Effect of upright posture on the aldosterone responses to dopamine, metoclopramide, angiotensin II, and adrenocorticotropin

Aldosterone secretion in man is stimulated by potassium (K), ACTH, and angiotensin II (AII) and inhibited by dopamine (DA). In normal sodium-replete supine individuals, aldosterone secretion is under maximum tonic inhibition by DA and is not inhibited further by DA administration. Sodium depletion alters plasma aldosterone responses to secretogogues. Upright posture, another physiological stimulus to aldosterone secretion, recently was demonstrated to sensitize the adrenal cortex to inhibition of aldosterone secretion by a large quantity of DA (4.0 micrograms/kg X min). The effect of upright posture on aldosterone responses to other secretogogues is unknown. In this study, we investigated the effect of upright posture on aldosterone responses to low infusion rates of DA, to the DA antagonist metoclopramide (M) and to AII and ACTH. Fourteen normal men eating a normal sodium diet were studied. In eight, PRA, plasma aldosterone (PAC), plasma cortisol (F), and serum K concentrations were determined after 4 h of upright posture and infusion of vehicle (D5W) or DA at 0.1, 0.4, and 2.0 micrograms/kg X min. Six other normal men were kept supine for 3 h and, on separate days, upright for 3 h and given iv M (10-mg bolus dose), AII (1 and 4 pmol/kg X min for 30 min), and ACTH (20 and 120 mU/h for 30 min). PAC, PRA, F, and K were measured before and after these three secretogogues were administered. In the presence of vehicle, mean PAC increased by 15.1 +/- 4.3 (+/- SEM) ng/dL after 4 h of upright posture. In the presence of DA infused at 0.1, 0.4, and 2.0 micrograms/kg X min, the PAC response to upright posture was decreased to 9.7 +/- 2.5 (P = NS), 7.5 +/- 3.9 (P less than 0.05), and 8.1 +/- 2.0 (P less than 0.05) ng/dL, respectively. This occurred without a decrease in PRA, F, or K. The stimulation of PAC 10 and 20 min after a 10-mg bolus dose of M was 9.6 +/- 3.3 and 9.3 +/- 2.6 ng/dL, respectively, in supine subjects and 8.3 +/- 2.3 and 10.8 +/- 3.4 ng/dL 10 and 20 min after the M dose in upright subjects. The responses of PAC to ACTH and AII also were unchanged after 3 h of upright posture. We conclude that upright posture sensitizes the adrenal cortex to inhibition of aldosterone secretion by DA without affecting other modifiers of aldosterone secretion.(ABSTRACT TRUNCATED AT 400 WORDS)     

BEHAVIOUR OF PLASMA RENIN ACTIVITY AND ALDOSTERONE DURING THE FIRST 72 H OF LIFE

Plasma renin activity (PRA) and plasma aldosterone concentrations (PAC) were determined in fifty normal newborns during the first 72 h of life. PRA was elevated in all cases and tends to increase from the first (6.79 +/- 0.69SE ng/ml/h) to the third day of life (8.24 +/- 0.96SE ng/ml/h). PAC was also elevated and rose from 24.06 +/- 3.23SE ng/dl on the first day to 39.20 +/- 4.25SE ng/dl on the third day. No significant correlation was observed between PRA and PAC. Serum sodium was within the normal range, whereas serum potassium was slightly elevated during the first 48 h of life. The physiological significance of the high levels of PRA and PAC in newborns is not clear at present. Many factors may be involved in the increased activation of the renin-angiotensin-aldosterone system: low blood pressure, hypersensitivity of the macula densa to catecholamines, relative insensitivity of the immature kidney to aldosterone, hyperkalaemia and other control mechanisms for aldosterone secretion all of which probably operate simultaneously during the first days of life.     

