Increase In Plasma Endothelin-1 Research Articles

Effect of Endothelin-1 on Resting Blood Pressure and the Blood Pressure Response to Hypoxia in Healthy Young Men

Objectives: Upregulation of endothelin-1 (ET-1) and its receptors have been linked to increases in hypoxic sensitivity of the carotid chemoreceptors and the development of hypertension. As such, chemoreflex sensitization has been shown in pre-clinical models to be attenuated by ET-1 receptor blockade. Herein, we sought to assess a role for ET-1 in the maintenance of resting blood pressure (BP) in healthy young men and determine whether chemoreflex control of BP could be altered by ET-1 blockade. We hypothesized endothelin receptor antagonism with oral bosentan would lower resting BP in healthy young men as well as the acute BP response to hypoxia. Methods: Twenty-four healthy young men (31±5 yrs, 26±3 kg/m2) completed two study visits (control, bosentan) separated by a minimum of 1 week. The nonspecific endothelin receptor antagonist bosentan (62.5 mg) was taken by mouth twice daily for 3 days prior to the second study visit. On each visit, beat-by-beat BP was assessed under 3 inspiratory air conditions: 1) steady-state normoxia (FiO2 0.21), 2) chemoreflex excitation produced by acute, graded hypoxia (FiO2 0.05 – 0.21), 3) chemoreflex inhibition elicited by transient hyperoxia (FiO2 1.00). Results: Oral bosentan treatment resulted in an increase in plasma ET-1 (0.9±0.9 to 1.3±0.6 pg/mL, p=0.004), supporting receptor blockade. Resting diastolic and mean BP were reduced following 3 days of bosentan treatment compared to control (diastolic: 73±5 to 69±7 mmHg, p=0.007; mean: 93±7 to 88±7 mmHg, p=0.005) with no change in systolic BP (p=0.507). Notably, the BP response to both acute hypoxia (-0.48±0.38 to -0.25±0.31 mmHg/%, p=0.004) and hyperoxia (main effect of bosentan, p=0.025) were attenuated following bosentan. Conclusions: Acute oral bosentan treatment resulted in a reduction in resting BP in healthy young men. The effect of endothelin receptor inhibition with bosentan further attenuated the rise in BP during chemoreflex excitation via acute, graded hypoxia as well as the fall in BP during chemoreflex inhibition (transient hyperoxia). Together these data support a role for ET-1 in control of resting BP in healthy young men, possibly through a chemoreceptor-mediated mechanism. NIH HL130339 (JL), Mayo Clinic Center for Biomedical Discovery (JL, SB). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

SUN-079 Loss of Endothelial CEACAM1 Induces Atherogenic Fibrous Plaque Formation

Loss of Endothelial CEACAM1 Induces Atherogenic Fibrous Plaque Formation Carcinoembryonic antigen-related cell adhesion molecule1 (CEACAM1), a substrate of insulin and VEGF receptors, regulates insulin sensitivity by promoting hepatic insulin clearance. Global Ceacam1 gene deletion impaired insulin clearance to cause chronic hyperinsulinemia and peripheral insulin resistance [1]. It also caused spontaneous endothelial dysfunction and hypertension [2] in addition to atherogenic-like plaques in addition to lipid and macrophage deposition, as well as elevated leukocyte rolling and adhesion to the aortic wall in the absence of hypercholesterolemia and hypertriglyceridemia when the mutation was propagated on the C57BL/6 genetic background [3]. Because CEACAM1 promotes endothelial survival, vascular integrity, and pro-angiogenesis, we investigated the cell-autonomous role of endothelial cell CEACAM1 in the pathogenesis of atherosclerosis. To this aim, we generated endothelial cell CEACAM1 knockout mice and backcrossed them with low density lipoprotein receptor deficient mice (ldlr–/– VECad+Cc1fl/fl) prior to feeding them a high cholesterol diet for 3 months and characterizing both of their metabolic and vascular phenotypes. By comparison to ldlr–/– mice, the mutants exhibited insulin sensitivity and moderate hypercholesterolemia. However, they exhibited decreased nitric oxide (NO) bioavailability with a reciprocal increase in plasma endothelin-1 and increased oxidative stress. The mutants also developed fibrotic plaques with elevated macrophage recruitment on the aortic wall without lipid deposition. We postulate that endothelin-1 contributes to fibrosis in these mice. Elevated endothelin-1 levels could stem from increased ras-MAPKinase signaling pathways in response to lower sequestration of Shc and increased coupling of Grb2 to insulin and VEGR in the absence of Ceacam1. Moreover, in the absence of Ceacam1, binding of Shp2 phosphatase to IRS1 increases to reduce IRS-1/Akt/eNOS activity and subsequently, lower NO production. Thus, the ldlr–/– VECad+Cc1fl/fl mouse can provide an in vivo system to delineate the endothelial cell-specific CEACAM1 effect on fibrosis independent of systemic risk factors.

