endothelin-1 and Hypertension--Renal

Endothelial cells regulate vascular tone largely by the actions of endothelin-1. Endothelin-1 is a potent vasoconstrictor, with effects that are dependent on the receptors to which it binds as well as their location. Endothelin-1 dysregulation is implicated in pathological conditions, including those of the pulmonary vasculature and the kidney. In this review, we describe the physiology and actions of endothelin-1 in lung and renal tissues and discuss therapies that disrupt these interactions in disease states. We provide an overview of the current clinical progress of these targeted agents and provide perspectives on the treatment of pulmonary and renal diseases with endothelin receptor antagonists.

Topics: Endothelin A Receptor Antagonists; Endothelin-1; Humans; Hypertension, Pulmonary; Hypertension, Renal

Since its discovery in 1988, there has been increasing evidence that endothelin-1 (ET-1) plays an important role in the pathophysiology of hypertension and its related end-organ damages. First studies, using ET-1 administration in animals or in humans suspected this role by demonstrating the hypertensive properties of ET-1. The latter, due to stimulation of ET(A) receptors inducing sustained vasoconstriction have been reported to follow transient vasodilation linked with activation of an endothelial ET(B) receptor releasing nitric oxide (NO). In certain instances, ET(B) smooth-muscle receptors might also induce contraction. Cloning of these receptors helped to develop ET-1 receptor antagonists. As soon as one of them became available, bosentan, a dual (ET(A) and ET(B)) ET-1 receptor antagonist, we tested its effects in the canine model of perinephritic hypertension. Bosentan was found to exert striking hypotensive effects, due to peripheral vasodilation but without affecting cardiac function. In further experiments, we observed that effects of bosentan were additional to those of ACE inhibitors or angiotensin II antagonists. This opened new therapeutic perspectives and also suggested a proper role of ET-1 in hypertension, independent of the renin-angiotensin system. To explain this role, we demonstrated a real imbalance characterized by an impairment of the NO system in favor of the ET-1 pathway. Recent studies suggest that such an imbalance may also occur in human hypertension. Furthermore, the contribution of ET-1 to human hypertension appears more convincing since bosentan was shown to decrease blood pressure in hypertensive subjects. Finally, ET-1 receptor antagonists might be of therapeutic interest to prevent hypertension induced end-organ damages. Whether or not these compounds are able to prevent or to reverse target organ injuries in man remains to be investigated.

Topics: Animals; Bosentan; Dogs; Endothelin Receptor Antagonists; Endothelin-1; Humans; Hypertension; Hypertension, Renal; Nitric Oxide; Receptors, Endothelin; Sulfonamides; Vasodilation

Due to the potent vasoconstrictor action of endothelin-1 and its synthesis throughout the vasculature and other tissues, most investigators believe that it is an active participant in the pathogenesis of hypertension. However, the autocrine and paracrine nature of the endothelin system has made its role difficult to define. In recent years, it has become apparent that endothelin-1 contributes to the regulation of renal salt and water excretion and that it is a major contributor to the hypertension associated with salt-dependency. Evidence suggests that endothelin-1 within the renal medulla is activated in conditions of salt loading and inhibits reabsorption of sodium in a nitric oxide-dependent manner. Blockade of endothelin A receptors lowers arterial pressure in animal models of salt-dependent hypertension. Furthermore, circulating levels of endothelin-1 are generally higher in African-Americans compared to white Americans as is the prevalence of salt-dependent hypertension. Therefore, it would appear that use of endothelin A-selective receptor antagonists should be targeted to those individuals at risk for salt-dependent hypertension. Blockade of endothelin B receptors would not be desirable because of their important role in eliminating a salt load.

Topics: Animals; Endothelin-1; Humans; Hypertension, Renal; Kidney

The endothelin system has been implicated in the pathogenesis of arterial hypertension and renal disorders. Endothelin-1, the predominant isoform of the endothelin peptide family, regulates vasoconstriction and cell proliferation in tissues both within and outside the cardiovascular system through activation of Gi-protein-coupled ET(A) and ET(B) receptors. Endothelin synthesis is regulated through autocrine mechanisms by endothelin converting enzymes, chymases, and non-endothelin converting enzyme metalloproteases. In-vitro experiments have demonstrated that endothelin-1 stimulates growth in vascular smooth muscle and in the kidney. Recent studies indicate that endothelin mRNA and protein are also increased in vivo in the kidney and vasculature in hypertension and renal disease. Studies using molecular or pharmacological inhibition of the endothelin system demonstrate that endothelin-1 contributes to the functional and structural changes associated with arterial hypertension and glomerulosclerosis, and that these effects are only in part dependent on blood pressure. These experimental studies and first clinical trials suggest that endothelin antagonists may offer therapeutic potential to reduce end-organ damage in diseases associated with vascular remodeling and renal injury.

Topics: Amino Acid Sequence; Animals; Blood Pressure; Blood Vessels; Endothelin-1; Endothelins; Humans; Hypertension; Hypertension, Renal; Hypertrophy; Kidney Diseases; Molecular Sequence Data; Rats; Receptors, Endothelin

Endothelin-1 (ET-1) was discovered 10 years ago. Because it is one of the most potent vasoconstrictors in vivo, a pathophysiological role for the peptide as a mediator of hypertension has been postulated. Several clinical studies, however, have been unable to identify elevated ET levels in the plasma of hypertensive patients, suggesting that it does not play a prominent role in this disease. More recently, evidence has been presented that ETs act predominantly at the autocrine/paracrine level and that measurements of plasma levels can give only an indirect view of the activity of the system. In addition, transgenic technology has uncovered new actions of the peptide systems in recent years, which point to a key function of the system in prenatal development. Moreover, investigation of conditions associated with hypertensive end-organ damage, such as chronic renal failure, has led to a re-evaluation of the role of the ET system in hypertension. This article discusses this recent evidence and defines the exact role of the ET system in hypertension and hypertensive end-organ damage.

Topics: Animals; Endothelin-1; Humans; Hypertension, Renal; Renal Insufficiency

Although angiotensin receptor antagonists and 3-hydroxy-3-methylgultaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have been shown to attenuate proteinuria individually, it remains unclear whether proteinuria may be additionally improved by statin therapy in well-controlled hypertensive patients treated with angiotensin receptor antagonists-based regimen and whether withdrawal of chronic statin treatment may abrogate this beneficial effect in normolipidemic patients.. A total of consecutive 82 proteinuric patients treated with antihypertensive agents, including losartan, were randomized 10 mg of pravastatin or placebo with a 6-month treatment. After completing 6 months of drug treatment, the pravastatin-treated patients were randomly assigned to continue (N= 19) or withdraw (N= 17) pravastatin for a further 6 months.. Subjects treated with pravastatin had significant further improvement of proteinuria at 6 months compared with placebo group (559 +/- 251 mg/24 hours vs. 1262 +/- 557 mg/24 hours) (P < 0.0001). Of 17 patients assigned to withdraw pravastatin, proteinuria returned to the pretreatment levels and was significantly higher than those who continued treatment. Multivariate analysis revealed that proteinuric improvement was significantly correlated with the continuous statin use. Urinary excretion of endothelin-1 (ET-1) is decreased in pravastatin-treated patients, but withdrawal of statin resulted in 27% up-regulation. The linear regression models in the initial statin-treated group showed that changes in urinary ET-1 correlated with urinary protein excretion (r= 0.83, P < 0.0001).. We conclude that pravastatin administration is associated with improved proteinuria probably by inhibiting urine ET-1 levels in patients with losartan-based treatment. However, statin withdrawal abrogates this beneficial effect in patients initially responsive to this therapy.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Drug Interactions; Drug Resistance; Endothelin-1; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension, Renal; Lipids; Losartan; Male; Middle Aged; Pravastatin; Proteinuria; Substance Withdrawal Syndrome

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

Recombinant human erythropoietin (rHuEPO) has been reported to induce hypertension. We investigated the effect of a single injection of rHuEPO on blood pressure in patients receiving hemodialysis (HD) and in patients with predialysis chronic renal failure (CRF). Forty-one patients receiving HD and 36 patients with predialysis CRF received an intravenous injection of rHuEPO, and blood pressure and plasma endothelin-1 were measured before and 30 min after the injection. Mean blood pressure was increased significantly in HD patients, but not in CRF patients (HD: 103+/-5 to 105+/-6 mmHg, p<0.05; CRF: 103+/-4 to 103+/-6, NS). The percentage of patients with increased mean blood pressure of more than 10 mmHg after rHuEPO injection was significantly larger in the HD than in the CRF group (27.0% vs. 5.5%, p<0.01). A positive correlation was found between changes in endothelin-1 level and mean blood pressure in the HD (r=0.43, p<0.01) but not in predialysis chronic renal failure. In conclusion, a single injection of rHuEPO increased blood pressure with a positive correlation with endothelin-1 release in hemodialysis patients, but not in predialysis chronic renal failure patients.

Topics: Adult; Aged; Anemia; Blood Pressure; Endothelin-1; Erythropoietin; Female; Humans; Hypertension, Renal; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

Indexes of myocardial ischemia and vasoconstrictive hormonal release were evaluated in order to investigate the difference between essential hypertension and hypertension during chronic renal failure.. Arterial hypertension induces several cardiovascular alterations that reflect themselves either on the heart and/or on the coronary blood flow enhancing the cardiovascular risk. Since chronic renal failure can influence the neuroendocrine response, various mechanisms involved in hypertension during chronic renal failure are still unclear. High endothelin 1 (ET-1) levels have been found both in arterial hypertension and during chronic renal failure. Interestingly, either ET-1 or catecholamines seem also to be implied in the pathogenesis of myocardial ischemia.. 20 hypertensive uremic and 20 essentially hypertensive patients underwent echocardiographic wall motion and wall thickening analysis performed at baseline and immediately after the end of exercise. Simultaneously, myocardial perfusion was evaluated by 99mTc-MIBI-SPECT. In addition, plasma norepinephrine and ET-1 concentrations were measured at baseline and at peak exercise.. The segmental radionuclide analysis showed a greater ischemic degree in hypertensive uremic patients. Yet, we were able to identify one or more regions of the left ventricle in which both systolic thickening measurements and wall motion after exercise were impaired. After exercise, wall thickening impairment was correlated with both wall motion abnormalities (r = 0.72, p < 0.01) and MIBI ischemic grade (r = 0.82, p < 0.001). Basal and after-exercise plasmatic norepinephrine and endothelin levels were higher in hypertensive uremic than in essentially hypertensive patients. Moreover, there was a significant correlation between increments in norepinephrine concentration and MIBI perfusion defects, and between the increment in ET-1 concentration and both MIBI perfusion defects, or kinetic alterations assessed by wall motion as well as by wall thickening.. This is the first cross-sectional study in which a higher degree of myocardial ischemia has been observed in hypertensive uremic patients combined with an enhanced plasma release of both norepinephrine and ET-1. This phenomenon may contribute to enhance the cardiovascular risk of these patients.

