H-adrenaline, and 3H-5-HT transport were saturable, the Km values being 2.1, 4.4, 1.9, and 3.6 mmol/liter. The corresponding Vmax values were 3.9, 1.0, 0. 59, and 2.5 nmol min-1.mg of protein-1, respectively. 1, 1'-diisopropyl-2,4'-cyanine (disprocynium24), a known inhibitor of OCT2 with a potent eukaliuric diuretic activity, inhibited 3H-dopamine uptake into 293OCT2r cells with an Ki of 5.1 (2.6, 9.9) nmol/liter. In situ hybridization reveals that, within the kidney, the OCT2r mRNA is restricted to the outer medulla and deep portions of the medullary rays indicating selective expression in the S3 segment of the proximal tubule. These findings open the possibility that OCT2r plays a role in renal dopamine handling.

Successes and failures of current treatment of heart failure

Successes and failures of current treatment of heart failure

Prostaglandin E2 inhibits renal collecting duct Na+ absorption by activating the EP1 receptor.

PGE2 exerts potent diuretic and natriuretic effects on the kidney. This action is mediated in part by direct inhibition of collecting duct Na+ absorption via a Ca++-coupled mechanism. These studies examine the role the Ca++-coupled PGE-E EP1 receptor plays in mediating these effects of PGE2 on Na+ transport. Rabbit EP1 receptor cDNA was amplified from rabbit kidney RNA. Nuclease protection assays demonstrated highest expression of EP1 mRNA in kidney, followed by stomach, adrenal, and ileum. In situ hybridization, demonstrated renal expression of EP1 mRNA was exclusively over the collecting duct. In fura-2-loaded microperfused rabbit cortical collecting duct, EP1 active PGE analogs were 10-1, 000-fold more potent in raising intracellular Ca++ than EP2, EP3, or EP4-selective compounds. Two different EP1 antagonists, AH6809 and SC19220, completely blocked the PGE2-stimulated intracellular calcium increase. AH6809 also completely blocked the inhibitory effect of PGE2 on Na+ absorption in microperfused rabbit cortical collecting ducts. These studies suggest that EP1 receptor activation mediates PGE2-dependent inhibition of Na+ absorption in the collecting duct, thereby contributing to its natriuretic effects.

Synthesis of some novel 2-oxo‐pyrano(2,3-b)- and 2-oxo‐pyrido(2,3-b)quinoline derivatives as potential antimalarial, diuretic, clastogenic and antimicrobial agents

Synthesis of some novel 2-oxo‐pyrano(2,3-b)- and 2-oxo‐pyrido(2,3-b)quinoline derivatives as potential antimalarial, diuretic, clastogenic and antimicrobial agents

Nociceptin/orphanin FQ and the opioid receptor-like ORL1 receptor

Homology cloning and, more recently, the sequencing of whole genomes, have identified many open reading frames encoding proteins of unknown function, in particular putative G protein-coupled membrane receptors. Identification of orphan receptors in this way has marked the advent of 'reverse pharmacology' to identify the corresponding physiological ligands. This approach has led to the discovery of the ORL1 (Opioid Receptor-Like 1) receptor, and of its natural ligand, nociceptin/orphanin FQ (noc/oFQ), the basic components of a new peptide-based signalling pathway in the nervous system. Based on genetic criteria, the ORL1 and opioid receptors belong to the same family, as do noc/oFQ and opioid peptides. The marked structural analogy between the ORLI and opioid receptors, especially the kappa-opioid receptor, and the noc/oFQ and opioid peptides, particularly dynorphin A, is not reflected anatomically since noc/oFQ and opioid peptides appear to be located in separate neuronal circuits. Noc/oFQ triggers the same G protein-mediated signalling pathways as do opioids, however, to produce pharmacological effects that sometimes differ from, and even oppose, those of opioids. Noc/oFQ stimulates an outward K+ current and/or inhibits voltage-gated Ca2+ channels, thereby reducing synaptic efficacy, i.e. neuronal activity. In the rat, noc/oFQ is endowed with supraspinal pronociceptive/anti-opioid properties (it suppresses opioid-mediated analgesia), while convergent electrophysiological and behavioural data indicate that the peptide is a spinal analgesic. Noc/oFQ has not yet been found to precipitate withdrawal in morphine-tolerant rats. Nor does it elicit motivational effects, suggesting it lacks abuse liability. Also, by acting supraspinally, noc/oFQ impairs motor performance, suppresses spatial learning, induces feeding, and regulates basal and stress-induced release of pituitary hormones. Noc/oFQ is also active when administered intravenously, exhibiting potent smooth muscle relaxant, diuretic, and antinatriuretic properties. Last but not least, noc/oFQ appears to regulate stimulated immune function, and to be involved in neuronal differentiation. The discovery of noc/oFQ, a neuropeptide with multiple functions, will certainly improve our knowledge of brain physiology, and may find therapeutic applications, for example in the management of pain or hyponatremic and water-retaining diseases. However, given the wide distribution of noc/oFQ and its receptor, the pharmacological profile of noc/oFQ is likely to be incomplete, and other as yet unknown functions of the peptide remain to be discovered. Most helpful in this respect will be the identification of new ligands of the ORL1 receptor, particularly antagonists. If research on noc/oFQ carries on unabated at the present pace, potentially clinically interesting new compounds could become available in the not too distant future.