Pathogenetic Relationship between Endothelial Dysfunction and Disorders of Blood Coagulation Potential in Pregnancy Complicated by Pre-Eclampsia

Until now, there is no systematic information on the role of endothelial dysfunction in the mechanisms of disorders of blood coagulation potential and microcirculation in different organs and tissues in preeclampsia. Our aim was to extend the existing principles of diagnosis of pre-eclampsia by establishing the role of endothelial dysfunction in the mechanisms of blood coagulation potential violations. A prospective comparative study was performed. Condition of coagulation processes studied by conventional techniques, parameters of a functional endothelium (nitric oxide metabolites, endothelin 1, thrombospondin, thrombomodulin and intercellular adhesion molecules in blood plasma)--by ELISA. The study group included 55 patients with moderate preeclampsia and 49 pregnant women with severe pre-eclampsia, in the control group--40 women with physiological pregnancy. In patients with pre-eclampsia moderate observed increase in plasma endothelin-1 (p < 0.001), thrombospondin (p < 0.001), intercellular adhesion molecules (p < 0.001) while reducing the level of nitrogen oxide (p < 0.001), increase in time of fibrinolysis (p < 0.050) and decreased international normalized ratio (p < 0.050) compared with the control group. With increasing severity of preeclampsia the researchers detected in blood plasma of patients a progressive increase in endothelin 1 (p1 < 0.020), thrombospondin (p1 < 0.001), intercellular adhesion molecules (p1 < 0.001) and decrease of nitric oxide metabolites (p1 < 0.001) and thrombomodulin (p1 < 0.001); the last combined with the activation of procoagulant hemostasis. There is a pathogenetic relationship between the development of endothelial dysfunction, impaired blood coagulation potential and the severity of clinical signs ofpreeclampsia. To widen the number of existing techniques to diagnose the severity of pre-eclampsia we recommende to mesure endothelin 1, thrombomodulin, thrombospondin, intercellular adhesion molecules and nitric oxide metabolites in the blood plasma, and use traditional indicators to assess the hemostatic system.

Inducible human endothelin-1 overexpression in endothelium raises blood pressure via endothelin type A receptors.

The mechanisms of blood pressure regulation by endothelin-1 produced by endothelial cells are complex and still unclear. Transgenic mice with endothelium-restricted human endothelin-1 (EDN1) overexpression presented vascular damage but no significant change in blood pressure, which could be because of adaptation to life-long exposure to elevated endothelin-1 levels. We now generated a tamoxifen-inducible endothelium-restricted EDN1 overexpressing transgenic mouse (ieET-1) using Cre/loxP technology. Sixteen days after tamoxifen treatment, ieET-1 mice presented ≥10-fold increase in plasma endothelin-1 (P<0.01) and ≥20 mm Hg elevation in systolic blood pressure (P<0.01), which could be reversed by atrasentan (P<0.05). Endothelin-1 overexpression did not cause vascular or kidney injury or changes in kidney perfusion or function. However, endothelin type A and B receptor expression was differentially regulated in the mesenteric arteries and the kidney. Our results demonstrate using this ieET-1 mouse model that 21 days of induction of endothelin-1 overexpression caused endothelin-1-dependent elevated blood pressure mediated by endothelin type A receptors.