Role for aldosterone in blood pressure regulation of obese adolescents

To determine the role of aldosterone in the regulation of blood pressure (BP) in obese adolescents, supine and 2-hour upright plasma renin activity (PRA), and aldosterone and cortisol were measured in 10 nonobese and 30 obese adolescents before and after a 20-week weight loss program. The obese adolescents had significantly higher supine and 2-hour upright plasma aldosterone concentrations (17 +/- 8 vs 6 +/- 2 ng/dl [p less than 0.01 supine obese vs nonobese] and 30 +/- 11 vs 14 +/- 8 ng/dl [p less than 0.01 2-hour upright]). Although PRA was not significantly different between the 2 groups of children, a given increment in PRA produced a greater increment in aldosterone in the obese adolescents. In addition, obese subjects had a significantly increased mean BP (93 +/- 12 vs 74 +/- 8, p less than 0.005) and a weak correlation between BP and plasma aldosterone concentration. Compared with an obese control group, weight loss resulted in a significant decrease in plasma aldosterone (p less than 0.01) without an associated decrease in PRA. After weight loss there was also a significant decrease in the slope of the posture-induced relation between PRA and aldosterone. In addition to weight loss being associated with a significant decrease in BP (p less than 0.01), there was a significant correlation between the change in plasma aldosterone and the change in mean BP (r = 0.538; p less than 0.002 change in upright aldosterone vs change in mean BP). Obese adolescents have an increased plasma aldosterone concentration that may be important in the regulation of their BP.     

beta-Endorphin stimulates plasma renin and aldosterone release in normal human subjects

To determine the effect of beta-endorphin on the renin-angiotensin-aldosterone system, human synthetic beta-endorphin (0.3, 1.0, and 3.0 micrograms/kg X min) was infused iv in normal subjects. Each dose was administered for 30 min, and a control infusion of 5% dextrose and water was given on another day. Ten subjects were studied recumbent and in balance while ingesting a 10-meq Na+ diet. Plasma renin activity (PRA), plasma aldosterone (PA), and plasma cortisol (F) were measured basally and every 30 min for 210 min. The increments in PRA and PA above basal significantly (P less than 0.05) increased (3.1 +/- 1.2 ng/ml X h and 12.2 +/- 5.3 ng/dl, respectively; P less than 0.05) at the end of the beta-endorphin infusion. beta-Endorphin also significantly (P less than 0.01) suppressed F levels. Since in the low salt study, beta-endorphin suppressed F release while stimulating renin secretion, an additional five subjects were pretreated with dexamethasone (0.5 mg every 6 h) and were studied in balance while ingesting a 200-meq Na+ diet to suppress the renin-angiotensin system. Significant (P less than 0.025) increments in PRA (2.1 +/- 0.7 ng/ml X h) and PA (4.1 +/- 1.7 ng/dl) levels above basal were again found during the sequential dose infusion of beta-endorphin (0.3, 1.0, and 3.0 micrograms/kg X min). However, PA elevations were sustained for at least 120 min after the beta-endorphin infusion was stopped despite a drop in PRA 90 min earlier. In additional studies, an attempt was made to define the minimal effective dose of beta-endorphin by 60-min infusions (0.03, 0.1, and 0.3 micrograms/kg X min) in subjects on a 200-meq Na+ diet who were dexamethasone pretreated. The PRA and PA levels rose significantly (P less than 0.05) above basal at the 0.3 micrograms/kg X min dose, but not at the 0.03 or 0.1 micrograms/kg X min dosage levels. There were no changes in blood pressure or potassium during either the 10 or 200-meq Na+ studies. Thus, beta-endorphin stimulates aldosterone release in vivo. However, the underlying mechanisms are complex, since renin levels also increased. The data suggest that the early aldosterone rise may be secondary to an increase in renin release, but renin cannot account for the sustained postinfusion elevations of aldosterone.     

Individual renin-aldosterone responses of clinically healthy young Japanese men to dietary sodium and posture.

Responses to the changes in dietary sodium and posture were investigated in 9 young clinically healthy Japanese males who customarily consumed a larger amount of salt than North Americans or Europeans of mixed white ethnic background. Plasma renin activity (PRA), plasma aldosterone concentration (PAC), and urinary aldosterone excretion rate (AER) differed at each end of 3- to 4-day spans on a "control", a high-salt and a low-salt diet and of furosemide administration. PRA and PAC, also determined during the upright position following the supine blood sampling, increased after only 1 hour of standing in each condition (p less than 0.05 or more). PRA and PAC were well correlated in all 4 conditions, regardless of the posture (r = 0.806, p less than 0.001). There were also highly significant correlations between the "supine" PRA or PAC and the preceding 24-hour AER (r = 0.869, p less than 0.001) for PRA; r = 0.855, p less than 0.001 for PAC). Correlation coefficients between PRA and PAC in 9 individual subjects ranged from 0.823 to 0.987. The estimates of constant and slope of the regression line between PRA and PAC varied from subject to subject. The renin-aldosterone axis in response to changes in dietary sodium and posture must be individually assessed.     

