Increased renal production of transforming growth factor-beta1 in patients with type II diabetes.

Diabetic nephropathy is a common complication in patients with either type I or type II diabetes. The pathogenesis of diabetic nephropathy is thought to involve both metabolic and vascular factors leading to chronic accumulation of glomerular mesangial matrix. In this context, both transforming growth factor-beta (TGF-beta) and endothelin may contribute to these processes. To determine if diabetic patients demonstrate increased renal production of TGF-beta and endothelin, aortic, renal vein, and urinary levels of these factors were measured in 14 type II diabetic patients and 11 nondiabetic patients who were undergoing elective cardiac catheterization. Renal blood flow was measured in all patients to calculate net mass balance across the kidney. Diabetic patients demonstrated net renal production of immunoreactive TGF-beta1 (830 +/- 429 ng/min [mean +/- SE]), whereas nondiabetic patients demonstrated net renal extraction of circulating TGF-beta1 (-3479 +/- 1010 ng/min, P < 0.001). Urinary levels of bioassayable TGF-beta were also significantly increased in diabetic patients compared with nondiabetic patients (2.435 +/- 0.385 vs. 0.569 +/- 0.190 ng/mg creatinine, respectively; P < 0.001). Renal production of immunoreactive endothelin was not significantly increased in diabetic patients. In summary, type II diabetes is associated with enhanced net renal production of TGF-beta1, whereas nondiabetic patients exhibit net renal extraction of circulating TGF-beta1. Increased renal TGF-beta production may be an important manifestation of diabetic kidney disease.

Increased urinary endothelin-1-like immunoreactivity excretion in NIDDM patients with albuminuria.

OBJECTIVE: To determine the urinary endothelin-1-like immunoreactivity (ET-1-LI) in non-insulin-dependent diabetes mellitus (NIDDM) patients and to investigate whether urinary ET-1-LI excretion is elevated in patients with albuminuria. RESEARCH DESIGN AND METHODS: Urinary ET-1-LI substance was determined by radioimmunoassay in 45 normoalbuminuric and 28 albuminuric NIDDM patients. RESULTS: The mean amounts of 24-h ET-1-LI excretion in NIDDM patients with normoalbuminuria and albuminuria were 154.9 +/- 13.5 and 174.4 +/- 12.9 ng/day, respectively. The latter was significantly higher than that of the 40 normal control subjects (111.8 +/- 7.9 ng/day, P < 0.01). CONCLUSIONS: The increase in urinary ET-1-LI substance excretion in patients with albuminuria suggests that ET-1 may be a pathogenetic factor in diabetic nephropathy.

Carotid atherosclerosis in adolescents and young adults with IDDM. Relation to urinary endothelin, albumin, free cortisol, and other factors.

OBJECTIVE: To investigate 1) alterations of carotid intimal-plus-medial thickness (IMT) in subjects with IDDM and 2) the relation of IMT to indexes of diabetic angiopathy and to risk factors of atherosclerosis. RESEARCH DESIGN AND METHODS: IMT was assessed by ultrasound B-mode imaging in 39 subjects with IDDM (23 male, 16 female young adults aged 17.5 +/- 5.2 years, diabetes duration 8.8 +/- 5.9) and in 22 control subjects (healthy siblings of the IDDM subjects) of comparable age. Urinary endothelin (UET1) and urinary free cortisol (UFC) were determined by radioammunoassay (RIA), urinary albumin by nephelometry, HbA1c by high-performance liquid chromatography (HPLC), and plasma renin by immunoradiometric assay (IRMA). RESULTS: The IMT values were greater in IDDM subjects than in control subjects (0.49 +/- 0.1 mm, 0.44 +/- 0.09 mm, respectively; P = 0.048) and greater in IDDM male subjects than in control male subjects (0.52 +/- 0.09 and 0.44 +/- 0.06 mm, respectively; P = 0.015), with no difference between IDDM and control female subjects. The IMT values were greater in diabetic male subjects than in female subjects (0.52 +/- 0.09 and 0.45 +/- 0.1 mm, respectively; P = 0.017). In IDDM subjects, but not in control subjects, there was a positive correlation of IMT to urinary albumin (P = 0.008), systolic blood pressure (P = 0.023), UET1 (P = 0.016), UFC (P = 0.002), and BMI (P = 0.021). Multiple regression analysis demonstrated that in IDDM subjects the variable that interacts independently with IMT was the BMI (P = 0.001). CONCLUSIONS: IMT, an index of atherosclerosis (macroangiopathy), is increased in IDDM subjects quite early (already in adolescence), and it is positively related to urinary albumin, UET1, blood pressure, and UFC.