High salt diet increases the pressor response to stress in female, but not male ETB-receptor-deficient rats.

Acute stress in both rodents and humans causes a transient rise in blood pressure associated with an increase in plasma endothelin-1 (ET-1). High salt (HS) intake also increases ET-1 production, and interestingly, blunts the pressor response to acute air jet stress in rats. We previously reported that female rats lacking functional ETB receptors everywhere except sympathetic nerves (ETB def) had a greater degree of hypertension in response to a HS diet compared to their male counterparts when measured by the tail cuff method. However, we now report that salt-induced hypertension is not different between sexes when measured by telemetry. Therefore, additional experiments were designed to test the hypothesis that female ETB def rats are more sensitive to acute stress when on a HS diet. The pressor response, measured by telemetry, to acute air jet stress was similar between male transgenic control (Tg control) and ETB def rats following chronic HS intake. In contrast, female ETB def rats had a significantly greater pressor response (about twofold higher) than female or male Tg control or male ETB def rats maintained on HS, a finding that cannot be explained by increased vascular reactivity to ET-1 in female rats as we observed that male ETB def rats had a greater pressor response to i.v. infusion of ET-1 compared to females. Furthermore, HS feeding exacerbated the pressor response to ET-1 in both male and female ETB def rats. Given our previous studies demonstrating that the ETA receptor functions to reduce the pressor response to acute stress, these findings further support a role for the ET receptor system in the pressor response to acute stress and that female rats have reduced ETA receptor activity when on a HS diet compared to males.

Endothelin-1 in the Human Myocardium and Circulating Plasma: Evaluation before, during and after Correction of Aortic Stenosis with Aortic Valve Replacement

Objectives: Due to the pathological effects of endothelin-1 (ET-1) on cardiomyocytes and the extracellular matrix, ET-1 levels may impact on the prognosis of aortic stenosis (AS) patients operated with aortic valve replacement (AVR). We examined ET-1 levels in AS patients throughout the whole AVR process, thus exposing potential therapeutic windows of opportunity. Methods: Plasma ET-1 levels were measured before and 2 days, 6 and 12 months after AVR in 22 patients with AS. Myocardial ET-1 was measured in biopsies from 7 patients undergoing AVR. Peroperatively, plasma ET-1 was analyzed in the coronary sinus and radial artery before aortic cross-clamp and at 5 and 20 min of reperfusion, in a second group of 30 patients. Results: Circulating ET-1 levels were transiently increased 2.6-fold 2 days following AVR. Myocardial ET-1 protein was 2.1-fold higher in patients with AS compared to controls. Plasma levels of ET-1 correlated to echocardiographic markers of diastolic dysfunction postoperatively. There was no increase in plasma ET-1 during early reperfusion, but veno-arterial differences indicated potential cardiac ET-1 extraction. Conclusions: Plasma ET-1 increases 2 days following AVR and myocardial ET-1 protein levels are increased in patients with AS before AVR. Peroperatively, no plasma ET-1 augmentation or release from the heart was observed in AS patients.

The Relationships Between Plasma Adrenomedullin and Endothelin-1 Concentrations and Doppler Echocardiographic Indices of Left Ventricular Function During Static Exercise in Healthy Men

