bq-123 and Proteinuria

Endothelin 1 is implicated in the development and progression of chronic kidney disease and associated cardiovascular disease. We, therefore, studied the effects of selective endothelin-A receptor antagonism with BQ-123 on key independent surrogate markers of cardiovascular risk (blood pressure, proteinuria and renal hemodynamics, arterial stiffness, and endothelial function) in patients with nondiabetic chronic kidney disease. In a double-blind, randomized crossover study, 22 subjects with proteinuric chronic kidney disease received, on 2 separate occasions, placebo or BQ-123. Ten of these subjects also received nifedipine (10 mg) as an active control for the antihypertensive effect of BQ-123. Blood pressure, pulse wave velocity, flow-mediated dilation, renal blood flow, and glomerular filtration rate were monitored after drug dosing. BQ-123 reduced blood pressure (mean arterial pressure: -7+/-1%; P<0.001 versus placebo) and increased renal blood flow (17+/-4%; P<0.01 versus placebo). Glomerular filtration rate remained unchanged. Proteinuria (-26+/-4%; P<0.01 versus placebo) and pulse wave velocity (-5+/-1%; P<0.001 versus placebo) fell after BQ-123, but flow-mediated dilation did not change. Nifedipine matched the blood pressure and renal blood flow changes seen with BQ-123. Nevertheless, BQ-123 reduced proteinuria (-38+/-3% versus 26+/-11%; P<0.001) and pulse wave velocity (-9+/-1% versus -3+/-1%; P<0.001) to a greater extent than nifedipine. Selective endothelin-A receptor antagonism reduced blood pressure, proteinuria, and arterial stiffness on top of standard treatment in renal patients. Furthermore, these studies suggest that the reduction in proteinuria and arterial stiffness is partly independent of blood pressure. If maintained longer term, selective endothelin-A receptor antagonism may confer cardiovascular and renal benefits in patients with chronic kidney disease.

Topics: Adult; Aged; Antihypertensive Agents; Arteries; Blood Pressure; Calcium Channel Blockers; Cross-Over Studies; Double-Blind Method; Endothelin Receptor Antagonists; Endothelin-1; Hemodynamics; Humans; Kidney Failure, Chronic; Middle Aged; Nifedipine; Peptides, Cyclic; Proteinuria; Renal Circulation; Sodium; Treatment Outcome

Endothelin (ET) is implicated in the pathophysiology of chronic renal failure (CRF). We therefore studied the systemic and renal hemodynamic effects of ET receptor antagonists in CRF and examined differences between selective ETA, selective ETB, and combined ETA/B receptor blockade.. We conducted a randomized, placebo-controlled, double-blind, 4-way crossover study comparing selective ET receptor antagonists BQ-123 (ETA) and BQ-788 (ETB), given alone and in combination, in acute studies in 8 hypertensive CRF patients and 8 matched healthy controls. BQ-123, alone and in combination with BQ-788, reduced blood pressure in CRF, particularly with BQ-123 alone (mean arterial pressure: controls -4+/-2%, CRF -13+/-2%, P<0.01 versus placebo). In CRF, in the face of this fall in blood pressure, BQ-123 substantially increased renal blood flow (38.8+/-23.9%, P<0.01 versus placebo) and reduced renal vascular resistance (-44.5+/-11.3%, P<0.01 versus placebo) when given alone but not when combined with BQ-788. These changes were accompanied by a reduction in effective filtration fraction. BQ-123, alone or in combination with BQ-788, had minimal effects on the renal circulation in healthy controls, and BQ-788 alone produced both systemic and renal vasoconstriction in CRF and healthy controls.. ETA receptor antagonism was highly effective in lowering blood pressure in CRF patients currently treated for hypertension. In addition, there were effects consistent with a renoprotective action. However, because the ETB receptor appears to play a key role in the maintenance of tonic renal vasodilation, combined ETA/B receptor antagonism, although it lowered blood pressure, did not confer these renal benefits.

Topics: Antihypertensive Agents; Blood Pressure; Cross-Over Studies; Double-Blind Method; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Hemodynamics; Humans; Hypertension, Renal; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Oligopeptides; Peptides, Cyclic; Piperidines; Proteinuria; Renal Circulation; Sodium

Preeclampsia is a life-threatening pregnancy disorder. However, its pathogenesis remains unclear. We tested the hypothesis that gestational hypoxia induces preeclampsia-like symptoms via heightened endothelin-1 (ET-1) signaling. Time-dated pregnant and nonpregnant rats were divided into normoxic and hypoxic (10.5% O2 from the gestational day 6-21) groups. Chronic hypoxia had no significant effect on blood pressure or proteinuria in nonpregnant rats but significantly increased blood pressure on day 12 (systolic blood pressure, 111.7 ± 6.1 versus 138.5 ± 3.5 mm Hg; P=0.004) and day 20 (systolic blood pressure, 103.4 ± 4.6 versus 125.1 ± 6.1 mm Hg; P=0.02) in pregnant rats and urine protein (μg/μL)/creatinine (nmol/μL) ratio on day 20 (0.10 ± 0.01 versus 0.20 ± 0.04; P=0.04), as compared with the normoxic control group. This was accompanied with asymmetrical fetal growth restriction. Hypoxia resulted in impaired trophoblast invasion and uteroplacental vascular remodeling. In addition, plasma ET-1 levels, as well as the abundance of prepro-ET-1 mRNA, ET-1 type A receptor and angiotensin II type 1 receptor protein in the kidney and placenta were significantly increased in the chronic hypoxic group, as compared with the control animals. Treatment with the ET-1 type A receptor antagonist, BQ123, during the course of hypoxia exposure significantly attenuated the hypoxia-induced hypertension and other preeclampsia-like features. The results demonstrate that chronic hypoxia during gestation induces preeclamptic symptoms in pregnant rats via heightened ET-1 and ET-1 type A receptor-mediated signaling, providing a molecular mechanism linking gestational hypoxia and increased risk of preeclampsia.

Topics: Animals; Blood Pressure; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Female; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney; Peptides, Cyclic; Placenta; Pre-Eclampsia; Pregnancy; Proteinuria; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Signal Transduction

Topics: Antihypertensive Agents; Arteries; Blood Pressure; Drug Therapy, Combination; Endothelin Receptor Antagonists; Humans; Kidney Failure, Chronic; Peptides, Cyclic; Proteinuria; Treatment Outcome

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Drug Therapy, Combination; Endothelin Receptor Antagonists; Glomerulosclerosis, Focal Segmental; Heart Rate; Humans; Kidney Failure, Chronic; Peptides, Cyclic; Proteinuria; Renin-Angiotensin System; Treatment Outcome

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