Role of neutral endopeptidase in the metabolism of endothelin.

Endothelin is a potent vasoconstrictor produced by endothelial cells. Although endothelin has been studied extensively, little is known about its metabolism in vivo. Neutral endopeptidase EC.3.4.24.11 is reported to degrade endothelin in vitro. Therefore, we studied the effect of neutral endopeptidase inhibition by SQ29,072 on plasma levels and urinary excretion of endogenous and exogenous endothelin. Injection of 30 or 60 mg/kg SQ29,072 into anesthetized rats increased the urinary excretion of endothelin nearly 14-fold. The response was maximal during the first 30 minutes of collection and lasted for 90 minutes. The larger dose of inhibitor caused a 37-43% increase (p less than or equal to 0.05) in the plasma concentration of endothelin. Only 0.20 +/- 0.04% of the total radioactivity injected as 125I-endothelin (1 microCi; 1,308 pg) into normal rats was recovered in the urine within 30 minutes. Urinary radioactivity increased to 0.54-0.63% (p less than or equal to 0.05) of the total infused in rats pretreated with SQ29,072. Chromatographic analysis of radioactivity in the urine revealed that intact endothelin accounted for only 6-9% of the total counts in control rats but 50-56% in rats pretreated with the inhibitor. We also studied the effects of another inhibitor of neutral endopeptidase, SQ28,063, on the distribution of radioactivity in the urine, kidney, and lung of rats injected with 125I-endothelin. SQ28,063 increased urinary excretion of labeled endothelin and increased total radioactivity accumulated in the lung and kidney from 157 and 105 pg to 234 and 157 pg, respectively. Intact endothelin accounted for 90% or more of the accumulated counts in both tissues. These results indicate that 1) little circulating endothelin is cleared into the urine, 2) endothelin in the urine is likely of renal origin, and 3) neutral endopeptidase EC.3.4.24.11 plays a major role in the inactivation of endothelin.

Effects of cyclosporin A on the synthesis, excretion, and metabolism of endothelin in the rat.

Increasing evidence suggests that endothelin, a potent vasoconstrictor, is implicated in cyclosporin A (CsA)-induced nephrotoxicity. Increased levels of urinary and circulating endothelin have been described in CsA-treated humans and animals. The exact mechanisms by which CsA induces these increases are still unknown, and no data indicate whether these elevated levels reflect increased synthesis or decreased clearance of endothelin. In the present study, we investigated the effects of CsA administration (50 mg/kg per day i.p. for 6 days) to rats on plasma and urinary levels of endothelin; expression of endothelin-1 (ET-1), ET-3, and endothelin-converting enzyme in renal tissue; clearance of infused 125I-ET-1; and degradation of 125I-ET-1 by recombinant neutral endopeptidase. Rats given CsA for 6 days developed severe renal insufficiency, as shown by a 74% decrease in creatinine clearance rate (Ccr) (P < .006). Ccr was remarkably improved in CsA-treated rats that received bosentan, the combined antagonist of both endothelin A and endothelin B receptors. Urinary excretion of endothelin increased from an undetectable level to 31.7 +/- 6.0 pg/24 h (P < .001), and plasma levels of endothelin were unchanged (2.8 +/- 0.2 to 3.1 +/- 0.2 pg/mL). Reverse transcription followed by quantitative polymerase chain reaction revealed that ET-1 mRNA in the renal medulla increased by 59% (P < .006), whereas the expression of both ET-3 and endothelin-converting enzyme was unchanged. In other rats, neither acute nor chronic treatment with CsA affected either the clearance of 125I-ET-1 from the blood or the renal and pulmonary uptake of the peptide. Moreover, CsA did not affect the degradation of 125I-ET-1 by highly purified recombinant neutral endopeptidase, a well-known endothelinase. Taken together, these data suggest that the elevated urinary endothelin levels obtained after CsA treatment originate from the kidney and reflect increased renal synthesis of ET-1. Moreover, the production of endothelin appears to be regulated at the mRNA transcription level, and expressions of ET-1 and ET-3 are regulated independently.