Our previous study showed a significant relationships between static exercise-induced changes in plasma adrenomedullin (ADM) and those in endothelin-1 (ET-1), noradrenaline (NA) and pre-ejection period/left ventricular ejection time ratio (PEP/LVET) in older healthy men. It is hypothesized that ADM, ET-1, NA and adrenaline (A) may function as endogenous regulators of cardiac function by modulating myocardial contractility during static exercise. The present study was undertaken to assess the relationships between exercise-induced changes in plasma ADM, ET-1, NA, A concentrations and those in ascending aortic blood flow peak velocity (PV) and mean acceleration (MA) measured by Doppler echocardiography in 24 healthy older men during two 3-min bouts of handgrip at 30% of maximal voluntary contraction, performed alternately with each hand without any break between the bouts. Plasma ADM, ET-1, NA and A as well as heart rate (HR), blood pressure (BP), PV and MA were determined. During handgrip, plasma ADM, ET-1, NA and A as well as HR, BP increased, whereas PV and MA decreased. The increases in plasma ADM correlated positively with those in ET-1, NA and diastolic BP, and correlated negatively with changes in PV (r= −0.68) and MA (r= −0.62). The increases in plasma ET-1 correlated positively with those in NA and BPs and correlated negatively with changes in PV (r= −0.67) and MA (r= −0.60). The results of this study suggest that in healthy older men the exercise-induced changes in plasma ADM, ET 1 and catecholamines are related to alterations in left ventricular contractile state and may co-operatively counteract age-related deterioration of cardiac performance in men.

Cardiovascular and hormonal responses to static handgrip in young and older healthy men

The purpose of this study was to investigate the effect of age on cardiovascular changes and plasma concentrations of adrenomedullin (ADM), catecholamines, endothelin-1 (ET-1) and plasma renin activity (PRA) in healthy men. A total of 15 young (21 ± 0.3 years) and 15 older (64 ± 0.7 years) healthy men performed two 3-min bouts of static handgrip at 30% of maximal voluntary contraction, alternately with each hand without any break between the bouts. During exercise heart rate (HR), blood pressure (BP), stroke volume (SV) and pre-ejection period (PEP) and left ventricle ejection time (LVET) were measured. Blood samples were taken before exercise, at the end of both exercise bouts and in the fifth minute of the recovery period. The handgrip-induced increases in HR and cardiac output were significantly smaller in older than in young men (p < 0.01). SV decreased only in older men (p < 0.001). There were no differences between groups in BP increases. The baseline plasma ADM and catecholamines were higher in older man compared to young subjects. Handgrip caused increases in plasma ADM, ET-1 and PRA only in older men (p < 0.05). The increases in plasma ADM correlated positively with those of noradrenaline (NA), PRA, ET-1 and LVET and negatively with changes in total peripheral resistance (TPR), SV, PEP and PEP/LVET ratio. The increases in plasma ET-1 correlated positively with those of NA, PRA, TPR, mean BP and SV. These results revealed that ADM, ET-1 and angiotensin II can contribute to maintain vascular tone during static exercise in older but not in younger men.

Vehicular Emissions Induce Vascular MMP-9 Expression and Activity Associated With Endothelin-1–Mediated Pathways

Mechanisms of air pollution-induced exacerbation of cardiovascular disease are currently unknown, thus we examined the roles of vascular endothelin-1 (ET-1) and reactive oxygen species (ROS) in regulating mediators of vascular remodeling, namely matrix metalloproteinases (MMPs), after exposure to vehicle engine emissions. ApoE(-/-) mice were exposed by inhalation to filtered air or gasoline engine exhaust (GEE, 1:12 dilution) 6 hours per day for 1 or 7 days. Concurrently, mice were treated with either ET(A) receptor antagonist BQ-123 (100 ng/kg/d) via osmotic minipumps, Tempol (approximately 41 mg/kg/d, orally), or vehicle. GEE-exposure increased vascular MMP-2 and -9, endothelin-1 (ET-1), tissue inhibitor of metalloproteinases (TIMP)-2 mRNA and ROS levels. Aortic MMP protein and plasma MMP-9 were similarly upregulated. GEE-mediated increases in vascular ROS were attenuated by Tempol-treatment, as were MMP-2 and TIMP-2; whereas BQ-123 ameliorated GEE-induced vascular expression of MMP-9, MMP-2, ROS, and ET-1. In a parallel study, diesel exhaust exposure in volunteer human subjects induced significant increases in plasma ET-1 and MMP-9 expression and activity. These findings demonstrate that acute exposure to vehicular source air pollutants results in upregulation of circulating and vascular factors associated with progression of atherosclerosis, mediated in part through activation of ET-1-ET(A) receptor pathways.