Topics: Aged; Cross-Sectional Studies; Echocardiography; Endothelin-1; Exercise Test; Female; Hemodynamics; Humans; Hypertension; Hypertension, Renal; Image Interpretation, Computer-Assisted; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Ischemia; Norepinephrine; Tomography, Emission-Computed, Single-Photon

Hypertension is regarded as a condition of mild inflammation and endothelial imbalance. The aim of the study was to evaluate serum concentrations of biomarkers of inflammation and endothelial function: tumour necrosis factor alpha (TNF-α), endothelin-1 (ET-1), and N-terminal fragment of pro-atrial natriuretic peptide (NTpro-ANP) in hypertensive and normotensive children.. We studied 63 children aged 13.56 ± 3.73 years, divided into two groups: a group with primary hypertension (n = 50) and a group with renal hypertension (n = 13). The control group consisted of 34 normotensive children aged 12.76 ± 3.96 years. Biomarkers were measured with ELISA tests.. ET-1 levels were significantly higher in primary hypertension (9.93 ± 1.73 pg/ml) and renal hypertension (10.77 ± 1.50 pg/ml) in comparison to controls (4.03 ± 0.97 pg/ml), (p < 0.001, p < 0.001, respectively). NT-pro ANP concentrations in primary hypertension (71.03 ± 10.02 pg/ml), and renal hypertension (84.78 ± 6.44 pg/ml) were significantly higher than in the control group (29.62 ± 5.56 pg/ml) (p < 0.001, p < 0.001, respectively). TNF-α concentrations in primary hypertension (8.36 ± 1.60 pg/ml) and renal hypertension (7.35 ± 0.93 pg/ml) significantly exceeded concentrations in controls (4.49 ± 0.93 pg/ml), (p < 0.001, p < 0.001, respectively). ET-1 and NT-pro ANP concentrations in renal hypertension significantly exceeded those in primary hypertension (p = 0.049, p < 0.001, respectively) while TNF-α levels in renal hypertension were significantly lower than in primary hypertension (p = 0.046).. The results of our study show that ET-1, NT-pro ANP, and TNF-a concentrations are increased in hypertension in children. Our investigation indicates significant importance of inflammation and endothelial involvement in hypertension in youth.

Topics: Adolescent; Atrial Natriuretic Factor; Biomarkers; Child; Child, Preschool; Endothelin-1; Essential Hypertension; Female; Humans; Hypertension, Renal; Male; Peptide Fragments; Tumor Necrosis Factor-alpha

Hypertension is the most prevalent life-threatening disease worldwide and is frequently associated with chronic kidney disease (CKD). However, the molecular basis underlying hypertensive CKD is not fully understood.. We sought to identify specific factors and signaling pathways that contribute to hypertensive CKD and thereby exacerbate disease progression.. Using high-throughput quantitative reverse-transcription polymerase chain reaction profiling, we discovered that the expression level of 5'-ectonucleotidase (CD73), a key enzyme that produces extracellular adenosine, was significantly increased in the kidneys of angiotensin II-infused mice, an animal model of hypertensive nephropathy. Genetic and pharmacological studies in mice revealed that elevated CD73-mediated excess renal adenosine preferentially induced A2B adenosine receptor (ADORA2B) production and that enhanced kidney ADORA2B signaling contributes to angiotensin II-induced hypertension. Similarly, in humans, we found that CD73 and ADORA2B levels were significantly elevated in the kidneys of CKD patients compared with normal individuals and were further elevated in hypertensive CKD patients. These findings led us to further discover that elevated renal CD73 contributes to excess adenosine signaling via ADORA2B activation that directly stimulates endothelin-1 production in a hypoxia-inducible factor-α-dependent manner and underlies the pathogenesis of the disease. Finally, we revealed that hypoxia-inducible factor-α is an important factor responsible for angiotensin II-induced CD73 and ADORA2B expression at the transcriptional level.. Overall, our studies reveal that angiotensin II-induced renal CD73 promotes the production of renal adenosine that is a prominent driver of hypertensive CKD by enhanced ADORA2B signaling-mediated endothelin-1 induction in a hypoxia-inducible factor-α-dependent manner. The inhibition of excess adenosine-mediated ADORA2B signaling represents a novel therapeutic target for the disease.

Topics: 5'-Nucleotidase; Adenosine; Adult; Angiotensin II; Animals; Cells, Cultured; Chronic Disease; Endothelial Cells; Endothelin-1; Female; Gene Expression; GPI-Linked Proteins; Humans; Hypertension, Renal; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Receptor, Adenosine A2B; Signal Transduction; Vasoconstrictor Agents

Chronic kidney disease (CKD) is a prevalent life-threatening disease frequently associated with hypertension, progression to renal fibrosis, and eventual renal failure. Although the pathogenesis of CKD remains largely unknown, an increased inflammatory response is known to be associated with the disease and has long been speculated to contribute to disease development. However, the causative factors, the exact role of the increased inflammatory cascade in CKD, and the underlying mechanisms for its progression remain unidentified. Here we report that interleukin 6 (IL-6) expression levels were significantly increased in the kidneys collected from CKD patients and further elevated in CKD patients characterized with hypertension. Functionally, we determined that angiotensin II is a causative factor responsible for IL-6 induction in the mouse kidney and that genetic deletion of IL-6 significantly reduced hypertension and key features of CKD, including renal injury and progression to renal fibrosis in angiotensin II-infused mice. Mechanistically, we provide both human and mouse evidence that IL-6 is a key cytokine functioning downstream of angiotensin II signaling to directly induce fibrotic gene expression and preproendothelin 1 mRNA expression in the kidney. Overall, both the mouse and human studies reported here provide evidence that angiotensin II induces IL-6 production in the kidney, and that, in addition to its role in hypertension, increased IL-6 may play an important pathogenic role in CKD by inducing fibrotic gene expression and ET-1 gene expression. These findings immediately suggest that the IL-6 signaling is a novel therapeutic target to manage this devastating disorder affecting millions worldwide.

Topics: Adult; Angiotensin II; Animals; Biopsy; Blood Pressure; Disease Progression; Endothelin-1; Female; Fibrosis; Humans; Hypertension, Renal; Interleukin-6; Kidney; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Middle Aged; Organ Culture Techniques; Proteinuria; Renal Insufficiency, Chronic; Signal Transduction; Vasoconstrictor Agents

Increased production of tumor necrosis factor-α (TNF-α) in chronic kidney disease may be involved in the progression of renal failure and injury, and cardiovascular disease. We investigated the effect of TNF-α neutralization on renal failure, inflammation and fibrosis, and blood pressure in rats with renal failure.. Renal failure was induced by renal mass reduction and the animals were treated with PEG-sTNFR1, a pegylated form of soluble TNF type 1 receptor that neutralizes TNF-α, for 6 weeks. Systolic, diastolic and mean arterial pressures were higher in renal failure rats that were associated with increased serum creatinine, albuminuria and renal injury comprised of blood vessel media hypertrophy, focal and segmental glomerulosclerosis, tubular atrophy and interstitial inflammation and fibrosis. These changes were associated with greater levels of TNF-α, transforming growth factor (TGF)-β1, nuclear transcription factor NF-ĸB and cytosolic phospho-IĸB-α, and inflammatory markers expression (ICAM-1, VCAM-1 and MCP-1). Moreover, endothelin (ET)-1 production was also increased, whereas nitric oxide (NO) release was decreased. TNF-α neutralization reduced hypertension, albuminuria and renal inflammation and fibrosis, which were coupled to a reduction in renal NF-ĸB activation, inflammatory markers expression, TGF-β1 and ET-1 production, and an increase in NO release.. Neutralization of TNF-α in rats with renal failure decreases NF-ĸB activity that is associated with a reduction in renal TGF-β1 and ET-1 production, and an improvement of NO release. These effects likely reduce renal inflammation and fibrosis, and blood pressure indicating a pivotal role for TNF-α, at least, in the progression of renal injury.

Topics: Animals; Blood Pressure; Body Weight; Chemokine CCL2; Disease Progression; Endothelin-1; Fibrosis; Heart Rate; Humans; Hypertension, Renal; Intercellular Adhesion Molecule-1; Male; NF-kappa B; Nitric Oxide Synthase Type III; Polyethylene Glycols; Rats; Rats, Sprague-Dawley; Receptors, Tumor Necrosis Factor, Type I; Renal Insufficiency, Chronic; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

The study is to observe the effect of racemic TJ0711 on blood pressure and heart rate as well as protection of cardiovascular system of renal hypertensive rats after long-term administration. The renal hypertensive models were established by the two-kidney, one-clip (2K1C) method in Wistar rats. Four weeks later, assigned the rats whose SBP had increased at least 4 kPa randomly into 5 groups: racemic TJ0711 10, 20 and 40 mg x kg(-1) groups, carvedilol control group, model group and sham group (n=10), ig administration once daily. The changes of BP (blood press) and HR (heart rate) before and after administration were measured by tail-cuff method weekly. Plasma samples of all animals were taken in 6-8 weeks, and plasma MDA as well as renin, angiotensin II (Ang II) and endothelin-1 (ET-1) levels were measured. Left ventricle was cut off after 9 weeks, and left ventricular weight index (LVWI) and hydroxyproline were measured. The significant decrease of the BP of TJ0711 40 mg x kg(-1) group was observed after TJ0711 ig administration for 4 weeks, and this effect remained till the end of the study. In 8th week, the systolic blood pressure values were: TJ0711 40 mg x kg(-1) group 18.93 +/- 1.82 kPa (vs 21.30 +/- 2.30 kPa, P < 0.05); 20 mg x kg(-1) group 20.68 +/- 3.29 kPa (vs 22.19 +/- 2.88 kPa). The plasma MDA level of all treated groups was significantly lower than that of model group, so were the plasma renin, Ang II and ET-1 levels (P < 0.05). LVWI and hydroxyproline content of myocardial tissue decreased to some extent, but was not significant as compared with that of model group. The study showed that TJ0711 repeated dosing could reduce BP level beginning from drug administration; besides block adrenal alpha and beta receptors to play an antihypertensive role. The sustained antihypertensive effect also related to reduce plasma vasoconstrictor substances and oxidation product MDA. These effects benefited cardiovascular protection.

Topics: Angiotensin II; Animals; Antihypertensive Agents; Blood Pressure; Endothelin-1; Female; Heart Rate; Heart Ventricles; Hydroxyproline; Hypertension, Renal; Longitudinal Studies; Male; Malondialdehyde; Organ Size; Phenoxypropanolamines; Random Allocation; Rats; Rats, Wistar; Renin

Previous investigations suggested that agonistic autoantibodies to the angiotensin II type I receptor (AT1-AA) might mediate a hypertensive response through dysregulation of the endothelin-1 system. AT1-AA induced hypertension was attenuated by the AT1 receptor and/or endothelin-1 type A receptor antagonists.. This study was undertaken to determine if AT1-AA induced hypertension was associated with renal endothelial dysfunction.. We compared the vascular reactivity of renal interlobar arteries from normal pregnant control rats and AT1-AA long-term infused pregnant rats in the presence and absence of endothelin type A (ET(A)) receptor antagonism. Renal endothelial function was tested using isolated renal interlobar arteries in a pressure myograph, which were exposed to acetylcholine or sodium nitroprusside.. Vasodilatory responses to the endothelial-dependent agonist acetylcholine were impaired in AT1-AA rats (74 [10]%) compared with normal pregnant controls (95 [5]%, P < 0.05). In the presence of ET(A) receptor antagonism, no differences were observed between controls or the AT1-AA treated group with regard to endothelial-dependent (acetylcholine) relaxation.. AT1-AA induced hypertension during pregnancy was associated with disparate renal endothelial responses to acetylcholine. The difference in renal vascular responses between AT1-AA and normal pregnant rats was abolished by ET(A) receptor blockade.