Increased basal concentrations of plasma endothelin in borderline hypertension.

BACKGROUND: There is evidence for an altered endothelial function in established hypertension but little is known about endothelial function in borderline hypertension. It has also been suggested that the early stages of hypertension are characterized by an increased sympathetic drive. OBJECTIVE: To investigate whether alterations in endothelin, neuropeptide Y (NPY) and calcitonin gene-related peptide (CGRP) are already present in the borderline hypertensive stage. DESIGN: A case-control study of age-matched men recruited from a population screening programme. METHODS: Seventy-five men with stable borderline hypertension [diastolic blood pressure (DBP), 85-94 mmHg] and 75 age- and sex-matched normotensive controls (DBP < or = 80 mmHg) were investigated. Plasma samples were drawn in a standardized fashion, and extracted and analysed using competitive radio immunoassays. RESULTS: Basal concentrations of NPY and CGRP were similar in the two groups (28.4 versus 26.7 pmol/l and 24.2 versus 21.7 pmol/l, respectively). Basal concentrations of endothelin were significantly higher in the borderline hypertensive group (2.0 versus 1.5 pmol/l, P < 0.0001). CONCLUSIONS: These results suggest that a disturbed endothelial function, represented by endothelin, could be involved in the early hypertensive processes. They also suggest that these changes could be present before the basal sympathetic/parasympathetic drive alters, warranting further research into this area.

Effects of chronic increased salt intake on nitric oxide synthesis inhibition-induced hypertension.

OBJECTIVE AND METHOD: Experimental evidence suggests that endogenous nitric oxide plays an important role in the homeostatic response to an increase in sodium intake. In the present study we evaluated the influence of a high sodium intake (1% NaCl as drinking water) on arterial hypertension induced by long-term (6-7 weeks) inhibition of nitric oxide synthesis [NG-nitro-L-arginine methyl ester (L-NAME), 75 mg/100 ml in the drinking fluid] in rats. RESULTS: Treatment with L-NAME induced progressive elevations in tail-cuff systolic blood pressure, but there were no differences between rats drinking tap water and rats drinking 1% NaCl. Direct measurement of blood pressure at the end of the treatment confirmed the hypertension and the lack of differences between the two groups treated with L-NAME. Metabolic studies performed at the end of L-NAME treatment showed a reduced glomerular filtration rate and elevated urinary excretion of immunoreactive endothelin in the two hypertensive groups treated with L-NAME. Drinking intake, diuresis and natriuresis were significantly higher only in the L-NAME group drinking 1% NaCl. Both groups treated with L-NAME showed an accelerated and increased diuretic and natriuretic response to an isotonic 0.9% NaCl load (2.5 ml/100 g body weight, intraperitoneally). At the end of the study ventricular hypertrophy was observed in both L-NAME groups. CONCLUSION: The present results indicate that the time-dependent elevation in blood pressure produced by long-term inhibition of nitric oxide production is not affected by an increased sodium intake. However, salt supplementation induced the development of a polyuria and polydipsia syndrome in rats treated with L-NAME. The elevated excretion of endothelin in both groups treated with L-NAME suggests the possible participation of endothelin in the development of L-NAME hypertension.

Increased urinary excretion of endothelin during hypothermic perfusion preservation in kidneys subjected to preretrieval warm ischemic injury.

The purpose of the study was two-fold: 1) to determine whether endothelin (ET) levels could be detected in the ureteral effluent during hypothermic perfusion preservation (HPP) and; 2) to determine whether preretrieval warm ischemic (WI) injury is associated with increased ureteral excretion of ET. In situ pre-WI injury was induced in Lewis rats (n=10) by a 30-min extrinsic occlusion of the suprarenal aorta. The left kidney underwent 16 hr of HPP, and ureteral effluent (UE) from ischemic and control kidneys (n=10) was collected over 16 hr of HPP. The UE ET concentration and total ET excretion over 16 hr of HPP were significantly higher in kidneys subjected to pre-WI injury compared with nonischemic controls. Kidneys subjected to pre-WI injury can be distinguished from nonischemic control kidneys during HPP by a significantly higher concentration of ET in the UE and a higher overall excretion of ET during HPP.

