[Preliminary clinical analysis of direct renin inhibitor aliskiren in the treatment of severe coronavirus disease 2019 patients with hypertension].

Objective: To explore the feasibility of direct renin inhibitor aliskiren for the treatment of severe or critical coronavirus disease 2019 (COVID-19) patients with hypertension. Methods: The antihypertensive effects and safety of aliskiren was retrospectively analyzed in three severe and one critical COVID-19 patients with hypertension. Results: Four patients, two males and two females, with an average age of 78 years (66-87 years), were referred to hospital mainly because of respiratory symptoms. Three were diagnosed by positive novel coronavirus 2019 (2019-nCoV) nucleic acid or antibody, and the critical patient with cardiac insufficiency was clinically determined. Two patients were treated with calcium channel antagonist (CCB), one with angiotensin converting enzyme inhibitor (ACEI), and one with angiotensin Ⅱ receptor antagonist (ARB). After admission, ACEI and ARB were discontinued, one patient with heart failure was treated by aliskiren combined with diuretic.Three patients were treated with aliskiren combined with CCB among whom two withdrew CCB due to low blood pressure after 1 to 2 weeks. Based on comprehensive treatment including antiviral and oxygenation treatment, blood pressure was satisfactorily controlled by aliskiren after three to four weeks without serious adverse events. All patients were finally discharged. Conclusion: Our preliminary clinical data shows that antihypertensive effect of aliskiren is satisfactory and safe for severe COVID-19 patients complicated with hypertension.

[The application of captopril challenge test in the diagnosis of primary aldosteronism].

Objective: To evaluate the value of captopril challenge test (CCT) in the diagnosis of primary aldosteronism (PA). Methods: A total of 674 patients [(45.0±13.7) years, men 341, women 333] admitted to Peking Union Medical College Hospital from 2000 to 2015 were analyzed. Among them, 222 subjects were with essential hypertension (EH), 28 were with pheochromocytoma (PHEO), 246 were with idiopathic hyperaldosteronism (IHA) and 178 were with aldosterone producing adenoma (APA). All patients received CCT. 24 h urine sodium was measured in partial patients. Plasma renin activity (PRA), aldosterone (ALD) were detected. Results: Compared with EH [PRA: before 0.5(0.2, 0.9) µg·L(-1)·h(-1,) after 0.8(0.4, 1.5) µg·L(-1)·h(-1;) ALD: before (393±122) pmol/L, after (360±97) pmol/L] and PHEO [PRA: before 0.3(0.1, 0.9) µg·L(-1)·h(-1,) after 0.4(0.1, 1.6) µg·L(-1)·h(-1;) ALD: before (396±108) pmol/L, after (374±114) pmol/L], lower levels of PRA and higher levels of ALD before and after CCT were observed in PA patients [PRA: before 0.1 (0.1, 0.2) µg·L(-1)·h(-1,) after 0.1 (0.1, 0.2) µg·L(-1)·h(-1;) ALD: before (468±216) pmol/L; after (457±199) pmol/L]. After CCT, the suppression rate of ALD [2.8% (-8.8%, 15.4%) vs 6.6% (-4.3%, 17.6%)] and increasing rate of PRA [0(0, 50%) vs 50%(0, 200%)] in PA patients were lower than those in EH patients. The ALD/PRA ratio (ARR) were higher in PA than that in EH or PHEO patients. In the EH subjects, ALD levels of seated posture were higher than those of recumbent posture both before and after receiving captopril, but with no changes in ARR after CCT. No significant differences in ALD and ARR (before and after receiving captopril) were observed between seated and recumbent position in the PA group. The ARR after CCT tended to decrease in EH subjects with elevated urine-sodium compared with those with normal urine-sodium. No changes could be viewed in ALD and PRA levels between normal urine-sodium and elevated urine-sodium groups among APA, IHA and EH patients either before or after CCT. Among patients with APA, the ALD levels before CCT and the ARR after CCT were lower in the patients with AngiotensionⅡ(AngⅡ) reactive than those without. A ROC curve analysis suggested that the optimal cutoff value was 46.2 (ALD unit: ng/dl; PRA unit: µg·L(-1)·h(-1)) for ARR after challenge in diagnosing PA, with the sensitivity of 88.7% and specificity of 84.8%. Conclusions: ARR after 25 mg captopril had high sensitivity and specificity in diagnosis of PA with the cutoff of 46.2. Seated CCT could replace recumbent CCT as a more confirmatory test. The PRA increasing rate should be taken into consideration when diagnosis of PA.