Photosensitive Lichenoid Reaction to Torsemide—a Loop Diuretic

Photosensitive Lichenoid Reaction to Torsemide—a Loop Diuretic

Effect of κ opioid agonist RU 51599 on osmotic and non-osmotic stimulated arginine vasopressin release and gene regulation in small cell lung carcinoma cells

Arginine vasopressin (AVP) is synthesized in the hypothalamus, stored in the posterior pituitary, and osmotic and non-osmotic stimuli release AVP into the circulation for antidiuretic and vascular actions on target tissue. The κ-opioid agonist, RU 51599, exhibits a potent diuretic activity in both experimental animals and humans. This diuretic activity is characterized by a water diuresis without an associated increase in electrolyte excretion. Studies with cultured rat hypothalamo-neurohypophysial system explant showed that AVP mRNA level changed in parallel to the RU 51599-induced changes in AVP secretory rate. There are, however, no hypothalamic neuronal cell lines to study AVP gene regulation system, and it is not known whether RU 51599, regulates AVP secretion and biosynthesis under osmotic and non-osmotic stimulatory conditions of AVP release. The effect of RU 51599 on AVP release, AVP mRNA, and AVP gene promoter activity in osmotic and non-osmotic conditions was therefore studied using cultured small cell lung carcinoma (SCLC) cell lines. RU 51599 significantly inhibited AVP release by osmotic stimulation (330 mOsm) and non-osmotic stimulators, angiotensin II (AII) and endothelin 3 (ET3). However, RU 51599 did not show any effect on the AVP mRNA and AVP gene promoter activity stimulated by high osmolality and ET3. These results indicate, therefore, that RU 51599 suppresses AVP secretion by inhibition at the step of AVP release during osmotic and non-osmotic stimulation but does not affect the AVP gene transcription level in the SCLC cells.

Changes in neurokinin A (NKA) airway responsiveness with inhaled frusemide in asthma.

BACKGROUND: Inhaled frusemide exerts a protective effect against bronchoconstriction induced by several indirect stimuli in asthma which could be due to interference of airway nerves. A randomised, double blind, placebo...

Diuretic and antidiuretic diuretic of the leaf extracts ofVernonia cinerea (Less) (Fam. Compositae)

The diuretic and anti-diuretic potency of the leaf extracts of Vernonia cinerea was studied in albino rats. The chloroform extract of the leaf induced significant diuresis, while the methanol and aqueous extracts induced significant antidiuresis in rats. In both cases, the observed effects on urine volume and electrolyte excretion were dose dependent. The trend was a significant increase (in the case of diuresis) in natriuretic and kaliuretic activity and a significant decrease (in the case of antidiuresis) in natriuresis and kaliuresis. © 1997 John Wiley & Sons, Ltd.

Torasemide versus furosemide in patients with congestive heart failure: a double-masked, randomized study

A new loop diuretic torasemide has recently been introduced into international pharmacopoeia. Its chemical structure, 1-isopropyl-3-[4-(3-methyl-phenylamino)pyridine]-3-sulphonyl urea (pyridinyl-sulfonyl-urea), is not related to other loop diuretics, such as furosemide. It has been considered suitable for a broad spectrum of clinical settings, including heart failure, hepatic cirrhosis, hypertension, and chronic renal failure. In this study, we compared the efficacy and tolerability of torasemide and furosemide in patients with congestive heart failure (New York Heart Association) classes II and III. We observed that torasemide induced an intense diuresis (a statistically significant increase of 38% from day 3 and 75% on day 28 with respect to baseline) and increased excretion of urinary sodium and potassium levels was observed during the treatment period. Furosemide induced a comparable statistically significant increase of diuresis (24% on day 3 and 65% on day 28) and urinary potassium excretion associated with a significant decrease in serum potassium levels at the end of the treatment period. Two patients in group A and one patient in group B were withdrawn from treatment because of adverse reactions (muscular cramps). It can be concluded that torasemide, as well as furosemide, appear to be potent diuretic compounds. The administration of torasemide produces an acceptable incidence of clinical side effects and can be indicated for use in chronic clinical conditions requiring an efficacious diuretic.