Prevention of chronic renal allograft rejection in rats with an oral endothelin A receptor antagonist.

BACKGROUND: Chronic rejection is the most common cause of graft loss in renal transplantation. The pathomechanisms underlying chronic rejection are poorly understood, and no treatment has yet successfully been established. We hypothesized that, in analogy to models of reduced renal mass, the administration of a selective endothelin (ET) A receptor antagonist could improve the course of chronic rejection in renal allografts. METHODS: Experiments were performed in the Fisher-to-Lewis rat model of chronic rejection. Lewis-->Lewis isografts served as controls. Animals were treated with either the oral selective ET-A receptor antagonist LU135252 (50 mg/kg/day) or vehicle. Animal survival, blood pressure, creatinine clearance, proteinuria, and urinary ET excretion were investigated for 24 weeks. Kidneys were removed for light microscopical evaluation, determination of ET mRNA expression and tissue protein concentration, and immunohistochemical assessment of cell surface markers. RESULTS: Rats with chronic rejection showed an increase in renal ET mRNA synthesis and ET protein content. Treatment with LU135252 resulted in a significant improvement in survival after 24 weeks (0.92 vs. 0.38, P<0.01 by log-rank test). Creatinine clearance was higher in animals treated with the selective ET-A receptor antagonist (P<0.05). LU135252 had no influence on blood pressure and proteinuria. Selective ET-A blockade was associated with significantly less morphological changes and a significant reduction of expression of cell surface markers for macrophages (ED1), T cells (R73), and MHC II (F17-23-2). CONCLUSION: The renal ET-A system plays an important role in the pathomechanisms underlying chronic renal allograft rejection, because the treatment with a selective ET-A receptor antagonist dramatically improves the course of chronic renal failure after allograft transplantation. These results offer a novel therapeutical option for treatment of chronic renal allograft rejection, for which so far no therapy is known.

Increased endothelin excretion in rats with renal failure induced by partial nephrectomy.

1. Six weeks following partial nephrectomy in rats, significant increases in serum urea nitrogen and serum creatinine concentration and a significant decrease in creatinine clearance were observed. 2. Measurement of systolic blood pressure by tail plethysmography indicated that animals that had undergone partial nephrectomy were hypertensive. 3. Compared to sham-operated animals, there were 4 fold increases in both urinary protein excretion and urinary endothelin excretion. 4. There was a significant correlation between urinary protein and urinary endothelin excretion (r = 0.77). There was also a correlation (r = 0.65) between urinary endothelin excretion and systolic blood pressure. 5. Plasma endothelin concentrations were not different in sham-operated and partially nephrectomized rats. 6. The data indicate that there is an increased renal endothelin production in rats with chronic renal failure.

Endothelin excretion in hypertensive pregnancy. Relationship to glomerular filtration rate, blood pressure, and sodium excretion.

The objective of this study was to determine whether urinary endothelin (ET) excretion is altered in pregnant women with preeclampsia or essential hypertension compared with normal pregnant and nonpregnant women, and whether urinary ET excretion is significantly related to glomerular filtration rate (GFR), blood pressure, or sodium excretion in hypertensive pregnant women. Subjects included 85 hypertensive women in their third trimester (32 with severe preeclampsia, 37 with mild preeclampsia [some of whom may be classified as having "transient (gestational) hypertension" by other classifications], and 16 with essential hypertension), 42 normal third-trimester pregnant women, and 26 normal nonpregnant women. Twenty-four-hour urine ET and creatinine excretion were measured in all women. ET was extracted from urine and measured by radioimmunoassay. Plasma creatinine, serum uric acid and albumin concentrations, and urine protein and sodium excretion were also measured. Twenty-four-hour ET excretion was significantly higher (P < .01) in normal pregnant women (14.7 [9.1 to 20.1] pmol/day; median [interquartile range]) than in nonpregnant women (8.4 [6.4 to 15.2] pmol/day) and was reduced significantly (P < .01) in hypertensive pregnant women (severe preeclampsia: 9.0 [5.5 to 12.4] pmol/day; mild preeclampsia: 7.2 [5.7 to 9.9] pmol/day; essential hypertension: 7.5 [6.4 to 9.4] pmol/day) compared to values for normal pregnant women. Twenty-four-hour urine ET excretion in hypertensive pregnant women was correlated positively but weakly with both creatinine clearance (r = 0.31, P < .01) and urine sodium excretion (r = 0.34, P < .01). Urinary ET excretion is increased in normal pregnancy and reduced from these values in pregnancies complicated with preeclampsia or essential hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Urinary endothelin: a possible biological marker of renal damage.