A kinetic study of plasma renin and aldosterone during changes of posture in man.

Cardiovascular parameters, hematocrit (Ht), plasma electrolytes, renin activity (PRA) and aldosterone concentration (PAC) were measured in 12 normal human subjects (6 males and 6 females) eating an ad lib diet. At 8 AM, volunteers assumed the following postural changes: 1 hour supine, then 2 hours upright and finally 1 hour supine. Orthostatism induced the following changes: heart rate, systolic and diastolic blood pressure increased immediately; Ht rose significantly at the 5th min in males but not in females; Plasma sodium showed no variations but potassium increased after 30 min; PRA rose significantly at the 5th min and, after 120 min of orthostatism, was found to be 3 times greater than its value after recumbency; and PAC increased significantly at the 15th min and exhibited a plateau 4.5 times its basal values after 90 min of upright posture. When subjects returned to the supine position all the parameters, except PAC decreased. During active orthostatism, a significant correlation was found between PAC and plasma potassium, but correlation was closer between PAC and PRA and between PAC and PRA + potassium. It can be concluded that the renin-angiotensin system is a more potent stimulus for aldosterone secretion than plasma potassium in normal man assuming postural changes. The results presented here can be applied to the development of a short posture test in non-hospitalized patients.     

评价卧立位醛固酮与肾素比值诊断原发性醛固酮增多症的价值

目的 探讨高血压患者卧立位检测血浆醛固酮浓度(plasma aldosterone concentration,PAC）与血浆肾素浓度(plasma renin concentration, PRC)比值（ratio of aldosterone/rennin,ARR）对原发性醛固酮增多症（primary aldosteronism,PA）的诊断价值与临床应用。 方法 回顾性分析2018~2019年240例高血压卧立位试验阳性或可疑阳性患者,通过卡托普利试验阳性联合盐水负荷试验阳性确诊114例PA患者及126例原发性高血压（essential hypertension,EH）患者。采用化学发光法检测卧立位PAC及PRC,基于受试者工作特征曲线分析诊断PA卧立位PAC、ARR截断点,评价不同指标诊断PA的敏感性及特异性。 结果 PA组与EH组间年龄、性别等基线资料差异无统计学意义,以卡托普利试验联合盐水负荷试验同时阳性为诊断标准,卧位ARR诊断PA最佳截断点6.73,敏感度=79.8%,特异度=90.5%,ROC曲线下面积为0.916(95% CI:0.873,0.948）;卧位PAC诊断PA的截断点18.15,敏感度83.3%,特异度64.3%,ROC曲线下面积为0.777 (95% CI:0.719,0.828）;立位ARR诊断PA的截断点4.08,敏感度58.8%,特异度87.3%,ROC曲线下面积为0.798 (95% CI:0.742,0.847）;立位PAC诊断PA截断点24.39,敏感度69.3%,特异度74.6%,ROC曲线下面积为0.744 (95% CI:0.687,0.801）。 结论 卧立位ARR较卧立位PAC诊断PA的特异度强而敏感度差,综合两种体位下的激素检查结果可提高诊断PA的准确性。     