FK453: A Novel Non‐Xanthine Adenosine A1 Receptor Antagonist as Diuretic

Adenosine is a purine nucleotide that is widely distributed throughout the body; it modulates a wide variety of physiological functions via extracellular receptors. Adenosine receptors, located on the cell membranes, are classified into two major subtypes, adenosine A, and A, receptors. This classification was originally based on the effects of a series of adenosine analogs on adenylate cyclase activity; activation of the adenosine A, receptor inhibits, while activation of the adenosine A2 receptor stimulates, adenylate cyclase (26,46). Many adenosine agonists that have a preferential affinity for adenosine A, receptors depress heart rate, myocardial contractility. and impulse conduction velocity (5,10,14). The agonists that have a greater affinity for adenosine A, receptors induce vasodilation ( 1 1.15,17,24,28). A number of workers have found that another adenosine receptor, which has been classified as an adenosine A , receptor, is present in many tissues. This receptor was recently subdivided into adenosine A, and A, receptor subtypes. As knowledge of the different types of adenosine receptors increases, these receptors may prove to be possible targets for novel pharmacologically active drugs. Adenosine itself is used in the acute treatment and diagnosis of supraventricular arrhythmias. To date, however, no selective adenosine receptor agonist or antagonist has been used therapeutically. FK453 is a novel pyrazolopyridine derivative that was synthesized at Fujisawa Pharmaceutical Co., Ltd. (Osaka, Japan). During a search for diuretics, FK453 was found to possess a potent diuretic activity with renal vasodilatory and uricosuric effects (40). In addition. FK453 markedly antagonized the negative inotropic effects of adenosine in isolated guinea pig atria, but was less potent in inhibiting the relaxation induced by adenosine in guinea pig aorta. These results suggested that FK453 is a potent and selective

The three-dimensional structure of the human Pi class glutathione transferase P1-1 in complex with the inhibitor ethacrynic acid and its glutathione conjugate.

The potent diuretic drug ethacrynic acid has been tested in clinical trials as an adjuvant in chemotherapy. Its target is the detoxifying enzyme glutathione transferase which is often found overexpressed in cancer tissues. We have solved the crystal structures of human pi class glutathione transferase P1-1 in complex with the inhibitor ethacrynic acid and its glutathione conjugate. Ethacrynic acid is found to bind in a nonproductive mode to one of the ligand binding sites of the enzyme (the H site) while the glutathione binding site (G site) is occupied by solvent molecules. There are no structural rearrangements of the G site in the absence of ligand. The structure indicates that bound glutathione is required for ethacrynic acid to dock into the H site in a productive binding mode. The binding of the ethacrynic acid-glutathione conjugate shows that the contacts of the glutathione moiety with the protein are identical to those observed in crystal structures of the enzyme with other glutathione-based substrates and inhibitors. The ethacrynic acid moiety of the conjugate binds in the H site in a fashion that has not been observed in crystal structures of other glutathione-based inhibitor complexes. The crystal structures implicate Tyr 108 as an electrophilic participant in the Michael addition of glutathione to ethacrynic acid.

Aib-Containing Analogues of the Insect Kinin Neuropeptide Family Demonstrate Resistance to an Insect Angiotensin-Converting Enzyme and Potent Diuretic Activity

Nachman, R. J., R. E. Isaac, G. M. Coast and G. M. Holman. Aib-containing analogues of the insect kinin neuropeptide family demonstrate resistance to an insect angiotensin-converting enzyme and potent diuretic activity. Peptides 18(1) 53–57, 1997.—Analogues of the insect kinin family in which the Xaa 2 residue of the C-terminal pentapeptide core sequence Phe-Xaa 1-Xaa 2-Trp-Gly-NH 2 (Xaa 1 = Asn, His, Phe, Ser, or Tyr; Xaa 2 = Ala, Ser, or Pro) is replaced with sterically hindered aminoisobutyric acid (Aib) prove to be resistant to hydrolysis by housefly ( Musca domestica) angiotensin-converting enzyme (ACE), an endopeptidase capable of hydrolysis and inactivation of the naturally occurring insect kinin peptides. The Aib residue is compatible with formation of a turn in the active core region that is important for the biological activity of the insect kinins. One of the Aib-containing analogues, pGlu-Lys-Phe-Phe-Aib-Trp-Gly-NH 2, is five- and eightfold more active than the most active endogenous insect kinins in cockroach ( Leucophaea maderae) hindgut myotropic and cricket ( Acheta domesticus) Malpighian tubule fluid secretion assays, respectively. As the analogue is blocked at both the amino- and the carboxyl-terminus and resistant to an endopeptidase present in insects, it is better adapted than the endogenous peptides to survive for long periods in the hemolymph. Enzyme-resistant insect kinin analogues can provide useful tools to insect researchers studying the neuroendocrine control of water and ion balance and the physiological consequences of challenging insects with diuretic factors that demonstrate enhanced resistance to peptidase attack. If these analogues, whether in isolation or in combination with other factors, can disrupt the water and/or ion balance, they hold potential utility for the control of pest insect populations in the future.