Endothelin (ET) is a powerful vasoconstrictor peptide synthesized and secreted by the vascular endothelium. Significant amounts of ET are also produced by nonendothelial cells, mainly tubular-epithelial and mesangial cells. Large amounts of ET are found in the urine compared with the small amounts present in blood. Because most of the ET filtered from plasma is subject to degradation by neutral endopeptidase (EC 3.4.24.11) in the proximal tubule, urinary ET is probably of renal origin. The range of urinary ET excretion in healthy persons is 20 to 90 ng/day. The excretion of endothelin is modulated by several mechanical and chemical stimuli such as angiotensin II, phenylephrine, radiocontrast media, cyclosporine, and cis-platin. In addition, enhanced urinary ET excretion has been found in several forms of renal failure, both acute and chronic, and in diabetes mellitus. Thus, urinary ET has the potential of serving as a marker for renal disease.

Regulation of the urinary excretion of endothelin in the rat.

The regulation of the urinary excretion of endothelin (UETV) and its clinical significance has not yet been established. The present study was designed to examine the effect of angiotensin II (A-II), arginine vasopressin (AVP), and nifedipine on UETV. Anesthetized Munich-Wistar rats were infused with low (50 ng/kg/min) and high (500 ng/kg/min) doses of A-II for 30 min. Both doses significantly increased UETV, from nondetectable (ND) levels to 155 +/- 54 (P < .03) and 450 +/- 86 fg/min (P < .001), respectively. This effect was accompanied by a significant increase in urine flow (UV), from 6 +/- 1 to 67 +/- 12 and 89 +/- 10 microL/min, and in mean arterial pressure (MAP), from 139 +/- 4 to 187 +/- 5 and 217 +/- 3 mm Hg. Infusions of A-II with its nonspecific antagonist, saralasin, resulted in a further increase in UETV to 647 +/- 126 and 782 +/- 117 fg/min (P < .002), respectively. However, infusion of A-II with its specific antagonist, losartan, completely blocked its stimulatory effect on UETV. Infusion of AVP, 10 or 100 mU/kg/h, produced increases in MAP, from 134 +/- 3 to 165 +/- 7 and 203 +/- 4 mm Hg, and in UV from 6 +/- 1 to 37 +/- 6 and 97 +/- 17 microL/min, comparable to A-II, but AVP did not have a marked effect on UETV.(ABSTRACT TRUNCATED AT 250 WORDS)

Lead-induced hypertension: possible role of endothelial factors.

The results of this study confirm that low lead (0.01%) but not high lead (0.5%) administration results in increased blood pressure in rats treated for up to 12 months. This effect appeared to be related to an imbalance of endothelially-derived vasoconstrictor and vasodilator compounds in low lead-treated animals but not in high lead-treated animals. In low lead-treated rats, measurement of plasma endothelins 1 and 3 (ET-1 and ET-3) revealed that ET-3 concentration increased significantly after both 3 months (Experimental, 92.1 +/- 9.7 v Control, 46.7 +/- 12.0 pmol/mL; P < .001) and 12 months (Experimental, 105.0 +/- 9.3 v Control, 94.1 +/- 5.0 pmol/mL; P < .01) while ET-1 was unaffected. Plasma and urinary cGMP concentrations (as a reflection of endothelium-derived relaxing factor (EDRF)) decreased significantly at 3 months (plasma, Experimental, 1.8 +/- 0.9 v Control, 4.2 +/- 1.6 pmol/mL; P < .001) and 12 months (plasma, Experimental, 2.2 +/- 0.7 v Control, 4.2 +/- 0.9 pmol/mL; P < .001). Thus, the path to development of hypertension in low lead rats may be through an increase in the concentration of the vasoconstrictor hormone, ET-3, and a decrease in the vasodilator hormone, EDRF. High levels of lead exposure did not result in hypertension, perhaps because plasma concentrations of ET-1, ET-3 and cGMP were unaltered at 3 months, while ET-1, ET-3 and cGMP concentrations were coordinately and significantly decreased at 12 months.