Antiserum against homologous atrial natriuretic peptide diminishes the natriuretic response during mineralocorticoid escape in rats.

To elucidate the physiological role of atrial natriuretic peptide (ANP) in plasma during mineralocorticoid escape, we investigated the effects of passive immunization with ANP-specific antiserum on deoxycorticosterone (DOCA)-treated rats. Sodium was retained in excess of intake during the first day after treatment with DOCA, and sodium balance returned to control values by the second day, whereas the excretion of potassium exceeded the intake during all days after DOCA treatment. These changes in electrolyte balance were associated with a significant increase in plasma levels of ANP. Administration of ANP-specific antiserum significantly impaired the return to normal sodium balance as well as the augmented kaliuresis that were observed on the second day after injection of DOCA. No significant effect was observed on either sodium or potassium balance after the injection of normal rabbit serum. These results suggest that plasma ANP plays an important role in mineralocorticoid escape.

Endothelin stimulates aldosterone secretion in vitro from normal adrenocortical tissue, but not adenoma tissue, in primary aldosteronism.

In addition to vasoconstriction, endothelin (ET) has been reported to show various endocrine actions in animals. However, no data have emerged concerning the effect of ET on adrenal function in humans. We, therefore, investigated the effects of ET on aldosterone and cortisol secretion from adrenocortical tissues obtained from normal subjects (n = 6) and patients with primary aldosteronism (n = 5). Adrenal tissue slices were incubated at 37 C for 120 min in modified Krebs-Ringer solution containing glucose and HEPES. ET increased aldosterone secretion from normal adrenocortical tissue in a dose-dependent manner, with an ED50 of 0.036 nmol/L, although the maximum response was small compared with that to angiotensin-II. ET also stimulated aldosterone secretion from tissues adjacent to the adenoma, but not from the adenoma, in patients with primary aldosteronism. The effects of ET on aldosterone secretion were significantly suppressed by calcium channel blockade with nicardipine. ET did not affect cortisol secretion from the adrenal tissues. These results suggest that ET is one of the factors that regulates aldosterone secretion in humans.

Renal and hemodynamic effects of endothelin in anesthetized dogs.

The effects of endothelin on systemic hemodynamics and renal functions were investigated in anesthetized dogs. Infusion of endothelin at a dose of 1 ng/kg/min decreased renal blood flow and increased renal vascular resistance and filtration fraction. Endothelin at doses higher than 10 ng/kg/min significantly decreased cardiac output, glomerular filtration rate, renal plasma flow, urine volume, and urinary sodium excretion. Mean arterial pressure showed a transient decrease at doses higher than 50 ng/kg/min. These results showed that endothelin in systemic administration has effects on renal functions as well as on systemic hemodynamics.

Effects of endothelin on renal hemodynamics and excretory functions in anesthetized dogs.

The effects of endothelin on renal hemodynamics and excretory functions were investigated in anesthetized dogs. Infusion of endothelin at a rate of 1 ng/kg.min resulted in a slight but significant decrease in renal blood flow and an increase in renal vascular resistance and filtration fraction. Endothelin at doses higher than 10 ng/kg.min significantly decreased cardiac output, glomerular filtration rate, urine volume, and urinary sodium and potassium excretion, whereas it increased systemic vascular resistance. Mean arterial pressure and heart rate showed a transient decrease and increase, respectively, at doses higher than 50 ng/kg.min. Plasma renin activity and plasma aldosterone concentrations were increased only at the dose of 100 ng/kg.min. These effects lasted for more than 60 min. These results suggest that endothelin may have an important role in the modulation of renal functions as well as in the modulation of systemic hemodynamics.