应用血浆肾素浓度进行原发性醛固酮增多症筛查的评价及不同体位筛查效率的比较

目的 比较应用血浆醛固酮/血浆肾素活性(PAC/PRA,ARR)及PAC/血浆肾素浓度(PAC/PRC,AARR)进行原发性醛固酮增多症(PA)筛查的特异性和敏感性差异,评价测定血浆肾素浓度在PA筛查中的价值,并比较不同体位下AARR的筛查效率.方法 (1)对28例通过确诊试验或手术病理证实的PA患者和51例原发性高血压患者测定卧位、立位1 h和立位2 h的AARR,比较不同体位和时间下测定的AARR在PA筛查中的效率.(2)对31例PA患者、242例原发性高血压患者及145名健康志愿者测定立位1h PAC、PRA和PRC,计算ARR和AARR,通过构建ARR和AARR对诊断PA的受试者工作特征曲线(ROC),比较两者在PA筛查中的敏感性和特异性,探讨AARR在筛查PA中的价值,并确定最佳的切点.结果 (1)卧位、立位1 h和立位2 h AARR的ROC曲线下面积分别是0.950(95%CI 0.906～0.994,P<0.01)、0.979(95%CI 0.956～1.000,P<0.01)和0.917(95%CI0.856～0.979,P<0.01).立位1 h AARR具有最高的筛查效率.(2)立位1 h Log-PRA和Log-PRC相关系数为0.705,Log-ARR和Log-AARR的相关系数为0.788.ARR和AARR的ROC曲线下面积分别为0.998(95%CI0.981～1.000,P<0.01)和0.957(95%CI0.929～0.985,P<0.01).AARR的最佳切点为42.36 ng·dl-1/ng·dl-1,其敏感性和特异性分别达到87.10%和93.75%.结论 应用AARR和ARR在高血压患者中进行PA的诊断效果相当,以立位1 h测定的AARR具有最佳的筛查效率,最佳切点为42.36 ng·dl-1/ng·dl-1.     

Hormonal and volume dysregulation in women with premenstrual syndrome

Premenstrual syndrome (PMS) presents with emotional and physical symptoms. Although the emotional symptoms have been extensively studied, the pathophysiology of the fluid-retention symptoms is not currently known. We tested the hypothesis that the fluid regulatory mechanisms are disturbed in PMS. Nine regularly menstruating women with PMS were compared with 9 healthy age-matched women. Hemodynamic parameters and upright plasma volume shift (extrapolated from changes in hematocrit), plasma renin activity (PRA), and plasma aldosterone and sex hormones were measured at different times during the menstrual cycle. During the early follicular and the midluteal phases, the plasma volume shift, supine and upright PRA, and plasma aldosterone were similar in both groups, and none of the participants had edema. However, during the late luteal phase, ankle edema was present only in women with PMS, and their maximal plasma volume shift was lower compared with controls (11.7+/-1.3 versus 15.6+/-0.6; P=0.004). The area under the curve (estimates the amount of the total plasma shift during 30 minutes standing) was 300+/-28 and 406+/-16 in PMS and controls, respectively (P=0.01). PRA and aldosterone levels were higher during the late luteal phase in women with PMS compared with controls (supine PRA: 1.4+/-0.3 [PMS] versus 1.1+/-0.4 [control; P value not significant], upright PRA: 3.9+/-0.08 versus 1.6+/-0.3 ng/mL per hour [P=0.015], supine plasma aldosterone: 131+/-30 versus 68+/-17 pg/mL [P=0.09], and upright plasma aldosterone: 208+/-40 versus 102+/-16 pg/mL [P=0.03]). We, therefore, conclude that women with PMS have increased plasma fluid-regulatory hormones and disturbed fluid distribution only during their late luteal menstrual phase.     

Influence of angiotensin on the secretion of aldosterone in idiopathic hyperaldosteronism

The purpose of study was to investigate the role of angiotensin II in idiopathic primary aldosteronism (IPA) and to evaluate the interest of angiotensin converting enzyme inhibitors (ACEI) in its management. The study concerned 10 hypertensive patients, mean 49 +/- 11 years with idiopathic primary aldosteronism due to bilateral adrenal hyperplasia: plasma renin activity (PRA) less than 1.5 ng/ml/h and plasma aldosterone (PA) greater than 25 ng/100 ml. Adrenal venography and adrenal vein aldosterone levels demonstrated bilateral hyperplasia. PRA and PA were evaluated in recumbent position, then after 4 hours in upright posture. The next day, a "captopril screening test" was performed with PA assays before and three hours after a single oral administration of captopril (1 mg/kg). Upright PRA and PA were slightly increased and acute administration of captopril reduced significantly PA levels in all patients. Blood pressure (BP was unmodified under captopril. These hormonal results demonstrated that adrenal glomerulosa remained sensitive to low concentrations of angiotensin II, and underlined the potential interest of ACEI in the management of IPA. Brown R. demonstrated already an increase of adrenal sensitivity to angiotensin II infusions, and isolated an aldosterone-stimulating factor (ASF). Plasma aldosterone levels were related to increased ASF concentrations but there was no link between PRA and ASF. Carey R. suggested that ASF acts through an increase of the sensitivity of aldosterone production to angiotensin II.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of dietary sodium on the renin-angiotensin-aldosterone system and prevalence of left ventricular hypertrophy by EKG criteria