Effects of angiotensin II and phenylephrine on urinary endothelin in normal female volunteers.

Endothelin (ET) is a 21-amino acid peptide produced and secreted mainly by endothelial cells. Small amounts of ET are found in plasma, whereas large amounts are present in the urine. Despite the abundance of ET in the kidneys and urine, little is known about its regulation and clinical significance. The present study was designed to examine the effects of angiotensin II (Ang II) and phenylephrine (Phe) on the excretion of ET in normal female volunteers. Ang II and Phe were infused for 1 hour each and titrated to increase the mean arterial pressure by 20 mm Hg. There was a 60-minute recovery period before the second drug, and the order of the drugs was randomized. Infusion of Phe induced mild diuresis and natriuresis, which were associated with a significant increase in the excretion of ET. In addition, Phe significantly increased plasma atrial natriuretic factor (ANF). In contrast, infusion of equipressor doses of Ang II decreased urinary sodium excretion and did not significantly alter the excretion of ET. Moreover, Ang II induced only a small and nonsignificant increase in plasma ANF. These results demonstrate that (1) physiological doses of Ang II do not affect excretion of either ET or ANF; (2) Phe markedly increased the excretion of ET and ANF, independently of its effect on blood pressure; and (3) neither agent changed plasma ET, but Phe increased plasma ANF.

Does gender influence human cardiovascular and renal responses to water immersion?

We hypothesized that women and men exhibit similar cardiovascular and renal responses to thermoneutral water immersion (WI) to the neck. Ten women and nine men underwent two sessions in random order: 1) seated nonimmersed for 5.5 h (control) and 2) WI for 3 h, with subjects seated nonimmersed for 1.5 h pre- and 1 h postimmersion. We measured left atrial diameter, heart rate, arterial pressure, urine volume and osmolality, and urinary endothelin, urodilatin, sodium, and potassium excretion. No significant difference existed between groups in cardiovascular responses. The groups also exhibited mostly similar renal responses to immersion after adjustment for body mass. However, female urodilatin excretion per kilogram during immersion was over twofold that of men, and the female kaliuretic response to immersion was delayed and less pronounced relative to that in men. Men may excrete more potassium than women during immersion because men possess greater lean body mass (potassium per kilogram). Results obtained in men during WI may be cautiously extrapolated to women, yet urodilatin and potassium responses exhibit gender differences.

Endothelin family peptides in human plasma and urine: their molecular forms and concentrations.

Molecular forms and concentrations of endothelin (ET) family peptides in normal human plasma and urine were investigated using five different sandwich-type enzyme immunoassays (sandwich-EIAs) and reverse-phase high performance liquid chromatography (RP-HPLC). We found that immunoreactive (IR-) big ET-3 and IR-big ET-2 were the major species in both plasma and urine from normal humans. Big ET-2(1-38) was found to be the major form of IR-big ET-2 in plasma. Urinary IR-big ET-2 and plasma and urinary IR-big ET-3 were heterogeneous, and the IR-big ET-3s were larger (M(r) 6,000-12,000) than authentic big ET-3. IR-big ET-1, IR-ET-1, and IR-ET-3 were found at relatively low concentrations in human plasma and urine, and their major forms were identical to authentic big ET-1, ET-1, and ET-3, respectively. Although ET-1 and other ET family peptides have often been measured using RIAs with board-spectrum antibodies, the presence of high concentrations of IR-big ET-2 and IR-big ET-3, but not IR-ET-1, in plasma and urine indicates that the clinical significance of ET family peptides should be investigated with assay methods specific to each ET and big ET.