Topics: Animals; Autoantibodies; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Female; Hypertension, Pregnancy-Induced; Hypertension, Renal; Kidney; Pregnancy; Pregnancy, Animal; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1

Endothelin-1 (ET-1) is a vasoactive peptide with vasoconstrictor and mitogenic properties. We investigated whether plasma levels of C-terminal pro-ET-1 (CT-proET-1), a newly described stable fragment of the ET-1 precursor, are associated with target-organ damage in hypertension.. Participants included 981 African Americans (65 ± 9 years, 71% women) and 812 non-Hispanic whites (61 ± 9 years, 54% women) ascertained from sibships with hypertension. We measured plasma CT-proET-1 by an immunoluminometric assay. Measures of target-organ damage included the ankle-brachial index (ABI) and urinary albumin:creatinine ratio (UACR). Multivariable regressions analyses were employed to assess whether plasma CT-proET-1 levels were independently associated with ABI and UACR.. In hypertensive African Americans, higher plasma levels of CT-proET-1 were significantly associated with lower ABI (P < 0.01) and higher UACR (P < 0.01). After adjustment for age, sex, body mass index, systolic blood pressure (SBP) and diastolic blood pressure (BP), diabetes, serum glucose, insulin use, estimated glomerular filtration rate (eGFR), history of smoking, total and high-density lipoprotein cholesterol, medication use, and previous history of myocardial infarction (MI) or stroke, higher plasma levels of CT-proET-1 remained significantly associated with lower ABI (P < 0.01) and higher UACR (P = 0.02). In non-Hispanic white hypertensives, higher plasma levels of CT-proET-1 were weakly associated with higher UACR (P = 0.02) and with lower ABI (P = 0.07). After adjustment for the relevant covariates, no statistically significant associations between CT-proET-1 and ABI or UACR were present in whites.. Plasma levels of CT-proET-1 were independently associated with lower ABI and greater UACR in African American but not non-Hispanic white adults with hypertension.

Topics: Aged; Albuminuria; Ankle Brachial Index; Black or African American; Creatinine; Endothelin-1; Female; Humans; Hypertension, Renal; Male; Middle Aged; Multivariate Analysis; Protein Structure, Tertiary; Regression Analysis; Risk Factors; White People

The Br/+ mutant mouse displays decreased embryological expression of the homeobox transcription factor Six2, resulting in hertitable renal hypoplasia. The purpose of this study was to characterize the renal physiological consequences of embryonic haploinsuffiency of Six2 by analyzing renal morphology and function in the adult Br heterozygous mutant. Adult Br/+ kidneys weighed 50% less than those from wild-type mice and displayed glomerulopathy. Stereological analysis of renal glomeruli showed that Br/+ kidneys had an average of 88% fewer glomeruli than +/+ kidneys, whereas individual glomeruli in Br/+ mice maintained an average volume increase of 180% compared with normal nephrons. Immunostaining revealed increased levels of endothelin-1 (ET-1), endothelin receptors A (ET(A)) and B (ET(B)), and Na-K-ATPase were present in the dilated renal tubules of mutant mice. Physiological features of chronic renal failure (CRF) including elevated mean arterial pressure, increased plasma creatinine, and dilute urine excretion were measured in Br/+ mutant mice. Electron microscopy of the Br/+ glomeruli revealed pathological alterations such as hypercellularity, extracellular matrix accumulation, and a thick irregular glomerular basement membrane. These results indicate that adult Br/+ mice suffer from CRF associated with reduced nephron number and renal hypoplasia, as well as glomerulopathy. Defects are associated with embryological deficiencies of Six2, suggesting that proper levels of this protein during nephrogenesis are critical for normal glomerular development and adult renal function.

Topics: Animals; Down-Regulation; Endothelin-1; Gene Expression Regulation, Developmental; Homeodomain Proteins; Hypertension, Renal; Kidney Failure, Chronic; Kidney Glomerulus; Kidney Tubules; Mice; Mice, Inbred C3H; Mice, Mutant Strains; Microscopy, Electron; Nephrons; Receptors, Endothelin; Sodium-Potassium-Exchanging ATPase; Transcription Factors

Endothelin 1 (ET-1) and its receptors, ETA and ETB, play important roles in regulating renal function and blood pressure, and these components are expressed in sensory nerves. Activation of transient receptor potential vanilloid (TRPV) 1 channels expressed in sensory nerves innervating the renal pelvis enhances afferent renal nerve activity (ARNA), diuresis, and natriuresis. We tested the hypothesis that ET-1 increases ARNA via activation of ETB, whereas ETA counterbalances ETB in wild-type (WT) but not TRPV1-null mutant mice. ET-1 alone or with BQ123, an ETA antagonist, perfused into the left renal pelvis increased ipsilateral ARNA in WT but not in TRPV1-null mutant mice, and ARNA increases were greater in the latter. [Ala1, 3,11,15]-endothelin 1, an ETB agonist, increased ARNA that was greater than that induced by ET-1 in WT mice only. [Ala1, 3,11,15]-endothelin 1-induced increases in ARNA were abolished by chelerythrine, a protein kinase C inhibitor, but not by H89, a protein kinase A inhibitor. Chelerythrine, H89, and BQ788, an ETB antagonist, did not affect ARNA triggered by capsaicin in WT mice. Substance P release from the renal pelvis was increased by [Ala1, 3,11,15]-endothelin 1 in WT mice only, and the increase was abolished by chelerythrine but not by H89. Chelerythrine, H89, and BQ788 did not affect capsaicin-induced substance P release. Our data show that ET1 increases ARNA via activation of ETB, whereas ETA counterbalances ETB in WT but not in TRPV1-null mutant mice, suggesting that TRPV1 mediates ETB-dependent increases in ARNA, diuresis, and natriuresis possibly via the protein kinase C pathway.

Topics: Animals; Antihypertensive Agents; Cyclic AMP-Dependent Protein Kinases; Diuresis; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Hypertension, Renal; Isoquinolines; Kidney; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Natriuresis; Neurons, Afferent; Oligopeptides; Peptides, Cyclic; Piperidines; Protein Kinase C; Protein Kinase Inhibitors; Receptor, Endothelin A; Receptor, Endothelin B; Substance P; Sulfonamides; TRPV Cation Channels

We used patch-clamp electrophysiology to investigate regulation of the epithelial Na+ channel (ENaC) by endothelin-1 (ET-1) in isolated, split-open rat collecting ducts. ET-1 significantly decreases ENaC open probability by about threefold within 5 min. ET-1 decreases ENaC activity through basolateral membrane ETB but not ETA receptors. In rat collecting duct, we find no role for phospholipase C or protein kinase C in the rapid response of ENaC to ET-1. ET-1, although, does activate src family tyrosine kinases and their downstream MAPK1/2 effector cascade in renal principal cells. Both src kinases and MAPK1/2 signaling are necessary for ET-1-dependent decreases in ENaC open probability in the split-open collecting duct. We conclude that ET-1 in a physiologically relevant manner rapidly suppresses ENaC activity in native, mammalian principal cells. These findings may provide a potential mechanism for the natriuresis observed in vivo in response to ET-1, as well as a potential cause for the salt-sensitive hypertension found in animals with impaired endothelin signaling.

Topics: Animals; Cell Line, Transformed; Endothelin-1; Epithelial Sodium Channels; Female; Hypertension, Renal; Ion Channel Gating; Kidney Tubules, Collecting; Male; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinase 1; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; src-Family Kinases

Mice with a collecting duct-specific deletion of endothelin-1 are hypertensive and have impaired Na excretion. Because endothelin-1 activates NO synthase (NOS) in the collecting duct, we hypothesized that impaired renal NO production in knockout mice exacerbates the hypertensive state. Control and knockout mice were treated chronically with N(G)-nitro-l-arginine methyl ester, and blood pressure (BP) and urinary nitrate/nitrite excretion were assessed. On a normal Na diet, knockout systolic BP was 18 mm Hg greater than in controls. N(G)-nitro-l-arginine methyl ester increased BP in control mice by 30 mm Hg and 10 mm Hg in collecting duct-specific deletion of endothelin-1 knockout mice, thereby abolishing the difference in systolic BP between the groups. A high-Na diet increased BP similarly in both groups. Urinary nitrate/nitrite excretion was lower in knockout mice than in controls on normal or high Na intake. In separate experiments, renal perfusion pressure was adjusted in anesthetized mice, and urinary nitrate/nitrite and Na excretion were determined. Similar elevations of BP increased urinary Na and nitrate/nitrite excretion in control mice but to a significantly lesser extent in knockout mice. Isoform-specific NOS activity and expression were determined in renal inner medulla homogenates from control and knockout mice. NOS1 and NOS3 activities were lower in knockout than in control mice given normal or high-Na diets. However, NOS1 or NOS3 protein expressions were similar in both groups on normal or high-Na intake. These data demonstrate that collecting duct-derived endothelin-1 is important in the following: (1) chronic N(G)-nitro-l-arginine methyl ester-induced hypertension; (2) full expression of pressure-dependent changes in sodium excretion; and (3) control of inner medullary NOS1 and NOS3 activity.

Topics: Animals; Blood Pressure; Diuresis; Endothelin-1; Enzyme Inhibitors; Heart Rate; Hypertension, Renal; Kidney Medulla; Kidney Tubules, Collecting; Mice; Mice, Knockout; Natriuresis; NG-Nitroarginine Methyl Ester; Nitrates; Nitric Oxide; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Nitrites; Sodium

The pathogenesis of renal hypertension has not yet been fully clarified. As the potential role of endothelin-1 (ET-1) and nitric oxide (NO) has been postulated, their concentrations were determined in plasma and urine of diabetic patients. The study included 30 diabetic patients (both IDDM and NIDDM) with initial or advanced diabetic nephropathy (decreased endogenous creatinine clearance, proteinuria) and 20 healthy control subjects. The correlation with blood pressure and other renal function parameters was monitored and compared with the control group. Also, the effect of ACE inhibitors (ACEI) on ET-1 and NO patterns was monitored in correlation with arterial hypertension. In diabetic patients that did not receive ACEI therapy, the increase in plasma ET-1 was associated with both systolic and diastolic blood pressure elevation, whereas in those administered ACEI the increase in plasma ET-1 was associated with a systolic blood pressure decline. In addition, the increase in plasma NO was accompanied by a statistically significant decline of both systolic and diastolic blood pressure in diabetic patients receiving ACEI.