We investigated the interplay of dietary sodium and renin-angiotensin-aldosterone system (RAAS) activity with the prevalence of left ventricular hypertrophy (LVH) in essential hypertension. Electrocardiograms (EKG) were reviewed for the presence of LVH in 160 hypertensive patients. We then compared the rate of LVH to levels of plasma renin activity (PRA) and serum aldosterone under high and low sodium diet conditions. On high sodium diet, serum aldosterone was significantly higher (7.7+/-0.93 vs 5.7+/-0.35 ng/dl, P=0.02) in participants with LVH. With low sodium diet and upright posture, PRA was significantly lower in subjects with LVH vs those without (5.6+/-1.1 vs 7.6+/-0.56 ng/ml/h, P=0.026). Aldosterone levels on low sodium diet were not different between those with and those without LVH. PRA was then dichotomized at the lowest quartile under low sodium/upright posture conditions to define a 'low renin' group. In a multivariate logistic regression containing renin status (low renin vs normal/high renin), aldosterone on a high sodium diet, age, body mass index, gender, race, duration of hypertension, systolic and diastolic blood pressure and salt-sensitivity only low-renin status on a low sodium diet (P=0.019) and serum aldosterone on a high sodium diet (P=0.04) were significant predictors of LVH. Thus, reduced modulation of renin activity in response to sodium restriction and an increased aldosterone on a high sodium diet appear to identify characteristics of hypertensive patients predisposed to abnormal cardiac remodelling.     

Dopaminergic control of plasma catecholamine and aldosterone responses to acute stimuli in normal man

This study examines the influence of dopamine on catecholamine and aldosterone secretion in normotensive individuals. The responses of plasma aldosterone (PA), norepinephrine (NE), and PRA to upright posture and isometric handgrip were studied in five normal males on a constant 50-meq Na intake before and after 4 days of administration of the dopamine agonist, bromergocriptine (BEC; 2.5 mg three times a day). In addition, the PA responses to graded angiotensin II and ACTH infusions were examined before and during BEC. Supine PA and PRA were not altered by BEC, but basal NE was reduced significantly (P < 0.01) from 204 +/- 29 to 98 +/- 12 pg/ml after BEC. There was an accompanying significant reduction in upright mean arterial pressure during BEC administration. The PA and NE during upright posture and isometric handgrip were significantly suppressed by BEC, but PRA responses were unaltered. BEC produced a significiant (P < 0.025) suppression of the PA response to graded angiotensin II infusions but did not alter the PA response to graded ACTH. Our findings indicate that in normal man there is a pronounced inhibitory effect of dopaminergic pathways on catecholamine scretion and regulation of upright mean arterial pressure. Results of the posture study would suggest that dopamine-mediated PA alterations occur independently of changes in the levels of PRA. The finding that BEC suppressed PA responses to angiotensin II and posture but not to ACTH would imply that dopamine selectively exerts its effect or adrenal angiotensin II-mediated aldosterone secretion.     

Abnormal norepinephrine and aldosterone responses to upright posture in nonmodulating hypertension.

The subgroup of patients with nonmodulating hypertension demonstrates a number of abnormalities of the renin-angiotensin-aldosterone axis. We previously identified abnormalities in plasma and urinary dopamine in nonmodulators and posited that this may be in part due to a generalized defect in sympathetic nervous system activity. In the present study we assessed the state of activation of the renin-angiotensin system and the sympathetic nervous system in normal subjects and patients with modulating, nonmodulating, and low renin essential hypertension during sodium depletion and change from supine to upright posture. Levels of plasma norepinephrine were higher in non-modulators during the posture study (P < 0.05). PRA rose with upright posture in all groups, but low renin subjects had a blunted response. Nonmodulators and low renin subjects had lower aldosterone levels both supine (P< 0.05) and upright (P< 0.01). However, the aldosterone/PRA increment ratio was increased in low renin subjects (P< 0.01), whereas it was decreased in nonmodulators. Twenty-four-hour urine collections for catecholamine determinations were obtained in a subgroup of the subjects, with nonmodulators showing higher levels of norepinephrine excretion which approached significance (P = 0.08). In vitro experiments using rat and human adrenal glomerulosa cells showed that norepinephrine does not affect aldosterone secretion per se. These observations extend the series of abnormalities observed in nonmodulating hypertension. However, it is likely that the alterations in norepinephrine levels during sodium depetion and upright posture are a secondary event and not linked to the altered aldosterone production in these patients.     

