bq-123 and Kidney-Diseases

Topics: Animals; Cyclosporine; Endothelins; Humans; Kidney; Kidney Diseases; Peptides, Cyclic; Receptors, Endothelin

Evidence suggests that urinary excretion of endothelin-1 (ET-1) reflects renal ET-1 production and is independent of systemic ET-1 activity. The influence of ET receptors on urinary ET-1 excretion has not been studied in humans, yet peritubular ETB receptors are abundant within the kidney. We have studied the effects of acute ETA and ETB receptor blockade with BQ-123 and BQ-788, respectively, on urinary ET-1 excretion in a randomized, placebo-controlled, double-blind study in 16 subjects with a wide range of GFRs (15-152 ml/min). Plasma ET-1 concentrations (pET-1) and urinary ET-1 excretion rate (uET-1) at baseline correlated inversely with GFR (R2 = 0.18 and 0.36, respectively, P < 0.01). However, changes in pET-1 after ET receptor antagonism were not related to changes in uET-1 (R2 = 0.007, P = 0.18). pET-1 increased only after BQ-788, alone or in combination with BQ-123, consistent with ETB receptor-mediated clearance of ET-1 from the circulation. uET-1 was reduced only after BQ-788 alone [-4.7 pg/min (SD 5.5), P < 0.01]. Because BQ-788 also reduced GFR, fractional excretion of ET-1 (FeET-1) was calculated. FeET-1 fell after BQ-788 alone [-41% (SD 26%), P < 0.01] or in combination with BQ-123 [-40% (SD 29%), P < 0.01]. FeET-1 was not altered by placebo or BQ-123 alone. In conclusion, urinary ET-1 excretion does not appear to relate to the pool of plasma ET-1. Because of the short duration of this study, it is unlikely that ET receptor blockade had significant effects on renal ET-1 production. Therefore, the reduction in FeET-1 after ETB blockade appears to indicate that renal excretion of ET-1 is at least partly facilitated by ETB receptor activation.

Topics: Adult; Aged; Chronic Disease; Double-Blind Method; Drug Combinations; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Glomerular Filtration Rate; Humans; Kidney Diseases; Male; Middle Aged; Oligopeptides; Osmolar Concentration; Peptides, Cyclic; Piperidines

Kidney disease is a universal public health problem, and epidemiological studies demonstrated that the incidences of chronic kidney disease are increasing day by day. However, the efficiency of currently available drugs on the progression of nephropathy is limited. Therefore, the current research was designed to evaluate the therapeutic efficacy of captopril and BQ123 against hyperlipidemia-induced nephropathy in rats.. The objective of this study was to examine the implication of Endothelin-1 in experimentally induced hyperlipidemic nephropathy in rats.. Animals were divided into various groups, and the administration of a high-fat diet for six weeks induced hyperlipidemia. After confirmation of hyperlipidemia, treatment was started for the next 14 days. At the end of the experimental period, the animals were sacrificed, and various biochemical parameters and histopathological studies were performed.. Treatment of both the agents in combination effectively decreased BUN levels, serum creatinine, serum nitrite, and proinflammatory markers and ameliorated the pathological injuries to kidneys.. Furthermore, both treatments also inhibited oxidative stress and restored the hyperlipidemia-induced reduction in the level of antioxidant enzymes.

Topics: Animals; Captopril; Endothelin-1; Hyperlipidemias; Kidney Diseases; Rats

Renal vasoconstriction with resultant tissue hypoxia, especially in the renal medulla, has been suggested to play a role in contrast media (CM)-induced nephropathy. Endothelin (ET) is released into the blood stream following CM injection and has been proposed as a potential mediator through its vasoconstrictive properties.. To investigate the possible protective influence of ET-receptor antagonists against CM-induced reduction in renal function, we studied the effects of injection of iopromide with and without pretreatment with BQ123 (ET-A antagonist) or BQ788 (ET-B antagonist) on renal superficial cortical flow (CBF), outer medullary blood flow (OMBF) and outer medullary oxygen tension (pO2) in normal rats.. Administration of CM (1600 mg I/kg b.w.) did not affect CBF in any of the groups. However, a transient decrease in OMBF occurred, which was unaffected by both BQ123 and BQ788. Also a transient decrease in outer medullary pO2 was induced by CM administration. The pO2 reduction was significantly smaller after pretreatment with BQ123, than after injection of CM alone or together with BQ788, and pO2 returned more rapidly to the control level. Neither receptor antagonist had an effect on CM-mediated increases in electrolyte excretion.. In the normal rat, activation of ET-A receptors is partly involved in the depression of outer medullary pO2 caused by injection of iopromide. However, the decrease in OMBF after iopromide injection is not mediated by ET receptors. The beneficial effects of the ET-A receptor antagonist on CM-induced changes in outer medullary pO2 seem therefore not primarily mediated on the hemodynamic level but may rather involve tubular transport mechanisms.