Endothelin-1 and big endothelin-1 levels in normal term pregnancy and in preeclampsia.

To study the concentrations of endothelin-1 (ET-1) and its precursor, big ET-1, in samples of amniotic fluid, fetal urine, umbilical arterial and venous blood, retroplacental blood and maternal uterine and brachial venous blood obtained from normal and preeclamptic women. Samples were collected from 31 healthy pregnant women (16 in labor and 15 undergoing elective cesarean section) and 35 preeclamptic women (9 in labor and 26 undergoing cesarean section). Big ET-1 and ET-1 were measured by radioimmunoassay and the ET-1 to big ET-1 ratios were calculated. In preeclamptic women there was a significant elevation of ET-1 in the maternal brachial and uterine veins and of big-ET-1 in the brachial vein. The ET-1 concentrations and the ET-1/big ET ratios were significantly higher on the fetal side (i.e., in the umbilical vein and amniotic fluid) than in maternal blood, but in these sampling locations there was no difference between the normal pregnancy and preeclampsia group. A significant negative correlation (r = -0.67, P < 0.01) was found between plasma ET-1 in the umbilical vein and birth weight in the preeclamptic group. ET-1 was significantly higher in amniotic fluid than in the first neonatal urine of corresponding pregnancies (15.0 +/- 2.0 vs. 3.0 +/- 2.9 pmol/l, P < 0.05). The ET-1 and big ET-1 concentrations are significantly higher in fetal plasma and amniotic fluid than in maternal plasma, indicating increased endothelin converting enzyme activity and increased ET-1 production in utero. The elevated ET-1 concentration in maternal blood in preeclamptic compared with normal pregnant women and the negative correlation between ET-1 in the umbilical vein and birth weight suggest that ET-1 plays a pathophysiological role in preeclampsia and other conditions with intrauterine growth restriction.

Effect of nifedipine on cyclosporine A-induced nephrotoxicity, urinary endothelin excretion and renal endothelin receptor number.

The aim of the present study was to determine the effect of a calcium channel blocker on renal function, urinary endothelin excretion and endothelin receptor number in rats. Administration of cyclosporine resulted in a significant impairment of renal function when measured by either [14C]inulin or 24 h creatinine clearances. This nephrotoxicity was associated with statistically significant (P less than 0.05) increases in urinary endothelin excretion and renal endothelin receptor number. Treatment with nifedipine attenuated cyclosporine A-induced renal dysfunction and reduced urinary endothelin excretion. The data provide further evidence of a role for endothelin in cyclosporine A-induced nephrotoxicity.

ETA receptor blockade attenuates hypertension and decreases reactive oxygen species in ETB receptor-deficient rats.

We hypothesize that endothelin-A receptor stimulation contributes to the elevated blood pressure and superoxide production in endothelin-B receptor-deficient rats on a high salt diet. Experiments were conducted on homozygous endothelin-B-deficient (sl/sl) and wild-type rats (wt) fed a high salt diet (8% NaCl) for 3 weeks. Separate groups were given normal drinking water or water containing the endothelin-A receptor antagonist, ABT-627 (5 mg/kg per day; n = 8-9 in all groups). On a normal salt diet, (sl/sl) rats had a significantly elevated systolic blood pressure compared with wt (138 +/- 3 vs 117 +/- 4 mmHg, respectively; P < 0.05). High salt diet caused a significant increase in systolic blood pressure in (sl/sl) rats compared with wt (158 +/- 2 vs 138 +/- 3 mmHg, respectively; P < 0.05). Endothelin-A receptor blockade decreased systolic blood pressure in (sl/sl) rats on high salt (125 +/- 5 mmHg; P < 0.05 vs without antagonist) without affecting the systolic blood pressure in wt (119 +/- 4 mmHg). Aortic superoxide production (lucigenin chemiluminescence) and plasma 8-isoprostane were elevated in sl/sl rats and were significantly reduced by endothelin-A receptor blockade in sl/sl, but not in wt rats. These findings suggest that endothelin-1, through the endothelin-A receptor, contributes to salt-induced hypertension and vascular superoxide production in endothelin-B-deficient rats.