Plasma aldosterone response to upright posture and angiotensin II infusion in aldosterone-producing adenoma.

Nineteen patients with primary aldosteronism due to surgically confirmed aldosterone-producing adenoma (APA) were examined to evaluate the response of aldosterone to upright posture and angiotensin II infusion. Upright posture reportedly decreases the plasma aldosterone concentration (PAC) in APA but raises it in idiopathic hyperaldosteronism. However, our findings showed the opposite result, in that the upright posture did not change or raised PAC in 15 of 19 cases (79%). Angiotensin II was infused i.v. at doses from 0.5-2 ng/min.kg body weight in six patients in whom the upright posture raised PAC, but did not raise PAC in all cases. This result supports the assumption that APA is functionally insensitive to angiotensin II. A concomitant rise of ACTH, pretreatment with calcium channel blockade, and other modulating factors may be involved in this PAC rise. Whatever the reason, such a high frequency of patients with increased PAC in APA raises some question about the clinical value of the upright posture test. We believe, then, there is reason to check any interpretation concerning increased PAC in the case of the upright posture test in distinguishing between APA and idiopathic hyperaldosteronism.     

Biochemical evidence of aldosterone overproduction and abnormal regulation in normotensive individuals with familial hyperaldosteronism type I

We examined in detail biochemical characteristics of 10 normotensive individuals (6 females; age range, 11-43 yr) with glucocorticoid-suppressible hyperaldosteronism (familial hyperaldosteronism type I) in an attempt to understand the development of hypertension in this disorder. All were normokalemic (median plasma potassium, 3.7 +/- 0.4 mmol/L SD), and upright plasma aldosterone levels (478 +/- 333 pmol/L) were within the normal range (140-1110 pmol/L) in nine subjects. However, upright PRA levels (3.3 +/- 30.5 pmol/L x min) were suppressed (<13 pmol/L x min), and the aldosterone to PRA ratio (169.0 +/- 308.3) was elevated (>65) in all but one subject. All subjects had elevated 24-h urinary levels of 18-oxo-cortisol (34.3 +/- 11.2 nmol/mmol creatinine; normal range, 0.8-6.5 nmol/mmol creatinine). Plasma aldosterone failed to rise by at least 50% during 2 h of upright posture in five of seven subjects, or during a 1-h infusion of angiotensin II (2 ng/kg x min) in each of six subjects so studied. Serial, second-hourly (day-curve) aldosterone levels correlated tightly with cortisol (r = 0.79-0.97, P < 0.01 to 0.001), but not with PRA (r = 0.13-0.40, not significant) levels in each of six subjects, and plasma aldosterone suppressed to less than 110 pmol/L during 4 days of dexamethasone administration (0.5 mg 6 hourly) in each of two studied, consistent with ACTH-regulated aldosterone production. In conclusion, biochemical evidence of excessive, abnormally regulated aldosterone production is present not only in hypertensive individuals with familial hyperaldosteronism type I, but also in those who are normotensive. The absence of hypertension in such individuals, therefore, cannot be attributed to lack of biochemical expression of the hybrid gene.     