Polyphenols restore endothelial function in DOCA-salt hypertension: Role of endothelin-1 and NADPH oxidase

Red wine polyphenols (RWPs) have been reported to exert beneficial effects in preventing cardiovascular diseases, such as hypertension. We studied the effects of chronic treatment with RWPs and apocynin, an inhibitor of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, on blood pressure, endothelial function, and oxidative status in deoxycorticosterone acetate (DOCA)-salt-induced hypertension. Rats were administered RWPs (40 mg/kg) or apocynin (33 μg/kg) daily by gavage for 5 weeks. Plasma catechin levels were detected only after RWP treatment. RWPs and apocynin prevented both the increase in systolic blood pressure and the proteinuria induced by DOCA-salt. Plasma malonyldialdehyde levels, urinary iso-prostaglandin F 2α excretion, aortic superoxide production, and aortic NADPH oxidase activity were found to be increased in animals of the DOCA group. RWP and apocynin treatments reduced these parameters in DOCA-salt rats, having no effect on control rats. However, only RWPs reduced the increase in plasma endothelin-1 (ET-1) levels and aortic p22 phox gene overexpression found in DOCA-salt animals. RWPs and apocynin also improved the blunted endothelium-dependent relaxation response to acetylcholine in noradrenaline-precontracted aortic rings. All these results suggest that chronic treatment with RWPs prevents hypertension and vascular dysfunction. RWPs prevent vascular oxidative stress by inhibiting NADPH oxidase activity and/or by reducing ET-1 release.

Cardiac hypertrophy in Aryl hydrocarbon receptor null mice is correlated with elevated angiotensin II, endothelin-1, and mean arterial blood pressure

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates toxicity of xenobiotics, such as 2,3,7,8-tetrachlorodibenzo- p-dioxin. Genetic deletion of the AhR leads to cardiac hypertrophy, suggesting a role for the AhR in cardiovascular physiology and disease; however, the pathways involved in the development of cardiac hypertrophy have not been determined. Thus, we investigated the role of (1) pressure overload using indwelling catheters and (2) vasoactive peptides endothelin-1 (ET-1) and angiotensin II (Ang II), assessed by RIA, in the progression of cardiac hypertrophy in AhR-null mice. Histochemical analysis, expression of cardiac hypertrophy marker genes, and echocardiography were used to assess the degree of cardiac hypertrophy. AhR-null mice developed elevated mean arterial pressures (MAP) by 5 months, which was associated with a two- and ninefold increase in plasma ET-1 and Ang II, respectively, compared to wild-type. Captopril-treatment (4 mg/kg) of AhR-null mice from 2 to 5 months of age significantly decreased MAP and plasma Ang II, but did not affect ET-1. Further, captopril improved cardiac function and reduced cardiac hypertrophy as evidenced by reduction in left ventricle mass, left ventricle internal dimension, and molecular cardiac hypertrophy markers. Captopril also decreased fibrosis of the heart and kidney. These findings show that pressure overload is associated with elevated ET-1 and hypertrophic growth of the heart and that cardiac hypertrophy is mediated, in part, by Ang II.

