Abnormal renal handling of water and sodium is implicated in the pathogenesis of hypertension in spontaneously hypertensive rats (SHR). Alteration of renal endothelin-1 synthesis is also reported in SHR. Endothelin-1, a potent vasoconstrictor and regulator of sodium reabsorption in the nephron, has a pathophysiological potential in the development of hypertension. Because synthesis of bioactive endothelin-1 requires endothelin converting enzyme-1 (ECE-1), we investigated whether renal ECE-1 gene expression is altered in the kidney of SHR. Kidneys from both 4- and 12-week-old SHR and age-matched Wistar-Kyoto rats (WKY) were studied. ECE-1 mRNA in microdissected nephron segments was assessed by reverse transcription-competitive polymerase chain reaction, and ECE-1 protein level by Western blot. In 4-week-old SHR, ECE-1 mRNA was significantly increased in the proximal straight tubule, medullary thick ascending limb, cortical thick ascending limb, and inner medullary collecting duct. ECE-1 protein level was increased in both the outer and inner medulla. In 12-week-old SHR, ECE-1 gene expression was significantly increased in the proximal straight tubule, medullary thick ascending limb, and also in the glomeruli. Glomerular preproendothelin-1 mRNA expression was not different between the two strains at both 4 and 12 weeks. We conclude that high ECE-1 gene expression in the nephron, via increase of endothelin-1 synthesis, may promote sodium retention that contributes to the development and/or maintenance of hypertension in SHR.
Background-The lung expresses large amounts of endothelin-converting enzyme-1 (ECE-1), which catalyzes a step in the biosynthesis of potent vasoactive endothelin-1 (ET-1) from the inactive intermediate big ET-1. Because there has been no report concerning a possible relationship between ET-1 and ECE-1, we investigated the effects of ET-1 on ECE-1 expression in cultured rat pulmonary endothelial cells. Methods and Results-ECE-1 messenger RNA (mRNA) and protein expression in cultured endothelial cells were assayed by Northern and Western blotting, respectively. Incubation with ET-1 for 6 hours caused a significant decrease in ECE-1 mRNA expression. The action of ET-1 on ECE-1 mRNA expression was antagonized by pretreatment with BQ788, a specific ETB receptor antagonist, but not by pretreatment with BQ123, a specific ETA receptor antagonist. The expression of ECE-1 protein was also inhibited at 6 hours after incubation with ET-1. The effects of ET-1 on ECE-1 mRNA and protein expression were shown to be mimicked by ionomycin, a calcium ionophore, but not by 12-O-tetradecanoylphorbol 13-acetate, a protein kinase C activator. Conclusions-The present results demonstrate that ET-1 suppressed ECE-1 protein levels by inhibiting ECE-1 mRNA expression through the ETB receptor, suggesting the existence of a feedback action of ET-1 on ECE-1 in pulmonary endothelial cells.(Circulation. 1998;97:234-236.)Key Words: endothelin Ⅲ endothelium Ⅲ receptors E ndothelin-1 is a potent vasoconstrictor peptide produced in vascular endothelial cells and is involved in pathophysiological conditions such as acute renal failure, 1 pulmonary hypertension, and systemic hypertension. ETA receptors are present on the vascular smooth muscle and mediate direct vasoconstriction, whereas ETB receptors are present on endothelial cells and produce vasodilation via the endothelininduced release of nitric oxide and prostacyclin. ET-1 is initially synthesized as preproET-1, which is processed to an inactive intermediate big ET-1. Mature ET-1 is produced from big ET-1. The final step is catalyzed by the endothelinconverting enzyme. An ECE-1 has recently been cloned 2,3 and is the major form of ECE in most tissues. A more recently cloned ECE-2 4 is a homologous protein that differs from ECE-1 in sensitivity to phosphoramidon, in optimal pH, and in tissue distribution and quantity.The lung is an organ that abundantly expresses ECE-1 2,3 as well as preproET-1 mRNA. The conversion of big ET-1 was reported to be more efficient in the lung than in the kidney or mesentery in isolated perfusion of rats.5 Increased pulmonary production of ET-1 has been demonstrated in pulmonary hypertension 6 and acute myocardial infarction. In such states, an elevation of ET-1 may not be beneficial to maintain pulmonary and systemic circulation. For the counterregulatory mechanism, ET-1 may act directly on ECE-1 expression. In the present study, we investigated the effects of ET-1 on ECE-1 expression in cultured rat pulmonary endothelial cells and evaluated whether those effects m...
