The DNA sequences of the ENaC in three patients with Liddle's syndrome were analyzed. In one family case, we found a new missense mutation of Pro (CCC) to Ser (TCC) at codon 616 in the 0 subunit of ENaC. A genetic analysis of the amiloride-sensitive epithelial sodium channel is recommended in assessing patients with low-renin, salt-sensitive hypertension whose blood pressure is not responsive to spironolactone treatment.
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.
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
To find the best timing for administration of long-acting antihypertensive drugs, we gave nitrendipine, a calcium antagonist of the dihydropyridine group, once a day to six hospitalized and drug-free patients with essential hypertension, changing the time of administration and studying the effects on the circadian rhythm of blood pressure. After control values of 24-hour blood pressure variations were taken with patients on placebo, a 10-mg tablet of nitrendipine was given for 3 days on three occasions -at 6 AM on awakening, at 8:30 AM after breakfast, and at 6 PM after supper; 24-hour blood pressure values for each period were recorded on the third day. The 24-hour blood pressure values during the control period showed a biphasic circadian rhythm, with higher values during wakefulness and lower values during sleep. The control period was also characterized by a rapid rise in blood pressure on awakening, the so-called morning surge of blood pressure, and a gradual decline during sleep at night. Although the morning surge was not completely suppressed by nitrendipine given after breakfast, it was diminished by the drug given on awakening or after supper, the latter brought a deeper decline in blood pressure during sleep compared with other times. The average of 24-hour blood pressure values obtained by nitrendipine given on awakening was the lowest among the three occasions. Thus, administration of long-acting calcium antagonists with a rapid onset of action on awakening in the early morning seems to be a more rational and beneficial alternative than the conventional administration after breakfast. The earlier administration may prevent dangerous cardiovascular catastrophes, including stroke, myocardial infarction, and sudden death, known to occur often during the morning surge of blood pressure. 91214 have been shown to increase between the hours of 6 and 9 AM compared with the rest of the day. A number of precipitating factors may be involved in these early morning catastrophes, but the marked rise in blood pressure almost certainly is a major factor, perhaps by causing a rupture of atherosclerotic plaques whereby thrombus is formed. 9 Antihypertensive drugs that are given once a day have come into common use in the treatment of essential hypertension. Nitrendipine is one of the long-acting calcium antagonists of the dihydropyridine group whose clinical usefulness in the treatment of essential hypertension has been established either as monotherapy 1517 or in combination with /J-blockers. 18 Nitrendipine has a rapid onset of action and is usually given once or twice From the Department of Internal Medicine III, Kumamoto (Japan) University Medical School.Correspondence to Teruhisa Umeda, MD, Department of Internal Medicine III, Kumamoto University Medical School, 1-1-1 Honjo, Kumamoto 860, Japan. a day. Pharmacokinetic studies on dihydropyridine calcium antagonists performed in hypertensive patients 19 ' 20 have also found a relatively straight correlation between the logarithmic value of the pla...
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