Endothelin A Receptor Blockade Reduces Hepatic Ischemia/Reperfusion Injury After Warm Ischemia in a Pig Model

It is well established that endothelin-1 (ET-1) is a very potent mediator of vasoconstriction that leads to microcirculatory disturbances. The aim of the study was to evaluate the effect of a selective endothelin A receptor antagonist on severe ischemia/reperfusion injury in a pig model. Fourteen pigs were subjected to 120 minutes of complete vascular exclusion of the liver with a passive bypass. The animals were randomized into two groups: a control group, which was given isotonic saline solution, and a therapy group, which received the selective endothelin A receptor antagonist BSF 208075 at the beginning of reperfusion. On postoperative days 4 and 7, animals were relaparotomized to obtain tissue specimens. Blood monitoring included aspartate aminotransferase (AST), alanine aminotransferase (ALT), glutamate dehydrogenase (GLDH), alkaline phosphatase, and ET-1. Partial oxygen tension (p tiO 2) was measured by a Clarke-type electrode and blood flow by laser Doppler. A semiquantitative scoring index was used for assessment of histologic injury and for immunohistochemical analysis of ET-1. Treatment with the endothelin A receptor antagonist significantly reduced the severity of the ischemia/reperfusion injury, as evidenced by lower levels of AST, ALT, and GLDH. The dramatic increase in plasma ET-1 in the therapy group is clear evidence of effective receptor blockade. Analysis of p tiO 2 and blood flow revealed a significant improvement in capillary perfusion and blood flow in the treated group and was associated with relevant reduction of tissue injury. In summary, in the control group we observed serious microcirculatory disturbances and severe histologic damage in the liver after reperfusion. Treatment with a selective endothelin A receptor antagonist attenuated the ischemia/reperfusion injury in a porcine model of severe ischemia/reperfusion, as demonstrated by improved microcirculation, a reduction in histologic damage, and an decrease in liver enzymes. ( J Gastrointest Surg 2003;7:331–339.)

Regional distribution of endothelin-1 and endothelin converting enzyme-1 in porcine endotoxemia.

Endothelin-1 (ET-1) levels are markedly increased in sepsis. Since ET-1 is primarily transcriptionally regulated, there should be a corresponding increase in pre-pro-endothelin-1 (ppET-1). Our objective was to determine whether ppET-1 is increased in pigs with a low systemic vascular resistance. We also examined the distribution of ET-1 and the regulation of endothelin-converting enzyme 1 (ECE-1), the rate limiting enzyme in ET-1 production. We anesthetized and ventilated 16 pigs. We measured arterial, pulmonary, and central venous pressures, as well as cardiac output. ET-1 was measured by radioimmunoassay in plasma and in multiple tissues. We infused 20 microg/kg of endotoxin over 2 h and then sacrificed the animals. ppET-1 and ECE-1 mRNA were assessed by Northern analysis. We performed immunohistochemistry for the assessment of tissue ET-1 and ECE-1. The systemic vascular resistance rose at 30 min, but fell by 120 min. Plasma ET-1 more than doubled by 2 h. However, there was no change in the concentration of ET-1 in any tissue except in the pulmonary artery. By immunohistochemistry, there was also no change in ET-1 in aorta, vena cava, heart, lung, liver, and kidney. Distribution of ECE-1 followed that of ET-1 on immunohistochemistry. There was a significant increase in ppET-1 mRNA in liver, kidney papillae, and vena cava, and a tendency for an increase in other tissues. This was paralleled by an increase in ECE-1 mRNA. In conclusion, the amount of ECE-1 mRNA and protein parallel those of ET-1. Endotoxemia is associated with a marked increase in plasma ET-1 and an increase in ppET-1 and ECE-1 mRNA in multiple tissues; however, there was no significant change in tissue ET-1 except in the pulmonary artery. The rise in plasma levels without a change in tissue levels suggests a greater release into the vasculature in sepsis than under normal conditions.

Aminoethyl-isothiourea inhibits the increase in plasma endothelin-1 caused by serogroup A streptococci and prolongs survival in rat peritoneal sepsis.