Topics: Animals; Antihypertensive Agents; Contrast Media; Disease Models, Animal; Endothelin Receptor Antagonists; Hypoxia; Iohexol; Kidney Diseases; Kidney Medulla; Male; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Endothelin; Renal Circulation

1. We examined the effects of a selective endothelin A (ETA)-receptor antagonist, BQ-123, on the development of hypertension and organ damage in stroke-prone spontaneously hypertensive rats (SHRSP) given 1% NaCl for 6 weeks. 2. BQ-123 at doses of 0.7, 2.1 and 7.1 mg/day was continuously administered for 6 weeks to 8 week old salt-loaded SHRSP, who were given water containing 1% NaCl for the following 6 weeks, via a subcutaneous osmotic minipump. 3. Development of high blood pressure was accelerated in salt-loaded SHRSP compared with that in non-salt-loaded SHRSP. After 6 weeks of salt-loading, incidence of cerebral infarction, renal sclerosis and renal fibrosis were greater in salt-loaded than non-salt-loaded SHRSP. 4. BQ-123 attenuated the age-related rise in blood pressure in a dose-dependent manner. The effect coincided with reduction in the incidence of cerebral infarction and prevention of renal sclerosis and fibrosis. Kidney function was improved as observed by an increase in glomerular filtration rate and decreases in urinary protein excretion, blood urea nitrogen and fractional sodium excretion. Furthermore, BQ-123 prevented increases in the heart weight/bodyweight ratio and aortic wall thickness in salt-loaded SHRSP. 5. These results suggest that endogenous endothelin-1 (ET-1) and ETA-receptors may be, at least in part, involved in the pathogenesis of hypertension and organ damage in salt-loaded SHRSP.

Topics: Animals; Blood Pressure; Blood Urea Nitrogen; Cerebrovascular Disorders; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Glomerular Filtration Rate; Hypertension; Infarction; Kidney; Kidney Diseases; Kidney Function Tests; Osmolar Concentration; Peptides, Cyclic; Proteinuria; Rats; Rats, Inbred SHR; Sodium; Sodium, Dietary

We assessed the role of endothelin in the development of renal dysfunction during acute rejection by examining the effect of a selective endothelin A (ETA) receptor antagonist BQ-123 in rats with acute liver rejection. Serum endothelin levels and endogenous creatinine clearance (Ccr) were monitored on days 1, 3, 5, 7, and 9 postoperatively. As indicators of renal hemodynamics, the estimated hemoglobin concentration of renal tissue (IHb) and the oxygen saturation of hemoglobin in renal blood (ISO2) were determined by reflectance spectrophotometry. In addition, the clearance of inulin and P-aminohippurate were determined, and the renal tissue blood flow was estimated by laser-Doppler flowmetry (LDF). As a model of allograft rejection, Lewis rats were transplanted orthotopically with DA rat livers. The serum endothelin level of allografted rejectors was significantly (P < 0.05) higher than that of isografted controls (Lewis rats with Lewis livers) on postoperative day 5, and it increased to a maximum of 5.38 +/- 0.95 pg/ml on day 9 (versus 1.23 +/- 0.18 pg/ml preoperatively). The values of Ccr, IHb, and ISO2 were all significantly (P < 0.05) lower in allografted rejectors than in isografted controls on day 5, and subsequently declined to a minimum on day 9 (P < 0.01). Treatment of allografted rejectors with BQ-123 markedly improved the renal parameters to levels similar to those in the isografted controls. These results strongly suggest that endogenous endothelin may play an important role in the development of renal impairment during acute liver rejection by reducing renal blood flow through binding with ETA receptor.

Topics: Acute Disease; Animals; Creatinine; Endothelin Receptor Antagonists; Endothelins; Graft Rejection; Inulin; Kidney Diseases; Laser-Doppler Flowmetry; Liver Transplantation; Male; Peptides, Cyclic; Rats; Rats, Inbred Lew; Renal Circulation

Cyclosporin A (CsA) is widely used to suppress graft rejection following transplantation and in the treatment of a variety of autoimmune diseases. Therapy with CsA is often accompanied by adverse effects which include hepatotoxicity, hypertension, and nephrotoxicity. The role of endothelin (Et) in CsA-induced nephrotoxicity has been the subject of recent investigations. BQ-123 is a recently discovered Et receptor antagonist which is selective for the EtA receptor. In the present study, BQ-123 was used to further characterize the role of Et in CsA-induced nephrotoxicity. All experiments were performed in Inactin (100 mg/kg, i.p.) anesthetized male Munich-Wistar rats (250 to 350 g). Animals were prepared for the recording of blood pressure (MAP) and heart rate (HR) as well as the measurement of urine volume (UV), UNaV, UKV, GFR and effective renal plasma flow (ERPF). GFR and ERPF were estimated from the clearance of 14C-inulin and 3H-PAH, respectively. On the day of the experiment, animals were randomly assigned to one of three groups and treated according to the following protocols: Group 1, pretreatment with BQ-123 (1 mg/kg, i.v. bolus with 0.1 mg/kg/hr i.v. infusion) followed by treatment with vehicle (cremophor; 0.15 ml, i.v.); Group 2, pretreatment with normal saline (1.0 ml/kg; plus 25 microliters/min infusion) followed by treatment with CsA (20 mg/kg, i.v.); and Group 3, pretreatment with BQ-123 (same as group 1) followed by CsA (20 mg/kg, i.v.). BQ-123 administration alone produced transient changes in several of the measured parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Pressure; Cyclosporine; Endothelin Receptor Antagonists; Kidney; Kidney Diseases; Kidney Function Tests; Male; Peptides, Cyclic; Pharmaceutical Vehicles; Polyethylene Glycols; Rats; Rats, Inbred Strains; Reference Values