Renin and aldosterone secretion under converting enzyme inhibition

The converting enzyme inhibitor (CEI) is known to inhibit the conversion of angiotensin I to angiotensin II. In order to analyse the regulatory mechanisms involved in aldosterone secretion independent of renin-angiotensin system, one of the CEIs, SQ 14,225 was infused to the dogs in association with several pharmacological agents. To the mongrel dogs under pentobarbital anesthesia, SQ 14,225 was administered intravenously as a bolus injection (0.5 mg/kg), followed by two hour infusion (0.5 mg/kg/hr). The effects of several pharmacological agents on plasma renin activity (PRA) and aldosterone concentration (PA) were examined in the condition in which endogenous angiotensin II production was blocked by CEI. PRA was increased significantly from the basal level (6.4 +/- 1.2; mean +/- SEM) to 14.1 +/- 2.6 ng/ml/hr 60 min after the administration of SQ 14,225. PA, on the other hand, was decreased from 12.2 +/- 3.6 to 7.6 +/- 2.2 ng/dl. The CEI-induced increase in PRA was completely blocked by infusion of angiotensin II (40 ng/kg/min), physiological saline (0.25 approximately 0.44 ml/kg/min), pretreatment of propranolol (0.5 mg/kg) or norepinephrine (200 ng/kg/min). Both pindolol and indomethacin had no significant effect on the CEI-induced increase in PRA. Increase in PRA was also observed by the infusion of furosemide, prostaglandin 1 or E1. PA was increased by KCl infusion (1.0 mEq/kg/hr), but was not affected significantly by the administration of furosemide, pindolol, prostaglandin A1 or E1, during the SQ 14,225 infusion. An elevation of PRA observed under the converting enzyme inhibition, was considered to be due to decreased feedback inhibition as a result of reduction of angiotensin II formation. It was suggested from the present results, that the CEI-induced increase in PRA might be mediated by beta-receptor and baroreceptor in addition to the direct negative feedback by angiotensin II. The present data also suggested that both furosemide and prostaglandins stimulated aldosterone secretion via the renin-angiotensin system, rather than by acting directly on the adrenal cortex.     

Effect of a calcium inhibitor, nicardipine, on aldosterone secretion in primary hyperaldosteronism

The purpose of the study was to evaluate the effects of a dihydropyridine calcium antagonist, nicardipine (N), on blood pressure (BP) and aldosterone secretion in hypertensive patients (pt) with primary aldosteronism. The study concerned 8 pts, mean age 55.6 +/- 7.7 years, 1 pt with aldosterone-producing adenoma (APA) and 7 pts with idiopathic aldosteronism: plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were respectively 0.30 +/- 0.2 ng/ml/h) and 314 +/- 109 pg/ml. Acute administration of 12 mg of nicardipine during 90 mn (three periods of N infusion during 30 mn: 0.4 mg/mn-5 mn; then 0.08 mg/mn-25 mn) significantly decreased BP, with an increase in heart rate (HR); the levels of PAC were significantly reduced with a slight but not significant increase in PRA, 60 mn after N: (table; see text) N decreased also PAC in the pt with APA [600 to 410 pg/ml] but did not improve hypokalemia (3.1 vs 3.3 mmol/l, n = 8 N.S.). In contrast, PAC levels were not modified 2 hours after acute oral administration of captopril (1 mg/kg): 302 +/- 164 pg/ml vs 332 +/- 191 pg/ml (NS). This study demonstrated the antihypertensive efficacy of acute infusion of nicardipine in primary aldosteronism; the decrease of PAC under this calcium antagonist suggested its potential interest in the management of idiopathic aldosteronism.     

Endocrine, renal, and hemodynamic responses to graded dopamine infusions in normal men

The present study was performed to determine the hemodynamic, hormonal, and natriuretic responses to infusions of dopamine (DA) that reflect physiological as well as pharmacological levels in blood or tissue. In six normal men, DA was infused for 2 h at three fixed dosages (0.03 or 0.1, 0.3, and 3.0 micrograms/kg X min) on three separate occasions, which resulted in increases in mean plasma DA concentrations from basal levels of less than 0.03 ng/ml to 0.69 +/- 0.12, 3.73 +/- 0.40, and 38.4 +/- 3.80 (+/- SE) ng/ml. Mean plasma PRL decreased and DA excretion increased significantly from basal levels during all three DA infusions. Plasma LH decreased and norepinephrine (NE) excretion increased during both the middle and high dose infusions, while sodium excretion, plasma NE, and heart rate increased only during the high dose DA infusion. Basal plasma aldosterone values were low and did not change with DA treatment. PRA, TSH, and FSH also did not change. GH responses were difficult to assess because of the frequency of episodic secretions. Since DA concentrations in hypophysial-portal blood may equal or exceed 1 ng/ml, these results support a role for DA in the acute regulation of PRL, and possibly LH, in normal men. As a natriuretic response occurred only at supraphysiological concentrations of circulating DA, if DA has a physiological role in modulating sodium excretion during normal sodium intake, it must be released from dopaminergic neurons or otherwise locally produced in very high concentrations in the kidney.     