Topics: Aged; Blood Pressure; Diabetic Nephropathies; Endothelin-1; Female; Humans; Hypertension, Renal; Male; Nitric Oxide

Intradialysis hypertension is a frustrating complication among hemodialysis (HD) patients. This study was conducted to investigate the physiological changes during intradialytic hypertension. The beat-to-beat continuous heart rate, hematocrit (Hct) changes during HD, serum levels of nitric oxide, plasma levels of catecholamine, renin, endothelin (ET-1), cardiac output (CO), and peripheral vascular resistance (PVR) were measured before and after HD in patients prone to develop intradialysis hypertension (n = 30) and from age, sex-matched control HD subjects (n = 30). It was found that the baseline values of Hct, serum levels of nitric oxide, plasma levels of catecholamine, renin, and ET-1, CO, PVR, and power index (low frequency/high frequency ratios) of heart rate variability were not significantly different between the patients and control subjects. In the hypertension-prone group, the plasma levels of catecholamine, renin, and the serial measurements of power index, did not show significant changes. However, the patients showed a significant elevation of systemic vascular resistance (56.8 +/- 9.2% vs 17.7 +/- 9.5; P < 0.05), ET-1 (510.9 +/- 43.3 vs 276.7 +/- 30.1 pg/ml; P < 0.05) and a significant decrease of nitric oxide (NO)/ET-1 balance (0.018 +/- 0.003 vs 0.034 +/- 0.005; P < 0.05) at the end of HD compared with the control patients. It was found that the physiological changes in intradialysis hypertension patients were characterized by inappropriately increased PVR through mechanisms that did not involve sympathetic stimulation or renin activation but might be related with altered NO/ET-1 balance.

Topics: Autonomic Nervous System; Blood Urea Nitrogen; Cardiac Output; Case-Control Studies; Catecholamines; Endothelin-1; Female; Heart Rate; Hematocrit; Humans; Hypertension, Renal; Kidney Failure, Chronic; Male; Middle Aged; Nitric Oxide; Renal Dialysis; Renin; Vascular Resistance

Collecting duct (CD)-derived endothelin-1 (ET-1) inhibits renal Na reabsorption and its deficiency increases blood pressure (BP). The role of CD endothelin B (ETB) receptors in mediating these effects is unknown. CD-specific knockout of the ETB receptor was achieved using an aquaporin-2 promoter-Cre recombinase transgene and the loxP-flanked ETB receptor gene (CD ETB KO). Systolic BP in mice with CD-specific knockout of the ETB receptor, ETA receptor (CD ETA KO) and ET-1 (CD ET-1 KO), and their respective controls were compared during normal- and high-salt diet. On a normal-sodium diet, CD ETB KO mice had elevated BP, which increased further during high salt feeding. However, the degree of hypertension in CD ETB KO mice and the further increase in BP during salt feeding were lower than that of CD ET-1 KO mice, whereas CD ETA KO mice were normotensive. CD ETB KO mice had impaired sodium excretion following acute sodium loading. Aldosterone and plasma renin activity were decreased in CD ETB KO mice on normal- and high-sodium diets, while plasma and urinary ET-1 levels did not differ from controls. In conclusion, the CD ETB receptor partially mediates the antihypertensive and natriuretic effects of ET-1. CD ETA and ETB receptors do not fully account for the antihypertensive and natriuretic effects of CD-derived ET-1, suggesting paracrine effects of this peptide.

Topics: Aldosterone; Animal Feed; Animals; Blood Pressure; Endothelin-1; Hypertension, Renal; Kidney Tubules, Collecting; Mice; Mice, Knockout; Natriuresis; Paracrine Communication; Receptor, Endothelin B; Renin; Sodium Chloride, Dietary

Vasopeptidase inhibitors by definition inhibit both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), therefore they may exceed the effect of ACE inhibitors in the treatment of hypertension. The present study investigated the effect of the vasopeptidase inhibitor AVE7688 in comparison to the ACE inhibitor ramipril on systolic blood pressure (SBP) and endothelial function in renovascular hypertension.. Wistar-Kyoto rats with renovascular hypertension (two-kidney one-clamp-model) were randomized 2 weeks after unilateral clamping of the right renal artery for 3 weeks' oral treatment with either AVE7688 (30 mg/kg/day), ramipril (1 mg/kg/day) or placebo. SBP was measured by the tail-cuff method and endothelium-dependent and -independent vascular function was assessed in isolated preconstricted (norepinephrine 10(-7) mol/l) aortic rings as relaxation to acetylcholine (10(-10)-10(-4) mol/l) and sodium nitroprusside (10(-10)-10(-4) mol/l), respectively.. Two weeks after clamping, SBP was significantly elevated (196 +/- 16 vs. 145 +/- 8 mm Hg for sham-operated rats; p < 0.01) and further increased in placebo-treated animals to 208 +/- 19 mm Hg. Treatment with AVE7688 and ramipril had a similar blood pressure-lowering effect (119 +/- 8 and 124 +/- 10 mm Hg, respectively; p < 0.01 vs. placebo). Maximum endothelium-dependent relaxation was reduced in hypertensive rats (72 +/- 6 vs. 99 +/- 7% in control rats; p < 0.05). Endothelium-dependent relaxation was restored by AVE7688 (101 +/- 6%) and ramipril (94 +/- 8%), respectively, whereas endothelium-independent relaxation was comparable in all groups.. In renovascular hypertension the vasopeptidase inhibitor AVE7688 exhibited similar blood pressure-lowering and endothelial protective properties as compared to the ACE inhibitor ramipril. Therefore, in high renin models of hypertension, vasopeptidase inhibition may be considered an alternative treatment option to ACE inhibition.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Endothelin-1; Endothelium, Vascular; Heart Rate; Heterocyclic Compounds, 3-Ring; Hypertension, Renal; Male; Neprilysin; Peptidyl-Dipeptidase A; Ramipril; Rats; Rats, Inbred WKY; Vasodilation

trans-Resveratrol (resveratrol) has been shown to have beneficial effects on the cardiovascular system in a number of studies. It is, however, unclear whether this naturally occurring compound can protect against cardiac hypertrophy. The aim of the present study was to investigate the effects of resveratrol on cardiac hypertrophy in vivo and the potential underlying mechanisms involving endothelin (ET), angiotensin (Ang) II and nitric oxide (NO) in partially nephrectomized rats. Animal models bearing cardiac hypertrophy were replicated in male Sprague-Dawley rats following partial nephrectomy (PNX). Resveratrol (10 or 50 mg/kg) was administered to rats by gavage for 4 weeks. Simultaneous PNX and sham operation controls were simultaneously established in the present study. The systolic blood pressure (SBP) of rats was measured at baseline and, along with heart weight, after 4 weeks treatment. Serum ET-1, AngII and NO concentrations were determined. In the present study, it was shown that, compared with rats in the sham-operated group, rats in the PNX group had significantly higher SBP (154.1 +/- 22.7 mmHg), heart weight (1.69 +/- 0.24 g) and serum ET-1 (125.70 +/- 26.27 pg/mL) and AngII serum concentrations (743.63 +/- 86.50 pg/mL), whereas serum NO concentrations were lower (21.1 +/- 6.9 micromol/L; all P < 0.05). These values in the sham control group were 114 +/- 10 mmHg, 1.28 +/- 0.13 g, 52.44 +/- 21.85 pg/mL, 528.7 +/- 158.5 pg/mL and 53.21 +/- 23.87 micromol/L, respectively. After 4 weeks treatment with 50 mg/kg resveratrol, SBP, heart weight and ET-1 and AngII concentrations had decreased to 135.4 +/- 15.8 mmHg, 1.39 +/- 0.15 g, 97.11 +/- 26.74 pg/mL and 629.64 +/- 116.18 pg/mL, respectively. However, the serum NO concentration had increased to 40.1 +/- 14.6 micromol/L. These values were significantly different from those obtained for the PNX group. In conclusion, trans-resveratrol appears to be able to protect against the increase in SBP and subsequent cardiac hypertrophy in vivo and the mechanisms responsible may involve, at least in part, modulation of NO, AngII and ET-1 production.

Topics: Angiotensin II; Animals; Blood Pressure; Cardiomegaly; Cardiovascular Agents; Endothelin-1; Hypertension, Renal; Male; Myocardium; Nephrectomy; Nitric Oxide; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes

As yet, there are only limited data available on the exact role of endothelin (ET) acting through endothelin-A (ETA) receptors in renal sodium and water regulation and the potential functional implications of an interaction of the renal ET system with renal nerves in normotensive and spontaneously hypertensive rats.. Experiments were carried out in 64 male conscious spontaneously hypertensive rats and in 56 normotensive Wistar-Kyoto (WKY) rats. Bilateral renal denervation (BRD) was performed in 32 spontaneously hypertensive rats and 28 WKY rats 7 days before the experiments. The ETA receptor antagonist, BQ-123 (16.4 nmol/kg x min intravenously) or the endothelin-B (ETB) receptor antagonist, BQ-788 (25 nmol/kg x min intravenously) were infused at a rate of 25 microL/min for 50 minutes.. Renal papillary ET-1 concentration in intact spontaneously hypertensive rats was 67.8% lower than in intact WKY rats (154 +/- 40 fmol/mg protein vs. 478 +/- 62 fmol/mg protein, P < 0.01). BRD decreased papillary ET-1 by 73.5% in WKY rats to 127 +/- 19 fmol/mg protein (P < 0.001), but had no effect in spontaneously hypertensive rats (122 +/- 37 fmol/mg protein). BRD, BQ-123, or BQ-788 did not affect glomerular filtration rate (GFR) or renal blood flow (RBF) in any of the groups. In intact WKY, BQ-123 decreased urine flow rate (V) from 4.65 +/- 0.44 microL/min.100 g body weight to 2.44 +/- 0.35 microL/min.100 g body weight (P < 0.01), urinary excretion of sodium (UNaV) from 238.2 +/- 27.4 to 100.2 +/- 17.0 (P < 0.01) and potassium (UKV) from 532.1 +/- 62.6 nmol/min.100 g body weight to 243.0 +/- 34.2 nmol/min.100 g body weight (P < 0.001), whereas BQ-788 decreased only V and UNaV. In renal denervated WKY, BQ-123 or BQ-788 did not alter V, UNaV, or UKV. In intact spontaneously hypertensive rats BQ-123 but not BQ-788 decreased V from 3.94 +/- 0.48 microL/min.100 g body weight to 2.55 +/- 0.44 microL/min.100 g body weight (P < 0.05). In renal denervated spontaneously hypertensive rats neither BQ-123 nor BQ-788 affected V, UNaV, or UKV.. An interaction between ET and renal nerves is involved in the control of renal function. Moreover, renal nerves participate in the regulation of ET-1 production within the kidney. Finally, decreased synthesis of ET-1 in the renal papilla of spontaneously hypertensive rats may contribute to development and/or maintenance of hypertension due to modulation of renal excretory function.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Denervation; Endothelin A Receptor Antagonists; Endothelin-1; Hypertension, Renal; Kidney Cortex; Kidney Medulla; Male; Natriuresis; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Endothelin A; Urine