The effects of low and high NaCl diets on plasma glucose and insulin responses to glucose ingestion were investigated in 15 patients with essential hypertension. Oral glucose (75 g) tolerance tests were carried out while patients were taking diets with low (2 g/day) and high (20 g/day) NaCl content. Fasting plasma glucose and insulin levels were both significantly lower during ingestion of the high NaCl diet (p less than 0.05). After glucose ingestion, the incremental areas under the two hour plasma glucose and insulin curves were significantly smaller during ingestion of the high NaCl diet (glucose p less than 0.005 and insulin p less than 0.025). These findings that low NaCl diets increase the glycemic response to glucose loads suggest that use of NaCl restriction for the treatment of essential hypertension may not always be desirable.
T cell-replacing factor (TRF)/IL-5 is a glycosylated polypeptide that acts as a key factor for B cell growth and differentiation. Since IL-5 action is probably mediated by specific cell surface receptor(s), we have characterized the binding of IL-5 to cells using biosynthetically [35S]methionine-labeled IL-5 and 125I-IL-5 that had been prepared using Bolton-Hunter reagent. The radiolabeled IL-5 binds specifically to BCL1-B20 (in vitro line) (a murine chronic B cell leukemic cell line previously shown to differentiate into IgM-secreting cells in response to IL-5) within 10 min at 37 degrees C. There are two classes of binding sites with high affinity (Kd = 66 pM) and low affinity (Kd = 12 nM) for IL-5 and an average number of binding sites for high affinity and for low affinity were 400 and 7,500 per cell, respectively. The specificity of binding of radiolabeled IL-5 has been confirmed by demonstrating that only unlabeled IL-5 and anti-IL-5 mAb but not by IL-1, IL-2, IL-3, IFN-gamma, and GM-CSF inhibit radiolabeled IL-5 binding to BCL1-B20 cells. Treatment of surface-bound radiolabeled IL-5 with bivalent crosslinkers identified a membrane polypeptide of Mr 46,500 to which IL-5 is crosslinked. A variety of cell types have been surveyed for the capacity to bind specifically radiolabeled IL-5 with high affinity. BCL1 cells MOPC104E (murine myeloma cell line) expressed IL-5-R, whereas BAL. 17 and L10 A (B cell lymphoma) did not. T cell line, mastocytoma cell line, or macrophage tumor cell line did not display detectable levels of IL-5-R. were hardly detectable on normal resting B cells but were expressed on LPS-activated B cells, fitting the function of IL-5 that acts on activated B cells for their differentiation into Ig-secreting cells. Intriguingly, early B cell lines (J-87 and T-88) that grow in the presence of IL-5 expressed significant but low numbers of high-affinity binding sites for IL-5. The biological effects of IL-5 were mediated by high-affinity binding sites. The identification and characterization of IL-5-R should provide new insight into the apparent diverse biological activities of IL-5.
SUMMARYIn order to investigate the validity of angiotensin converting enzyme inhibition with captopril as a screening test for primary aldosteronism (PA), 50mg of captopril were administered orally to 7 patients with PA, 17 with essential hypertension (EH), 5 with renovascular hypertension (RVH), 2 with renoparenchymal hypertension (RH) and 8 normal volunteers.The plasma aldosterone concentration (PAC) was suppressed to less than 15ng/dl in all of the EH, RVH and RH patients and normal subjects 90 min after administration of captopril, but not suppressed in 6 of 7 patients with PA. In addition, the plasma renin activity (PRA) was increased to greater than 1ng/ml/h in 10 of 17 patients with EH and in all with RVH, RH and the normal controls, but to less than that in 6 of 7 PA and the remaining EH patients. The PAC to PRA ratio after captopril was greater than 20 in all patients with PA, while it remained below 20 in EH, RVH and RH patients and normal controls.From these results, we conclude that the PAC to PRA ratio in the captopril administration test is a simple and useful tool to detect PA in hypertensive patients. In addition, the test has a great advantage in that it can be safely applied to outpatients with relatively severe hypertension. Additional Indexing Words: Primary aldosteronismAldosterone to renin ratio Captopril
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