Effects of high sodium diet on dopaminergic mechanism in normal and hypertensive subjects

To investigate the effects of dietary sodium on the peripheral dopaminergic mechanism, changes of unconjugated plasma dopamine(DA) and its related humoral factors were studied in 8 patients with essential hypertension(EH) and 8 age-matched normal controls(N) while they were receiving ordinary meals (Na, 130-180 mEq daily) followed by higher sodium (250-300 mEq daily) diets for a week. Plasma and urinary DA, norepinephrine(NE) and epinephrine(E) were measured by the highly sensitive COMT-mediated radioenzymatic procedure, which permits an accurate estimation of plasma DA as low as 5-6 pg/ml. Under high sodium diets, blood pressure and heart rate were not changed significantly in N and EH subjects. Urinary NE and E tended to decrease, while urinary DA increased significantly in both groups of subjects (p less than 0.05). There was a significant correlation between urinary sodium and DA (r = 0.590, p less than 0.001), but plasma DA failed to correlate significantly to urinary sodium or DA in all subjects. Plasma NE and E tended to decrease in both N and EH subjects, while plasma DA increased significantly (p less than 0.05) in EH from 7.2 +/- 0.8 pg/ml [mean +/- SEM] to 9.3 +/- 1.0 and slightly in N from 9.1 +/- 1.8 to 11.2 +/- 1.3. Plasma renin activity(PRA) and plasma aldosterone(PAC) were invariably decreased in all subjects, while plasma prolactin(PRL) remained unchanged. A significant correlation was observed between plasma DA and NE under ordinary meals (r = 0.733, p less than 0.01), but this correlation disappeared under high sodium diets. Plasma DA showed an inverse correlation to PAC (r = 0.351, p less than 0.05) under both dietary conditions. Upright posture induced a significant rise (p less than 0.05) in NE, E, DA, PRA and PAC with ordinary meals, but the responses of NE and PAC were apparently attenuated with high sodium diets. An intravenous injection of metoclopramide (MCP, 10 mg), a DA receptor antagonist, provoked a slight rise in plasma NE and DA with ordinary meals, of which responses were further enhanced with high sodium diets. MCP induced a definite rise in PAC and PRL in all subjects under both dietary conditions (p less than 0.01), while plasma E and PRA remained unchanged after MCP challenge. The results lend support to the view that unconjugated plasma DA could be a useful marker of peripheral dopaminergic activity, which might be a physiological regulator responsible for the suppression of aldosterone secretion and sympathetic nerve activity observed during high sodium intake.     

Effects of Atrial Natriuretic Factor Infusion on Plasma Prorenin Levels in Hypertensive Males

To evaluate the influence of atrial natriuretic factor (ANF) infusion on circulating prorenin, 20 essential hypertensive males, aged between 40 and 60 years, were studied. After 2 weeks under normal sodium intake (120 mmol NaCl per day), patients were randomly assigned to receive either ANF (0.01 fmol/Kg/min) (n.12 patients) or its vehicle (50 mL of isotonic Saline) (n.8 patients) over a period of 60 minutes. Blood samples for plasma renin activity (PRA), prorenin and aldosterone (PAC) were taken at time -60, 0, 20, 40, 60, 120, 180, 240 minutes (infusion time: from 0 to 60 minutes). PRA and PAC decreased during the ANF infusion (PRA: from 0.33±0.05 ng/L/s at time 0 to 0.10±0.06 ng/L/s at 60 minutes, p<0.0001; PAC: from 389.2±99.8 pmol/L at time 0 to 148.7±44.3 pmol/L at 60 minutes, p<0.0001), while returned immediately to baseline levels after the infusion was stopped (PRA: 0.37±0.11 ng/L/s at 180 minutes, PAC: 251.6±72.1 pmol/L at time 180 minutes). On the contrary, plasma prorenin increased during ANF infusion (from 1.66±0.58 ng/L/s at time 0 to 2.44±0.72 ng/L/s at 60 minutes, p<0.05), and returned to baseline levels after the end of the infusion (1.86±0.83 ng/L/s at 180 minutes). These data indicate that ANF infusion may alter only the circulating levels of active renin, without affecting plasma prorenin secretion.