The prevalence of hypertension is high in renal transplant recipients. It has been suggested that calcineurin inhibitors (CI) contribute to the development of post-transplant hypertension by stimulating endothelin (ET-1)-mediated and/or reducing nitric oxide (NO)-mediated vascular tone.. We tested this hypothesis using 2 groups of renal transplant recipients [normotensive patients without a need for antihypertensive medication (Normo-Tx), and hypertensive patients requiring antihypertensives (Hyper-Tx)] in the presence of CI-based immunosuppression. In addition, we studied matched control subjects (C). BQ 123 (ET-A receptor antagonist), BQ123 + BQ788 (ET-A/B-receptor antagonist), ET-1, L-NMMA (NO-synthase inhibitor), acetylcholine (ACH; endothelium-dependent vasodilator), glyceroltrinitrate (GTN, NO donor), and norepinephrine (NE, endothelium-independent vasoconstrictor) were infused into the brachial artery. Forearm blood flow (FBF) was measured by venous occlusion plethysmography.. Endothelium-independent vasomotion in response to GTN and NE was similar in all groups. Vascular responses to selective and combined blockade of ET receptors in both Normo-Tx and Hyper-Tx did not exceed those of C. In fact, we observed a significantly lower increase in FBF after BQ 123 (P= 0.03), as well as after BQ 123/788 (P= 0.03) in Hyper-Tx compared with Normo-Tx. This was associated with an increased vascular sensitivity to exogenous ET-1 in Hyper-Tx compared with Normo-Tx (P= 0.04). Vasoconstriction after L-NMMA was reduced in Hyper-Tx compared with Normo-Tx (P= 0.015), while the response to ACH was reduced in both groups of Tx patients to a similar degree (P= 0.005 vs. C).. Our results do not support a major role for the vascular endothelin system in the hypertension of renal transplant recipients, whereas deficient baseline NO production may be a contributing factor.

Topics: Adult; Arterioles; Blood Flow Velocity; Calcineurin Inhibitors; Case-Control Studies; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Female; Forearm; Humans; Hypertension, Renal; Kidney Transplantation; Male; Middle Aged; Nitric Oxide; Vasoconstrictor Agents; Vasodilator Agents

A growing body of evidence suggests that the interplay between the endothelin (ET) and the renin-angiotensin systems (RAS) plays an important role in the development of the malignant phase of hypertension. The present study was performed to evaluate the role of an interaction between ET and RAS in the development of hypertension and hypertension-associated end-organ damage in homozygous male transgenic rats harboring the mouse Ren-2 renin gene (TGRs) under conditions of normal-salt (NS, 0.45% NaCl) and high-salt (HS, 2% NaCl) intake.. Twenty-eight-day-old homozygous male TGRs and age-matched transgene-negative male normotensive Hannover Sprague-Dawley (HanSD) rats were randomly assigned to groups with NS or HS intake. Nonselective ET(A/B) receptor blockade was achieved with bosentan (100 mg/kg/day). Systolic blood pressure (BP) was measured in conscious animals by tail plethysmography. Rats were placed into metabolic cages to determine proteinuria and clearance of endogenous creatinine. At the end of the experiment the final arterial BP was measured directly in anesthetized rats. Kidneys were taken for morphological examination.. All male HanSD fed either the NS or HS diet exhibited a 100% survival rate until 180 days of age (end of experiment). The survival rate in untreated homozygous male TGRs fed the NS diet was 41%, which was markedly improved by treatment with bosentan to 88%. The HS diet reduced the survival rate in homozygous male TGRs to 10%. The survival rate in homozygous male TGRs on the HS diet was significantly improved by bosentan to 69%. Treatment with bosentan did not influence either the course of hypertension or the final levels of BP in any of the experimental groups of HanSD rats or TGRs. Although the ET-1 content in the renal cortex did not differ between HanSD rats and TGRs, ET-1 in the left heart ventricle of TGRs fed the HS diet was significantly higher compared with all other groups. Administration of bosentan to homozygous male TGRs fed either the NS or HS diet markedly reduced proteinuria, glomerulosclerosis and attenuated the development of cardiac hypertrophy compared with untreated TGR.. Our data show that nonselective ET(A/B) receptor blockade markedly improves the survival rate and ameliorates end-organ damage in homozygous male TGRs without significantly lowering BP.

Topics: Animals; Animals, Genetically Modified; Antihypertensive Agents; Blood Pressure; Bosentan; Creatinine; Electrolytes; Endothelin Receptor Antagonists; Endothelin-1; Homozygote; Hypertension, Renal; Kidney; Male; Organ Size; Proteinuria; Rats; Rats, Sprague-Dawley; Renin; Sodium, Dietary; Sulfonamides

To evaluate the role of endothelin-1 (ET-1) in hypertension, we investigated density and distribution of ETA and ETB receptors in hearts and kidneys of deoxycorticosterone acetate (DOCA)-salt and 1 kidney -- 1 clip (1K1C) hypertensive rats.. Five groups of uninephrectomized Wistar rats were put on a low salt diet. Three groups of rats drank tap water and two groups received saline. One group of each regimen received DOCA subcutaneously and two corresponding groups without DOCA served as controls. The fifth group of rats had the renal artery clipped to induce 1K1C hypertension. At 6 weeks, mean arterial pressure (MAP) was recorded and membrane binding assays using 125I-ET-1 were carried out.. MAP was increased from control 122 +/- 3 to 155 +/- 6 and 218 +/- 11 mmHg in DOCA-salt and 1K1C rats, respectively, and cardiac weight index was increased. ETA receptors were predominantly expressed in the heart, whereas ETB receptors were predominant in the kidney. In the kidneys, the density of the ETB receptor subtype was upregulated in DOCA-salt and 1K1C rats from 160 +/- 8 to 217 +/- 12 and 190 +/- 2 fmol/mg (P < 0.05), respectively, and ETA tended to be downregulated (P = 0.057). Plasma renin activity was decreased in DOCA-salt rats from 17 +/- 3 to 0.17 +/- 0.01 ng/ml per h and increased in 1K1C rats on low salt diet to 30 +/- 5 ng/ml per h.. Since ETB is the predominant endothelin receptor in the kidneys, upregulation of the ETB receptor mediating vasodilation and downregulation of the ETA receptor mediating vasoconstriction would be compatible with a mainly renal counter-regulatory effect of endothelin-1 to hypertension. Both low and high renin models of hypertension may be affected.

Topics: Animals; Blood Pressure; Body Weight; Desoxycorticosterone; Endothelin-1; Heart Rate; Hypertension, Renal; Iodine Radioisotopes; Kidney; Myocardium; Radioligand Assay; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Renin; Sodium Chloride; Up-Regulation

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by hypertension and renal vasoconstriction. Mediators of these hemodynamic changes are not well understood, but evidence suggests that endothelial-derived mediators may participate.. Baseline measurements of blood pressure, proteinuria, and urinary nitrite/nitrate excretion were performed in control and cystic male Han:SPRD rats (6 weeks of age). They were then treated with the nitric oxide (NO), nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), or vehicle, for 6 weeks. After repeat systemic measurements, renal function was determined using inulin and para-aminohippurate (PAH) clearances. Levels of renal endothelin-1 (ET-1) and renal endothelial NOS (eNOS) proteins were determined, and immunohistochemistry localized renal eNOS and neuronal NOS (nNOS).. Administration of L-NAME aggravated systemic hypertension and renal vasoconstriction in the cystic rats, but did not affect the progression of proteinuria or cystic expansion. Cystic rats demonstrated marked increases in renal ET-1 and eNOS levels. L-NAME reduced eNOS expression in the membrane compartment, but increased eNOS in the cytosol. Localization studies indicated that renal eNOS was abundant in nonvascular compartments, but not in renal vascular and glomerular structures, whereas renal nNOS was diffusely diminished.. These alterations of endothelial-derived mediators (up-regulation of ET-1, and dysfunction of the NO system) contribute to vasoconstriction, and thereby are likely to contribute to the progressive loss of renal function in polycystic kidney disease (PKD).

Topics: Animals; Blood Pressure; Endothelin-1; Endothelium, Vascular; Enzyme Inhibitors; Hypertension, Renal; Male; NG-Nitroarginine Methyl Ester; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Nitrites; Polycystic Kidney, Autosomal Dominant; Rats; Rats, Sprague-Dawley; Vasoconstriction

Inhibition of nitric oxide synthases causes systemic hypertension and renal injury in rats. Our objective was to examine whether omapatrilat, a vasopeptidase inhibitor that inhibits both angiotensin-converting enzyme (ACE) and neutral endopeptidase, could induce better regression of renal injury than ACE inhibitor alone. Ten groups of rats were studied. They were fed either a normal (0.8% NaCl) or a high (4% NaCl) sodium diet. Eight of these groups received NG-nitro-L-arginine methyl ester (L-NAME, 20 mg x kg(-1) x d(-1)) in their drinking water. After 4 weeks, 1 group on each diet was killed and considered the L-NAME group, whereas the others received L-NAME alone, captopril (200 mg x kg(-1) x d(-1)) plus L-NAME, or omapatrilat (80 mg x kg(-1) x d(-1)) plus L-NAME for 4 additional weeks. In rats receiving L-NAME alone for 8 weeks, the mortality rate was approximately 90%, irrespective of the diet. In contrast, all rats survived in the captopril and the omapatrilat groups. In rats fed a normal-sodium diet, captopril and omapatrilat normalized systolic blood pressure and induced a complete regression of renal injury. Creatinine clearance and proteinuria were also normalized. In the high-sodium-diet groups, both treatments were less efficient: blood pressure remained elevated, and the regression of renal fibrosis was only partial. Although proteinuria decreased significantly with captopril or omapatrilat, creatinine clearance remained lower than in the controls. These results demonstrate that, in nitric oxide-deficient rats fed a normal-sodium diet, ACE and vasopeptidase inhibitors exhibit a marked renoprotective effect, whereas these treatments are less efficient in rats fed a high-sodium diet.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Blood Vessels; Captopril; Cyclic GMP; Endothelin-1; Enzyme Inhibitors; Fibrosis; Hypertension, Renal; Kidney; Male; Neprilysin; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Protease Inhibitors; Pyridines; Rats; Rats, Sprague-Dawley; Sodium Chloride; Survival Rate; Thiazepines

Topics: Animals; Antihypertensive Agents; Blood Pressure; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Glomerulosclerosis, Focal Segmental; Humans; Hypertension, Renal; Kidney; Nephritis, Interstitial; Receptor, Endothelin A; Receptor, Endothelin B; Renin; Renin-Angiotensin System; Systole

Secondary activation of the renin-angiotensin system plays a major role in the progression of chronic nephropathies, and blockade of endothelin (ET) receptors has been shown to confer nephroprotection in experimental models of proteinuric renal disease. We tested the nephroprotective potential of selective endothelin A receptor (ETA) and non-selective ETA and endothelin B (ETA/B) receptor blockade in the TGR(mRen2)27 transgenic rat model with renin-dependent hypertension (Ren2).. Ren2 animals were treated between 10 and 30 weeks of age with the selective ETA receptor antagonist darusentan (Ren2-ETA) and the ETA/B receptor antagonist Lu420627 (Ren2-ETA/B), and compared with transgene negative Sprague-Dawley (SD) controls. Since the elevated systolic blood pressure in Ren2 was not affected in either Ren2-ETA or Ren2-ETA/ETB, an additional Ren-2 group was treated with a non-antihypertensive dose of the angiotensin II type 1 receptor blocker eprosartan (Ren2-AT1).. During the 20-week observation period 35% of untreated Ren2, 30% of Ren2-ETA/B, 50% of Ren2-ETA, and 83% of Ren2-AT1 animals survived compared with 100% of SD rats. Renal endothelin-1 mRNA expression and proteinuria (4.1-fold) were significantly elevated in Ren2 compared with SD rats (P < 0.05, respectively). Proteinuria was normalized to SD control levels in Ren2-AT1 (P < 0.05) but increased further in Ren2-ETA (7.7-fold) and Ren2-ETA/B (15-fold) (P < 0.05, respectively). Glomerulosclerosis, tubulointerstitial damage and renal osteopontin mRNA expression were reduced in Ren2-AT1 (P < 0.05, respectively) but remained unchanged or increased further in Ren2-ETA and Ren2-ETA/B compared with Ren2.. ET receptor blockade fails to improve renal damage and mortality in primary renin-dependent hypertension.