Hemodynamic Effects of a Single Intravenous Injection of Synthetic Human Brain Natriuretic Peptide in Patients With Heart Failure Secondary to Ischemic or Idiopathic Dilated Cardiomyopathy

Synthetic human brain natriuretic peptide (sBNP) is a polypeptide with the same amino acid sequence as the naturally occurring hormone. Preclinical studies have demonstrated that BNP has potent hemodynamic, diuretic, and natriuretic effects that might be beneficial in treating patients with heart failure. This study was a randomized, double-blind, placebo-controlled, ascending-dose trial of sBNP administered as a single intravenous bolus in 27 heart failure patients. Six groups of patients received sequentially increasing doses of sBNP (0.3, 1, 3, 10, 15, and 20 μg/kg, respectively) as a single intravenous injection, and hemodynamics were assessed by pulmonary artery monitoring catheter. The 10 and 15 μg/kg doses of sBNP resulted in significant reductions in pulmonary capillary wedge pressure (−73%, p <0.001), mean pulmonary artery pressure (−41%, p <0.001), mean arterial blood pressure (−28%, p = 0.001), and systemic vascular resistance (−53%, p = 0.004). Significant increases occurred in cardiac index (68%, p <0.001) and stroke volume index (72%, p <0.001). The magnitude and duration of hemodynamic changes were dose dependent. There were no adverse effects. sBNP injected as a single intravenous bolus in heart failure patients improves hemodynamics in a dose-related fashion. Further clinical investigations to determine the use of sBNP in decompensated heart failure are clearly warranted. (Am J Cardiol 1996;78:896–901)

An E-box motif conveys inhibitory activity on the atrial natriuretic peptide gene.

Atrial natriuretic peptide (ANP) is a potent diuretic, natriuretic, and vasorelaxant hormone that is expressed early in ventricular hypertrophy. Expression of human ANP is controlled by a series of regulatory elements located in the 5' flanking sequence of its gene. We generated a series of 5' deletion mutations extending from -2600 to -1150 relative to the transcription start site and linked them to a chloramphenicol acetyltransferase reporter gene. Using transient transfection analysis, we have identified a negative regulatory element between -1206 and -1152 relative to the start site. Each of a series of 5' deletion mutants, when introduced into fibroblast cultures, expressed the reporter function at a level that was significantly less (< 20%) than that seen with the -1152 reporter construct, whereas comparably transfected atrial cardiocytes demonstrated no change in reporter activity, implying that the repressor function is specific to cell type. The critical region (from -1206 to -1152) associates with a soluble protein present in cardiac fibroblast extracts in a sequence-specific fashion. Deoxyribonuclease I footprint analysis demonstrated the presence of several protected regions, including one that overlies an E-box motif (CAACTG), an element that in other systems has been implicated in promoting differentiation in the myocyte lineage. Site-directed mutagenesis of the E-box motif suppressed both the protein-binding and inhibitory activities of the 54-bp fragment. In summary, we have found a region in the 5' flanking sequence of the human ANP gene that represses transcriptional activity in nonmyocardial cells. This element may play an important role in the restriction of ANP gene expression to cardiac myocytes.

The acute effects of intravenous frusemide on the renal kallikrein kinin system in man: relationship to dose

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.

Protective Effect of a Platelet-Activating Factor Antagonist (WEB-2086) in Postischemic Renal Failure

The purpose of this study was to evaluate the renoprotective effect of a specific platelet-activating factor antagonist (WEB-2086) in an experimental model of normothermic renal ischemia. Twenty New Zealand white rabbits were studied for 2 days before and 24 hours after a 60-minute period of renal ischemia induced by bilateral clamping of the renal arteries. The animals were divided into two groups: a control group (group A; n = 10) and a treated group (group B; n = 10). In group A the urinary flow rate decreased significantly (from 0.098 +/- 0.008 ml/min to 0.029 +/- 0.005 ml/min) (p < 0.001) and there was a significant reduction in creatinine clearance (from 11.4 +/- 1.2 ml/min to 3.4 +/- 1.1 ml/min) (p < 0.001). In group B no significant changes were observed, although the urinary flow rate increased even in the postischemic period (from 0.09 +/- 0.008 ml/min to 0.11 +/- 0.02 ml/min). Microcirculatory cortical flow showed a postischemic reduction in both groups, although it was most significant in the control group (group A = 43.7%, group B = 71.5%; p < 0.001). Histologic study showed mild damage with patchy tubular necrosis in both groups, although this injury was less severe in the treated group. The results suggest that the preoperative administration of WEB-2086 produces a potent diuretic effect with significant attenuation of postischemic acute renal failure.