To elucidate the possible roles of nitric oxide (NO), endothelin-1 (ET-1), and reactive oxygen species (ROS) in the pathophysiology of serogroup A streptococcal (GAS) peritoneal sepsis, we investigated the effects of aminoethylisothiourea (AE-ITU), an inducible NO synthase (iNOS) inhibitor, and a ROS scavenger, and the ET-1 receptor antagonist bosentan. In rats, live GAS inocula, 3 x 10(8) and 1 x 10(9) cfu/kg, entailed a 24-h mortality of 10% and 90%, respectively. GAS caused increases in tissue iNOS activity (9 h), in serum nitrite/nitrate (9-24 h), and in intracellular leukocyte ROS levels (3-6 h). These changes were all prevented by the pre-treatment with AE-ITU. A novel finding was that AE-ITU also prevented the GAS-induced marked increase in plasma ET-1 at 6 h. Short-term (7-h) survival was improved by both AE-ITU and by bosentan. The mechanism(s) for the beneficial effects of AE-ITU may possibly be a combined mode of action; iNOS inhibition, ROS scavenging, and inhibition of the increase in plasma ET-1 caused by GAS.

Plasma endothelin-1 levels after stem cell transplantation.

Acute renal failure and veno-occlusive disease of the liver are serious complications following stem cell transplantation (SCT) and contribute to the non-relapse mortality associated with this procedure. Endothelins, a family of vasoconstrictor peptides, may be involved in the pathogenesis of a variety of renal and hepatic diseases, including CsA-associated hypertension and the hepatorenal syndrome. In order to study the relevance of endothelins to SCT-related liver and kidney dysfunction, we determined endothelin-1 (ET-1) levels in plasma samples obtained from 65 patients (38 autologous, 27 allogeneic) 7 days before and 7, 14 and 28 days after SCT. A steady increase in plasma ET-1 was observed after SCT (5.36 pg/ml, 95% CI 4.30-6.43 on day +28 vs 3.82 pg/ml, 95% CI 3.21-4.43 on day -7; P = 0.020). No differences in ET-1 levels existed between autologous and allogeneic SCT recipients at any of the time points studied (P = 0.561). In addition, no significant differences were observed among patients with renal dysfunction vs those without (P = 0.187), nor in patient groups with or without hepatic dysfunction (P = 0.075). In conclusion, even though plasma ET-1 levels showed a steady increase following SCT, no correlation could be found with development of SCT-related kidney or liver dysfunction.

Effect of nitric oxide synthase inhibition on cardiovascular and hormonal regulation during pregnancy in the rat

Recent studies have shown that nitric oxide (NO) biosynthesis increases in pregnancy and that inhibition of nitric oxide synthase (NOS) induces some pathological processes characteristic of preeclampsia. The current project sought to study the effect of the NOS inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME, 10 microg x min(-1), sc for 7 days) on plasma volume, plasma atrial natriuretic factor (ANF), plasma endothelin-1 (ET), and plasma renin activity (PRA) during gestation in conscious rats. NOS inhibition caused mean arterial pressure to increase in both virgin and 21-day pregnant rats. Plasma volume fell in the pregnant rats [L-NAME, 4.5 +/- 0.3 mL x 100 g(-1) body wt. (n = 7) vs. D-NAME, 6.8 +/- 0.2 mL x 100 g(-1) body wt. (n = 10); P < 0.05] but not in the virgin rats [L-NAME, 4.3 +/- 0.1 mL x 100 g(-1) body wt. (n = 6) vs. D-NAME, 4.8 +/- 0.2 mL x 100 g(-1) body wt. (n = 8)]. There was no effect of NOS inhibition on plasma ANF levels or PRA in either the virgin or pregnant rats. However, L-NAME did decrease plasma ET levels in the pregnant rats [L-NAME, 19.6 +/- 1.6 pg x mL(-1) (n = 8) vs. D-NAME, 11.6 +/- 2.5 pg x mL(-1) (n = 9); P < 0.05]. Our results confirm that NO is involved in cardiovascular homeostasis in pregnancy; NOS inhibition selectively reduces plasma volume in pregnant rats, thus mimicking a major pathophysiological perturbation of preeclampsia. However, it does not induce the hormonal changes characteristic of preeclampsia, namely the decrease in PRA and increase in plasma ET and ANF levels.