Topics: Acrylates; Animals; Antihypertensive Agents; Aspartic Acid Endopeptidases; Blood Pressure; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Glomerulosclerosis, Focal Segmental; Hypertension, Renal; Imidazoles; Kidney; Male; Metalloendopeptidases; Models, Cardiovascular; Nephritis, Interstitial; Organ Size; Osteopontin; Proteinuria; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Renin; Renin-Angiotensin System; RNA, Messenger; Sialoglycoproteins; Systole; Thiophenes

Topics: Angiotensin II; Animals; Blood Glucose; Blood Pressure; Body Weight; Catecholamines; Diabetes Mellitus, Experimental; Endothelin-1; Hypertension, Renal; In Vitro Techniques; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renal Circulation; Thromboxanes; Vasoconstrictor Agents

The contraction induced by endothelin-1 (ET-1) was evaluated in tail arteries from normotensive two-kidney (2K) and hypertensive two-kidney-one-clip (2K-1C) rats. Since the maximal effect induced by ET-1 (0.1-30 or 100 nmol/l) was lower in 2K-1C (1.11 +/- 0.10 g) than in 2K (1.46 +/- 0.14 g) tail arteries, we evaluated the possible mechanisms involved in this blunted response. The sensitivity and efficacy of ET-1 were not affected by endothelium removal in either group. ET-1 failed to induce contraction of 2K and 2K-1C arteries in Ca(2+)-free medium. The contractile response induced by 10 nmol/l ET-1 was similarly inhibited by 0.1 microM nifedipine in arteries from 2K (81.6 +/- 3.3%) and 2K-1C (81.3 +/- 3.8%) rats. The effect of nifedipine was not potentiated by 10 mumol/l SK&F 96365. The cytosolic Ca2+ concentration ([Ca2+]c) was similarly increased by 30 nmol/l ET-1 in smooth muscle cells isolated from tail arteries of 2K (30.80 +/- 11.94 nmol/l) and 2K-1C (54.06 +/- 10.98 nmol/l) rats. In conclusion, the blunted contraction induced by ET-1 in 2K-1C tail arteries was not dependent on the endothelium or on decreased Ca2+ influx through channels sensitive to nifedipine or SK&F 96365. Since the increase of [Ca2+]c upon stimulation with ET-1 was similar in 2K and 2K-1C tail artery cells, probably the sensitivity to Ca2+ is decreased in 2K-1C tail arteries.

Topics: Animals; Arteries; Calcium; Cells, Cultured; Dose-Response Relationship, Drug; Endothelin-1; Hypertension, Renal; In Vitro Techniques; Male; Rats; Rats, Wistar; Tail; Vasoconstriction

Etiology of dialysis induced hypotension and hypertension remains speculative. There is mounting evidence that nitric oxide (NO) and endothelin (ET-1) may play a vital role in these hemodynamic changes. We examined the intradialytic dynamic changes in NO and ET-1 levels and their role in the pathogenesis of hypotension and rebound hypertension during hemodialysis (HD).. The serum nitrate + nitrite (NT), fractional exhaled NO concentration (FENO), L-arginine (L-Arg), NGNG-dimethyl-L-arginine (ADMA) and endothelin (ET-1) profiles were studied in 27 end-stage renal disease (ESRD) patients on HD and 6 matched controls. The ESRD patients were grouped according to their hemodynamic profile; Group I patients had stable BP throughout HD, Group II had dialysis-induced hypotension, and Group III had intradialytic rebound hypertension.. Pre-dialysis FENO was significantly lower in the dialysis patients compared to controls (19.3 +/- 6.3 vs. 28.6 +/- 3.4 ppb, P < 0.002). Between the experimental groups, pre-dialysis FENO was significantly higher in Group II (24.1 +/- 6.7 ppb) compared to Group I (17.8 +/- 5.6 ppb) and Group III (16.1 +/- 4.2 ppb; P < 0.05). Post-dialysis, FENO increased significantly from the pre-dialysis values (19.3 +/- 6.3 vs. 22.6 +/- 7.9 ppb; P=0.001). Pre-dialysis NT (34.4 +/- 28.2 micromol/L/L) level was not significantly different from that of controls (30.2 +/- 12.3 micromol/L/L). Serum NT decreased from 34.4 +/- 28.2 micromol/L/L at initiation of dialysis to 10.0 +/- 7.4 micormol/L/L at end of dialysis (P < 0.001). NT concentration was comparable in all the three groups at all time points. Pre-dialysis L-Arg (105.3 +/- 25.2 vs. 93.7 +/- 6.0 micromol/L/L; P < 0.05) and ADMA levels were significantly higher in ESRD patients (4.0 +/- 1.8 vs. 0.9 +/- 0.2 micromol/L/L; P < 0.001) compared to controls. Dialysis resulted in significant reduction in L-Arg (105.3 +/- 25.2 vs. 86.8 +/- 19.8 micromol/L/L; P < 0.005) and ADMA (4.0 +/- 1.8 vs. 1.6 +/- 0.7 micromol/L/L; P < 0.001) concentrations. Pre-dialysis ET-1 levels were significantly higher in ESRD patients compared to the controls (8.0 +/- 1.9 vs. 12.7 +/- 4.1 pg/mL; P < 0.002), but were comparable in the three study groups. Post-dialysis ET-1 levels did not change significantly in Group I compared to pre-dialysis values (14.3 +/- 4.3 vs.15.0 +/- 2.4 pg/mL, P=NS). However, while the ET-1 concentration decreased significantly in Group II (12.0 +/- 4.0 vs. 8.7 +/- 1.8 pg/mL, P < 0.05), it increased in Group III from pre-dialysis levels (12.8 +/- 3.8 vs. 16.7 +/- 4.5 pg/mL, P=0.06).. Pre-dialysis FENO is elevated in patients with dialysis-induced hypotension and may be a more reliable than NT as a marker for endogenous NO activity in dialysis patients. Altered NO/ET-1 balance may be involved in the pathogenesis of rebound hypertension and hypotension during dialysis.

Topics: Adult; Aged; Arginine; Endothelin-1; Female; Humans; Hypertension, Renal; Hypotension; Kidney Failure, Chronic; Male; Middle Aged; Nitric Oxide; Renal Dialysis

Topics: Adult; Angiotensin Receptor Antagonists; Endothelin-1; Female; Glomerulonephritis; Humans; Hypertension, Renal; Kidney Function Tests; Losartan; Male; Middle Aged; Nitric Oxide

We documented recently that increased endothelin-1 (ET-1) production in blood vessels and glomeruli of uraemic rats plays a crucial role in the development of hypertension and the progression of chronic renal failure. Normally, biological effects and local production of ET-1 are attenuated by the immediate release of nitric oxide (NO). Increasing evidence suggest, however, that NO release is impaired in chronic renal failure. We investigated whether supplementation with L-arginine, the natural precursor of NO, improves NO synthesis in uraemic rats with reduced renal mass and modulates vascular and renal ET-1 production as well as blood pressure and renal failure progression.. One week after surgical renal mass reduction, the uraemic and sham-operated animals received either no treatment or 0.1% L-arginine in drinking water for 5 weeks. In another series of experiments, uraemic rats received 1% L-arginine for 5 weeks. Immunoreactive-ET-1 (ir-ET-1) levels in plasma, urine, and vascular and renal tissue preparations was measured by radioimmunoassay after sample extraction and purification.. Before treatment, systolic blood pressure was significantly elevated in uraemic animals compared to sham-operated controls (156+/-7 vs 111+/-3 mmHg, respectively; P<0.01). Thereafter, systolic blood pressure increased further in uraemic-untreated rats (systolic blood pressure at week 5; 199+/-9 mmHg, P<0.01), whereas it remained similar in uraemic rats supplemented with 0.1% L-arginine (171+/-9 mmHg, NS). At the end of the study, serum creatinine and urea, proteinuria and ir-ET-1 excretion were significantly augmented, while creatinine clearance was reduced in uraemic animals compared to the controls. Ir-ET-1 level was also increased in glomeruli as well as in thoracic aorta, mesenteric arterial bed, and pre-glomerular arteries, and was associated with vascular hypertrophy as assessed by tissue weight. In contrast, ir-ET-1 level was diminished in the renal papilla of uraemic rats. Treatment with 0.1% L-arginine significantly reduced proteinuria and urinary ir-ET-1 excretion (P<0.05) as well as ir-ET-1 level in glomeruli (P<0.01) and in thoracic aorta (P<0.05). These changes were associated with increased plasma NO metabolites NO2/NO3 levels in L-arginine-treated animals (P<0.01) and reduced aortic hypertrophy (P<0.05). In contrast, supplementation with 1% L-arginine had no effect on systolic blood pressure in uraemic rats, but exacerbated proteinuria and urinary ir-ET-1 excretion and increased serum urea (P<0.05) were observed.. These results indicate that improvement of NO release with a low dose but not with a high dose of L-arginine significantly attenuates the development of hypertension and the progression of renal insufficiency in rats with reduced renal mass. These protective effects may be mediated in part by the reduction of vascular and renal ET-1 production.

Topics: Animals; Arginine; Blood Pressure; Dietary Supplements; Endothelin-1; Hypertension, Renal; Male; Rats; Rats, Sprague-Dawley; Up-Regulation; Uremia

This study is aimed at investigating the contraction and relaxation responses in the thoracic and abdominal aortae at various stages of hypertension. Hypertension in the rats was produced by aortic banding and the responses in the abdominal and thoracic aortic rings were studied 2 and 8 weeks after aortic banding. Contractile responses to phenylephrine ( 10(-6)M), KCl (80 mM) or to endothelin-1 ( 10(-12)to 10(-6)M) and the relaxation responses to acetylcholine ( 10(-7)to 10(-5)M) were similar in the thoracic and abdominal rings of normotensive rats. The intact thoracic rings from 2 week aortic-banded hypertensive rats (ABHR) showed attenuated responses to all the contractile agents used. However, the relaxation to acetylcholine was not altered. In the rings from 8 week ABHR, the responses to contractile agents were not significantly altered but the acetylcholine-induced relaxations were significantly attenuated. The endothelial-derived relaxing factors might act to antagonize the vasoconstrictive responses during the onset of hypertension but might be disabled, as the endothelial dysfunction becomes predominant after 8 weeks of hypertension. The results thus suggest that the contractile and relaxant responses are differentially altered during different stages of hypertension.