Inhibition of nitric oxide synthesis increases the secretion of endothelin-1 in vivo and in cultured endothelial cells.

The aim of this study is to investigate the effects of nitric oxide, formed from L-arginine, on the production of endothelin-1 in vivo and in cultured endothelial cells. In mechanically ventilated anesthetized dogs (n = 5), mean pulmonary arterial pressure (PAPm) and pulmonary vascular resistance (PVR) during hypoxic ventilation (FIO2 = 0.10) was 25 +/- 3.1 kPa and 68.7 +/- 10.2 kPa.s/L respectively. NG-nitro-L-arginine methylester (L-NAME), an inhibitor of nitric oxide synthase, increased the peak value of PAPm and PVR during hypoxic ventilation to 36.6 +/- 4.7 kPa and 158.4 +/- 25 kPa.s/L and its effect lasted for 2-3 hours. Meanwhile, plasma endothelin-1 level in the femoral artery increased by 20.9 +/- 7.1, 25.6 +/- 7.7, 28.6 +/- 7.9 pg/ml at the 60th, 120th, 180th minute after the injection of L-NAME respectively (P < 0.05 vs hypoxic control before the injection). In cultured endothelial cells from umbilical veins, endothelin-1 level of culture medium in control group was 35.1 +/- 5.9 pg/10(5) cells/ml (n = 9). L-NAME increased endothelin-1 level to 42.8 +/- 4.9pg/10(5) cells/ml (n = 9, P < 0.05) in case of 10(-11) mol/L and to 43.0 +/- 4.7 pg/10(5) cells/ml in case of 10(-7) mol/L (n = 9, P < 0.05). These findings indicate that endogenous nitric oxide is an inhibitory modulator of hypoxic pulmonary vasoconstriction and that nitric oxide inhibits the production of endothelin-1 in vivo and in cultured vascular endothelial cells.

[The relationship between the plasma levels of endothelin and angiopathy in diabetic patients].

Plasma levels of endothelin (ET), vasoconstrictor peptide released from vascular endothelial cells, have been measured by radioimmunoassay in 48 patients with NIDDM and 20 healthy subjects. The plasma ET concentrations were found to be greatly elevated in the patients with diabetes compared with the healthy subjects (P < 0.001). We also find that the plasma levels of ET were higher in diabetic patients with complication of diabetes mellitus than in those without complication (P < 0.02). The elevated ET levels were related to hypertension and/or diabetic angiopathy. There were no significant correlations between plasma ET concentrations and blood glucose, HbA1 et al. In diabetic patients elevated ET levels may play a pathophysiological role in the development of diabetic complication.

[2 cases of familial multiple endocrine neoplasia syndrome].

Two cases of familial multiple endocrine neoplasia syndrome (MEN) are reported. Case 1. A 31-year-old woman began to have repeated attacks of coma in 1970. Blood examination showed fasting sugar as low as 2.05 mmol/L (37 mg/dl). Her disease was cured after the removal of two insulinomas in 1972. However, coma occurred again in 1982. Examination revealed the ratio of concentrations of serum insulin and sugar being more than 0.3. Another operation with removal of 19 insulinomas were performed in our hospital in 1985. After operation, the level of blood sugar returned to normal. Her father had suffered from Zollinger-Ellison Syndrome; the entire stomach and a part of pancreas were removed in 1967. So we examined her brother. His serum calcium level was 2.5-2.9 mmol/L (10.0-11.6 mg/dl) and plasma iPTH level 49.5-115.5 ng/L (normal value 21.4 +/- 7.7 ng/L n = 71). The high level of iPTH could not be suppressed by calcium load test. The total of two and a half of the remaining two parathyroid glands were removed. Pathology confirmed hyperplasia of parathyroid glands. The levels of serum calcium and iPTH returned to normal after operation. Case 2. A 25-year-old woman suffered from hypertension at the age of ten. Adrenal tumor with pheochromocytoma (2 x 2 x 1.5 cm3) was diagnosed and removed at that time. She complained of intermittent coma for 10 months and was thus admitted to our hospital in Nov. 1984. The level of blood sugar was 1.5-3.8 mmol/L (26-67 mg/dl).(ABSTRACT TRUNCATED AT 250 WORDS)

Immunoreactive prorenin and its profragment peptide are present in human juxtaglomerular cells.