Effect of nitric oxide synthase inhibition on cardiovascular and hormonal regulation during pregnancy in the rat

Recent studies have shown that nitric oxide (NO) biosynthesis increases in pregnancy and that inhibition of nitric oxide synthase (NOS) induces some pathological processes characteristic of preeclampsia. The current project sought to study the effect of the NOS inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME, 10 microg x min(-1), sc for 7 days) on plasma volume, plasma atrial natriuretic factor (ANF), plasma endothelin-1 (ET), and plasma renin activity (PRA) during gestation in conscious rats. NOS inhibition caused mean arterial pressure to increase in both virgin and 21-day pregnant rats. Plasma volume fell in the pregnant rats [L-NAME, 4.5 +/- 0.3 mL x 100 g(-1) body wt. (n = 7) vs. D-NAME, 6.8 +/- 0.2 mL x 100 g(-1) body wt. (n = 10); P < 0.05] but not in the virgin rats [L-NAME, 4.3 +/- 0.1 mL x 100 g(-1) body wt. (n = 6) vs. D-NAME, 4.8 +/- 0.2 mL x 100 g(-1) body wt. (n = 8)]. There was no effect of NOS inhibition on plasma ANF levels or PRA in either the virgin or pregnant rats. However, L-NAME did decrease plasma ET levels in the pregnant rats [L-NAME, 19.6 +/- 1.6 pg x mL(-1) (n = 8) vs. D-NAME, 11.6 +/- 2.5 pg x mL(-1) (n = 9); P < 0.05]. Our results confirm that NO is involved in cardiovascular homeostasis in pregnancy; NOS inhibition selectively reduces plasma volume in pregnant rats, thus mimicking a major pathophysiological perturbation of preeclampsia. However, it does not induce the hormonal changes characteristic of preeclampsia, namely the decrease in PRA and increase in plasma ET and ANF levels.

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Plasma endothelin-1 concentrations in patients with retinal vein occlusions

AIMSTo investigate whether plasma levels of endothelin-1 (ET-1), a potent vasoconstricting peptide that is crucial in regulating retinal blood flow, were elevated in patients with retinal vein occlusion (RVO).METHODSET-1 plasma...

Plasma endothelin-1 release in normal and varicose saphenous veins.

The aim of the study was to investigate the release of endothelin-1 (ET-1) in normal and varicose saphenous veins at baseline and after venous stasis test. Ten patients (eight women and two men, mean age 43 +/- 4) with primarily varicose great saphenous veins and ten controls (eight women and two men, mean age 42 +/- 6) were recruited. After 30 minutes of resting in supine position, venous occlusion in a leg was performed with a sphygmomanometer provided to keep the pressure in the cuff intermediate between systolic and diastolic blood pressure for 10 minutes. Blood samples were taken from the great saphenous vein just above the medial malleolus at baseline and 10 minutes after venous stasis was begun. Plasma ET-1 was determined by a radioimmunoassay system. Results are expressed as mean +/- SD. Plasma ET-1 concentration was higher in varicose than in normal saphenous veins (4 +/- 0.1 pmol/L vs 2.6 +/- 0.1 pmol/L, P < 0.001), and it significantly increased (P < 0.001) in both groups after venous stasis when compared with baseline (6.8 +/- 0.9 pmol/L and 3.6 +/- 0.1 pmol/L in varicose and normal saphenous veins, respectively). Absolute increase in plasma ET-1 was significantly greater in varicose than in normal saphenous veins (2.8 +/- 0.9 pmol/L vs 1.0 +/- 0.2 pmol/L, P < 0.01). In conclusion, increased local ET-1 release in varicose saphenous veins could be a marker for venous endothelial activation/damage and/or contribute to promote the morphologic alterations of the varicose vein wall by stimulating smooth muscle cell proliferation. On the other hand, increased ET-1 release could contribute to counterbalancing the varicose venous relaxation and to increasing preload in varicose patients via ET-1-induced venoconstriction.