Topics: Acetylcholine; Animals; Aorta; Blood Pressure; Endothelin-1; Heart Ventricles; Hypertension, Renal; Male; Organ Size; Phenylephrine; Potassium Chloride; Rats; Rats, Sprague-Dawley; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

Topics: Animals; Arginine; Blood Pressure; Endothelin-1; Hypertension, Renal; Nitric Oxide; Rats; Uremia

To explore the influence of angiotensin-converting enzyme inhibitors (ACEI) on plasma endothelin (ET-1), nitric oxide (NO) and renal function in renal-hypertension patients.. Sixty renal-hypertension patients (Group II) were treated with ACEI (lotensin) for 10 weeks then we measure their blood pressure (BP), plasma ET-1, NO and renal functions (BUN, Scr and proteinuria) before and after the treatment. Thirty healthy persons (Group I) acted as control.. The level of plasma ET-1 was higher and plasma NO was lower in Group II than those in Group I. After the treatment of ACEI plasma ET-1 and proteinuria were decreased (P < 0.01), and NO increased in Group II significantly (P < 0.01), while BUN and Scr decreased in abnormal-renal function patients (Group II2) (P < 0.05, P < 0.01).. The Study indicates that: ACEI is effective to renal hypertension; it decreases plasma ET-1 and increases NO in the renal hypertension patients; ACEI may play an important role in protection of renal functions and prolonging the chronic renal failure.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Benzazepines; Blood Urea Nitrogen; Endothelin-1; Female; Humans; Hypertension, Renal; Kidney Function Tests; Male; Middle Aged; Nitric Oxide

The changes in renal hemodynamics that develop with aging in spontaneously hypertensive rats (SHR) were examined. Micropuncture studies revealed that glomerular capillary pressure was elevated in SHR at 9 mo of age compared with 3-mo-old SHR and 9-mo-old normotensive Wistar-Kyoto rats. Glomerular hypertension developed because of a small increase in systemic blood pressure and a decline in preglomerular vascular resistance, allowing transmission of elevated systemic pressure to the glomerular capillaries. The hemodynamic alterations were not a compensatory response to injury, inasmuch as vascular and glomerular morphology were normal in 9-mo-old SHR. To determine the mechanism of these changes, the activity of several vasoactive systems was examined. Similar changes in renal hemodynamics were observed in young and old SHR after blockade of nitric oxide production and after intravenous administration of endothelin. However, ANG II produced a proportionally greater reduction in glomerular filtration rate than renal blood flow in older SHR. These data suggest that reduced endogenous activity of the renin-angiotensin system leads to glomerular hypertension in aging SHR. Late development of glomerular hypertension may contribute to the subsequent appearance of glomerular sclerosis and progressive renal failure in these rats.

Topics: Aging; Angiotensin II; Animals; Endothelin-1; Enzyme Inhibitors; Hemodynamics; Hypertension, Renal; Kidney Glomerulus; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Punctures; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renal Circulation

The aim of the present study was to analyze whether the cardiac endothelin system contributes to cardiac remodeling in rats with 2-kidney, 1 clip (2K1C) renovascular hypertension. The endothelin system seems to be a promising candidate for cardiac remodeling because endothelin (ET)-1 promotes growth of cardiomyocytes in vitro and induces cardiac collagen synthesis. The activity of the cardiac endothelin system was analyzed by measuring cardiac tissue big ET-1 and ET-1 concentrations as well as by estimating the cardiac expression of the ETA and ETB receptors 10 days, 4 weeks, and 12 weeks after the renal artery was clipped. The effects of long-term treatment with ETA, ETB, and combined ETA/ETB receptor antagonists on cardiac hypertrophy, media/lumen ratio of intracardiac arteries, and left ventricular fibrosis were also analyzed. This study demonstrated that the overall left ventricular cardiac endothelin system has a similar activity in the early, middle, and late stages of 2K1C renovascular hypertension compared with sham-operated controls. Fibrosis of the left ventricle and hypertrophy of intracardiac arteries, however, were markedly altered after long-term treatment with endothelin receptor antagonists in a blood pressure-independent manner. These 2 effects are mediated by different subtypes of endothelin receptors. ETA receptor blockade completely normalized the hypertrophy of intracardiac arteries (P<0. 01 compared with 2K1C without treatment) in renovascular hypertension, whereas the ETB antagonist reduced cardiac fibrosis of the left ventricle (P<0.001 compared with 2K1C without treatment) to baseline values. This study demonstrates that the cardiac endothelin system plays an important role in the development of cardiac fibrosis as well as in hypertrophy of intracardiac arteries in 2K1C renovascular hypertensive rats.

Topics: Animals; Blood Pressure; Coronary Vessels; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Heart Rate; Hypertension, Renal; Male; Protein Precursors; Rats; Rats, Inbred WKY; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Ventricular Remodeling

In a new model of spontaneous hypertension, namely the Prague hypertensive rat (PHR), hypertension is transferred with a kidney transplanted from the PHR to its normotensive counterpart (PNR) by an as yet unknown mechanism. One candidate may be endothelin (ET), since this potent vasoconstrictor affects vascular tone, renal haemodynamics and renal excretory function, and all members of this peptide family are located within the kidney and act in an autocrine/paracrine fashion. In the present study we investigated, in the renal tissue of PHRs and PNRs: (1) preproET-1 and preproET-3 mRNAs as well as ET-1 and ET-3 peptide distribution, (2) endothelin-converting enzyme (ECE)-1 mRNA expression, and (3) ET receptors and their characteristics in membranes of glomeruli and papillae. In addition, plasma ET concentration and urinary ET excretion were determined. Quantitative measurements by competitive reverse transcription-polymerase chain reaction revealed ET-1 mRNA levels in the renal cortex from PHRs and PNRs of 1.09+/-0.13 and 1. 29+/-0.18 amol/microgram of total RNA respectively, and in red medulla of 2.72+/-0.82 and 3.30+/-0.68 amol/microgram respectively. In contrast, renal papilla from PHRs showed significantly lower levels of preproET-1 mRNA (1.81+/-0.64 amol/microgram of total RNA, compared with 4.25+/-0.82 amol/microgram in PNRs; each n=5; P<0.05). The ET-1 peptide concentration in papillary tissue was also significantly lower in PHRs than in PNRs (120.2+/-30.8 and 491.3+/-53.4 fmol/mg of protein respectively; n=5; P<0.01), whereas it was similar in cortex and medulla from PHRs and PNRs. The preproET-3 mRNA content in renal tissue was much lower than that of preproET-1 mRNA. It was significantly higher in red medulla from PHRs compared with that from PNRs (0.25+/-0.05 and 0.13+/-0.02 amol/microgram of total RNA respectively; P<0.05), but was similar in papillae of PHRs and PNRs (0.04+/-0.02 and 0.05+/-0.01 amol/microgram respectively; n=5). Cortical preproET-3 mRNA was at the lower limit of detection. Similarly, the ET-3 peptide concentration was slightly but significantly higher in the red medulla of PHRs compared with PNRs (15.4+/-2.0 and 8.8+/-0.8 fmol/mg of protein respectively; n=5; P<0. 05), whereas no differences in ET-3 peptide concentration were found in papillae from PHRs and PNRs. ECE-1 mRNA levels were similar in the renal cortex, red medulla and papillae from PHRs and PNRs, ranging between 0.34+/-0.03 and 0.56+/-0.12 amol/microgram of total

Topics: Actins; Animals; Aspartic Acid Endopeptidases; DNA, Complementary; Endothelin-1; Endothelin-3; Endothelin-Converting Enzymes; Endothelins; Hypertension, Renal; Male; Metalloendopeptidases; Organ Size; Polymerase Chain Reaction; Protein Precursors; Rats; Rats, Inbred Strains; Receptors, Endothelin; RNA, Messenger

Animal experiments have shown an increase in prepro-endothelin-1 (prepro-ET-1) mRNA expression in the clipped kidney but none in the aortic and mesenteric arteries in 2-kidney, 1-clip Goldblatt hypertensive rats. The present study was aimed at investigating whether plasma and renal endothelin-1 (ET-1) systems are differently activated in patients with renovascular hypertension (RH). The plasma concentration and urinary excretion of ET-1 were measured in 5 patients with RH (before and after successful renal angioplasty), in 7 patients with essential hypertension (EH), and in 8 normotensive control subjects. Immediately before renal angioplasty, plasma samples for ET-1 and plasma renin activity (PRA) measurements were withdrawn from the aorta and both renal veins. Unlike the PRA, the plasma ET-1 concentration did not significantly differ between the involved and the uninvolved sides. The urinary ET-1 excretion level (Fig 1) was markedly increased in patients with RH (30+/-4 ng/g urinary creatinine (UC) vs. 2.5+/-0.2 ng/g UC and 2.6+/-0.5 ng/g UC in control subjects and patients with EH, respectively; P<.001), whereas the plasma ET-1 concentration was normal (0.8+/-0.2 pg/mL vs. 0.65+/-0.3 pg/mL and 0.8+/-0.2 pg/mL in control subjects and EH, respectively, not significant). Renal angioplasty was followed in all patients by normalization of blood pressure and PRA. One week after angioplasty, urinary ET-1 decreased to one fourth of baseline (8.04+/-5.23 ng/g UC, P<.001 vs. values before angioplasty and P<.04 vs. control subjects) and normalized 1 month thereafter (3.13+/-1.62 ng/g UC, not significant vs. control subjects), whereas plasma ET-1 remained steady. The present findings clearly indicate that in patients with RH, urinary ET-1 excretion is increased, whereas plasma ET-1 concentration remains normal. Successful percutaneous transluminal renal angioplasty induced a notable reduction in ET-1 urinary excretion, whereas it did not affect ET-1 plasma concentration.

Topics: Aged; Aldosterone; Angioplasty; Arteriosclerosis; Blood Pressure; Echocardiography; Endothelin-1; Female; Humans; Hypertension, Renal; Male; Middle Aged; Ventricular Function, Left

To investigate the relationship between plasma endothelin(ET), nitric oxide(NO) levels and, renal hypertension and renal function.. The plasma concentration of ET-1 was detected by immunofluorescence assay. The plasma concentration of NO was detected by biochemistry assay.. 1. In renal disease patients, plasma concentration ET-1 was markedly elevated, and plasma concentration of NO was decreased, compared with the healthy subjects(P < 0.01). 2. Plasma concentration of ET-1 was markedly increased and plasma concentration of NO was decreased in the patients with renal hypertension. 3. Plasma level of ET-1 was higher, and plasma level of NO was lower in the patients with renal function damage than that of those without renal function damage. 4. BP, BUN and Scr were positively correlated with plasma ET-1, but they were negatively correlated with plasma concentration of NO.. Plasma ET-1 and NO may play an important role in pathogenesis of renal hypertension; the change of their levels may be related to the progress of these renal diseases.