Although prorenin appears to be activated through the cleavage of its prosegment in the juxtaglomerular cells, the presence of prosegment peptide has never been demonstrated. We therefore studied prorenin in juxtaglomerular tumour cells, both by immunohistochemistry and by radio-immunoassay. Synthetic peptide covering the 14-carboxyterminal sequence of human renin prosegment was used to prepare both antibody and radiolabelled tracer. Intense immunostaining of prorenin was demonstrated in the tumour cells. By gel filtration, however, immunoreactive prorenin was shown to consist of two major components. The first peak, located at the elution position of activatable inactive renin, was regarded as prorenin. The other peak was located at an elution position with a smaller molecular weight, which was assumed to represent the profragment. These results suggest that both prosegment peptide and prorenin are present in the juxtaglomerular cells.

Natriuretic and diuretic effects of endothelin in isolated perfused rat kidney.

In an attempt to clarify the pathophysiological role of endothelin (ET), a novel vasoconstrictor peptide, we administered this peptide into the medium of isolated perfused rat kidney (IPK). ET increased renal vascular resistance by 53%, and reduced inulin clearance by 29% in IPK at a higher concentration of 500 PM. However, fractional excretion of sodium and urine flow rate were increased by 160% and 109%, respectively. These findings suggest that ET modulates the tubular sodium reabsorption as well as the renal hemodynamics.

Radioimmunoassay for endothelin and immunoreactive endothelin in culture medium of bovine endothelial cells.

Using a synthetic 21-residue endothelin as antigen, we have produced an antiserum for endothelin and developed a specific and sensitive radioimmunoassay (RIA) for endothelin. The minimum detection limit of the RIA was 1 pg/tube. Immunoreactive (ir-) endothelin was extracted from the culture medium by Bondelute C8 column. The ir-endothelin in the culture medium of endothelial cells (EC) from bovine pulmonary artery and carotid artery was 1.48 ng/ml and 3.31 ng/ml, respectively. Reverse-phase high performance liquid chromatography coupled with the RIA revealed that ir-endothelin in the culture medium comprised one major component corresponding to synthetic endothelin. In addition, the cultured EC of bovine pulmonary artery were specifically stained by immunohistochemical technique. These results suggest that endothelin could be produced in the EC of the pulmonary and carotid arteries besides the aorta. The RIA presented in this study could be an useful tool to investigate the pathophysiologic significance of endothelin.

Gene expression and roles of angiotensin II type 1 and type 2 receptors in human adrenals.

Although stimulation of aldosterone secretion is one of the functions of angiotensin II, the gene expression and biological significance of the angiotensin II receptor subtypes, AT1 and AT2, in the human adrenal have not been characterized. We therefore investigated the transcription levels of the receptor subtype genes and their roles in regulation of steroid secretion by human adrenals. The expression of AT1 and AT2 receptor mRNA was assessed by reverse transcription-polymerase chain reaction followed by Southern blot analysis in normal adrenocortical tissues (n = 6) and a series of adrenal tumour tissues: aldosterone-producing adrenocortical adenoma (n=6), Cushing's syndrome (n = 6) and pheochromocytoma (n = 6). The role of the two receptor subtypes in steroid secretion in vitro was examined by incubating the tissue with angiotensin II(1 microM) with or without the selective AT1 antagonist CV-11974 (1 microM). Both AT1 and AT2 receptor mRNA transcripts were demonstrated in all of the human adrenal tissues tested. Angiotensin II-induced aldosterone secretion was suppressed 50% upon the addition of CV-11974. The selective AT2 agonist CGP-42112 increased aldosterone secretion by 55% over the control, which was not suppressed by CV-11974. Angiotensin II and CGP-42112 did not affect cortisol secretion. These results suggest that both AT2 and AT1 receptors may be involved in the regulation of aldosterone secretion and tumorigenesis of the human adrenals.