Topics: Adult; Chronic Disease; Endothelin-1; Female; Glomerulonephritis; Humans; Hypertension, Renal; Kidney Function Tests; Lupus Nephritis; Male; Middle Aged; Nitric Oxide

Recently generated knockout mice with disrupted genes encoding endothelin (ET)-1 showed an elevation of arterial blood pressure (AP) and supplied an evidence for intrinsic ET-1 as one of the physiological regulators of systemic AP. Little is yet known, however, why deficiency of ET-1, which was originally found as a potent vasoconstrictor, led to higher AP in these mice. To address this apparent paradox, we first developed a method to measure renal sympathetic nerve activity (RSNA) in mice using rats as reference and successively compared it between normal and ET-1 deficient mice. RSNA was successfully recorded in urethane-anesthetized and artificially ventilated mice by a slight modification of the method used for rats. At basal condition, mean AP (MAP) and RSNA in ET-1 deficient mice (105+/-2 mmHg and 9.71+/-1.49 muVs, n=20) were significantly higher than those in wild-type mice (96+/-2 mmHg and 5. 07+/-0.70 muVs, n=25). Basal heart rate (HR) and baroreflex-control of HR was not significantly different between the two. On the other hand, resting RSNA, RSNA range, and maximum RSNA were significantly greater in ET-1 deficient mice, and thus MAP-RSNA relationship was upwards reset. Hypoxia-induced increase in RSNA was not different between ET-1 deficient (73.4+/-9.4%) and wild-type mice (91.2+/-12.0%), while hypercapnia-induced one was significantly attenuated in ET-1 deficient mice (18.8+/-3.6 vs. 39.1+/-5.2% at 10% CO2). These results indicate that endogenous ET-1 participates in the central chemoreception of CO2 and reflex control of the RSNA. Baroreceptor resetting and normally preserved hypoxia-induced chemoreflex may explain a part of the elevation of AP in ET-1 deficient mice.

Topics: Animals; Blood Gas Analysis; Blood Pressure; Cardiovascular System; Chemoreceptor Cells; Endothelin-1; Hypercapnia; Hypertension, Renal; Kidney; Male; Medulla Oblongata; Mice; Mice, Knockout; Pressoreceptors; Rats; Rats, Sprague-Dawley; Receptors, Endothelin; Reflex; Respiration; Sympathetic Nervous System

The purpose of this study was to determine the effect of chronic ETA receptor blockade, using the orally active antagonist A-127722 in rats with reduced renal mass. The initial series of experiments was designed to characterize the effects of the ETA-selective antagonist A-127722 on arterial pressure and renal function when administered via drinking water over a 4-wk period. Male Sprague-Dawley rats were acclimated to metabolism cages, and baseline 24-h urine collections were obtained. A-127722 was placed in the drinking water at concentrations that delivered doses of 1 to 10 mg/kg per d. The compound had no effect on any of the variables measured, including arterial pressure, food and water intake, urine volume, and sodium and potassium excretion. In a separate group of rats, ETA receptor blockade was verified after 3 d of drinking water containing A-127722. Rats were anesthetized, a jugular vein catheter was inserted for infusions, and a femoral artery catheter was used for monitoring arterial pressure. The pressor response to intravenous injection of Big endothelin-1 (1 nmol/kg, intravenously) was inhibited by > 50% in rats given A-127722 at 10 mg/kg per d, which confirms the efficacy of A-127722 in blocking ETA-mediated responses when placed in drinking water. In an additional series of experiments, rats were anesthetized, the right kidney was removed, and two of three major branches of the left renal artery were ligated. After recovery, rats were returned to their cages and given A-127722 in the drinking water to deliver 1 or 10 mg/kg per d. Control rats underwent the same surgical procedures but were given tap water to drink. After 4 wk, rats that were treated with A-127722 developed similar increases in arterial pressure and urinary protein excretion as rats that received tap water. Therefore, although the ETA receptor antagonist A-127722 can inhibit ETA-mediated hypertension, it has no effect on hypertension produced by a reduction in renal mass. It is concluded that ETA receptor activation does not play a significant role in the functional derangements associated with renal mass reduction in the rat.

Topics: Administration, Oral; Animals; Atrasentan; Blood Pressure; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Hypertension, Renal; Kidney; Kidney Failure, Chronic; Male; Nephrectomy; Protein Precursors; Proteinuria; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A

Surgical ablation of renal mass leads to a reduction in kidney function and commonly to the development of hypertension and chronic renal failure (CRF) in rats. The objective of this study was to determine whether endothelin (ET)-1 is involved in the maintenance of the hypertension that accompanies loss of renal mass. First, we demonstrated the antihypertensive efficacy of PD 155080, a selective, orally active ET(A) receptor antagonist, in a group of rats made hypertensive by continuous intravenous infusion of ET-1 (2.5 pmol x kg(-1) x min[-1]) for 7 days. ET-1 produced a sustained hypertension and PD 155080 (56.4 micromol/kg [25mg/kg] BID PO) normalized blood pressure (BP) during the 5 days of drug administration. In a second experiment, Sprague-Dawley rats underwent a 5/6 reduction in renal mass (RRM); 4 weeks later, PD 155080 administered for 7 days resulted in a sustained reduction in BP. Sham-operated rats also showed a slight hypotensive response to PD 155080 administration. Plasma urea nitrogen, plasma creatinine, urinary protein excretion, and creatinine clearance were not altered by PD 155080 administration in RRM or sham rats. In a third experiment, we investigated the contribution of the renin-angiotensin system to BP control in RRM rats given PD 155080. In these rats, PD 155080 reduced BP during 5 treatment days, and this antihypertensive effect was not altered by coadministration of the angiotensin-converting enzyme inhibitor enalapril in the drinking water (508 micromol/L [250 mg/L]). These results demonstrate that (1) ET-1 plays a role in established RRM hypertension through activation of the ET(A) receptor subtype, (2) lowering blood pressure with PD 155080 in RRM rats does not adversely affect renal function, and 3) the antihypertensive effect of ET(A) receptor antagonism is not opposed by the renin-angiotensin system.

Topics: Animals; Blood Pressure; Dioxoles; Enalapril; Endothelin Receptor Antagonists; Endothelin-1; Hypertension; Hypertension, Renal; Infusions, Intravenous; Kidney Failure, Chronic; Male; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Renin-Angiotensin System

Elevated plasma and urinary endothelin-1 (ET-1) levels have been reported in patients with renal failure as well as in remnant kidney models of chronic renal failure. We investigated whether these changes are related to increased ET-1 production in cardiovascular and renal tissues of rats with reduced renal mass. In uremic rats, systolic blood pressure rose in parallel with the progression of renal insufficiency. At week 6, changes in systolic blood pressure were positively correlated with serum creatinine levels (r = 0.728, p < 0.01). Plasma immunoreactive ET-1 (ir-ET-1) concentration was similar in uremic rats and sham-operated controls. In contrast, urinary ir-ET-1 excretion was significantly greater in uremic rats and was correlated with the elevation of serum creatinine and proteinuria (r = 0.795, and 0.922, p < 0.01, respectively). Compared to the controls, ir-ET-1 concentration in the thoracic aorta, preglomerular arteries and glomeruli were 1.4-, 3.5- and 6.7-fold higher, respectively, in uremic rats (p < 0.01) than in the controls. However, ir-ET-1 concentration in the mesenteric arterial bed and the left ventricle remained similar in the 2 groups, whereas it was significantly lower in the renal papilla of uremic rats (p < 0.01). Thus, ET-1 production is unchanged or slightly increased in extrarenal cardiovascular tissues of rats with reduced renal mass. In contrast, ET-1 production is significantly augmented in preglomerular arteries and glomeruli, but reduced in the papilla, suggesting that increased urinary ir-ET-1 excretion in uremic rats reflects ET-1 overproduction in the former renal tissues. Elevated ET-1 production in blood vessels and glomeruli may thus play a key role in the aggravation of hypertension and the progression of renal insufficiency in this rat remnant kidney model of chronic renal failure.

Topics: Animals; Biomarkers; Blood Vessels; Disease Models, Animal; Disease Progression; Endothelin-1; Hypertension, Renal; Kidney; Kidney Failure, Chronic; Kidney Glomerulus; Male; Organ Size; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Uremia

Plasma endothelin-1 (ET-1) and calcitonin gene related peptides (cGRP) were studied by immunoradiological method in 60 hemodialysis (HD) patients. The results showed that: (1) Plasma level of ET-1 and cGRP were increased in the HD patients. (2) Plasma level of ET-1 and cGRP varied in different times of HD. (3) A significantly positive relation between plasma ET-1 and blood pressure (BP) existed in the HD patients, while a significantly negative relation between plasma cGRP and BP existed in the HD patients. The results suggest that ET-1 and cGRP are major factors which lead to BP changes in HD patients.

Topics: Adult; Blood Pressure; Calcitonin Gene-Related Peptide; Endothelin-1; Female; Humans; Hypertension, Renal; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis

We reported previously that the endothelin converting enzyme (ECE) inhibitor phosphoramidon lowers mean arterial pressure (MAP) when infused in conscious, spontaneously hypertensive rats (SHRs). In this study we determined the dose-response relationship for this action in SHRs and in a high-renin hypertensive model, the renal artery-ligated rat. We also determined whether the ETA receptor antagonist BQ-123 (cyclo [D-Trp-D-Asp-Pro-D-Val-Leu]) might lower MAP in hypertensive rats. Phosphoramidon lowered MAP by 9 +/- 4, 31 +/- 4, and 40 +/- 4 mm Hg after 5 h when infused in SHRs at 10, 20, and 40 mg/kg/h. This lowering of MAP was associated with dose-related inhibition of the pressor response to a bolus intravenous injection of big ET (1-39) at 1 nmol/kg. BQ-123 also lowered MAP in SHRs (by 25 +/- 3 mm Hg), but only at a very high dose (50 mg/kg/h for 5 h). At this dose, BQ-123 blocked the pressor response to a bolus intravenous injection of ET-1 (1 nmol/kg), but the blockade was incomplete. Phosphoramidon infused in conscious, renal hypertensive rats lowered MAP by 31 +/- 9, 46 +/- 8, and 54 +/- 1 mm Hg after 5 h at 10, 20, and 40 mg/kg/h, respectively. This lowering of MAP was associated with blockade of the pressor response to big ET (1-39). BQ-123 did not lower MAP in renal hypertensive rats when infused at 30 mg/kg/h for 5 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amino Acid Sequence; Angiotensin I; Animals; Aspartic Acid Endopeptidases; Blood Pressure; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Glycopeptides; Hypertension; Hypertension, Renal; Male; Metalloendopeptidases; Molecular Sequence Data; Neprilysin; Peptides, Cyclic; Protein Precursors; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley