PRA Levels Research Articles

The natural history of salt-wasting disorders of adrenal and renal origin.

Twenty one patients with selective aldosterone deficiency due to type 2 corticosterone methyl-oxidase defect [hypoaldosteronism (HA)] and 7 with pseudohypoaldosteronism (PHA) were studied longitudinally for up to 18 yr. All individuals had spontaneous and progressive normalization of sodium and fluid balance with age. The severity of the clinical manifestations varied from acute salt-wasting crisis in infancy and unexplained short stature in childhood to an asymptomatic state in adults detectable only by biochemical studies. Infants with HA had extremely elevated plasma renin activity (PRA; 70-650 ng angiotensin 1/ml X h), which gradually decreased with age, and PRA was normal in adults. Cortisol followed a similar pattern, but marked elevations of plasma deoxycorticosterone (DOC; 28-553 ng/dl) and 18-hydroxycorticosterone (18-OHB; 650-6500 ng/dl) relative to aldosterone (3-29 ng/dl) persisted throughout life in all untreated patients. The plasma 18-OHB/aldosterone ratio, normally 6.2 +/- 3.5 (SD), ranged between 160-760. In contrast, patients with PHA had PRA (70-685 ng angiotensin 1/ml X h), DOC (56-1201 ng/dl), 18-OHB (650-6800 ng/dl), and aldosterone (150-2000 ng/dl) levels which all remained very elevated, but had normal 18-OHB/aldosterone ratios (6.9 +/- 5.1). Comparative studies in 14 untreated patients with 11 beta-hydroxylase deficiency, who had moderate to severe manifestations of mineralocorticoid excess, revealed DOC levels (38-1384 ng/dl) that were remarkably similar to those of patients with HA and PHA. PRA, DOC, and 18-OHB correlated significantly with each other during all variations in sodium balance (P less than 0.001). Sodium repletion partially suppressed these parameters in both disorders, but complete normalization was achieved only in HA when a mineralocorticoid was given. Although the degree of DOC and 18-OHB suppression was similar in all age groups, the changes in PRA were more marked in children than in adults since these were directly proportional to the initial elevations of PRA. Although angiotensin II and potassium increased plasma DOC and 18-OHB, dexamethasone failed to suppress them, indicating that these steroids originated predominantly from the zona glomerulosa. The spontaneous normalization of sodium balance is not due to quantitative differences in hormone secretion with age since the basic steroid abnormalities remain unchanged from infancy to adulthood.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal dysfunction in asymptomatic patients with adrenocortical autoantibodies.

Autoantibodies to the adrenal cortex (AA) were sought by indirect immunofluorescence using unfixed human adrenal tissue in 1675 patients with insulin-dependent diabetes (IDD), 2032 relatives of patients with IDD, and 2543 normal subjects. The frequencies of AA were significantly greater in patients with IDD (1.8%) and their relatives (1.4%) than in normal subjects (0.6%; P less than 0.013). Women more frequently had AA than men (P less than 0.011). There were no differences in the frequencies of AA between caucasoid and black individuals in all three patient groups. Patients with AA had higher frequencies of thyroid microsomal and gastric parietal cell autoantibodies than age-, sex-, and race-matched normal subjects (P less than 0.01). Adrenal function was studied in 30 asymptomatic patients (13 with AA, including 5 with IDD, and 17 subjects with no AA, including 8 with IDD). The mean plasma levels of ACTH at 0600 and 2000 h were significantly higher in those with AA than in matched subjects with no AA (P less than 0.01). The mean PRA levels (both recumbent and upright) were also significantly higher in those with AA than in subjects without AA (P less than 0.01). However, serum cortisol and aldosterone concentrations or 24-h urinary cortisol and aldosterone excretion were no different between the groups. These patients, therefore, appear to have compensated adrenal hypofunction, with the compensation maintained by increased ACTH and renin secretion. Whether these patients will remain in this compensated state of adrenal dysfunction or whether they will develop overt adrenal insufficiency requires longer follow-up.

AUTONOMIC DYSFUNCTION - A MECHANISM FOR RENAL FAILURE?

Familial dysautonomia, a rare autosomal recessive disorder, is characterized by a complex clinical symptomatology related to widespread autonomic and sensory dysfunction. We have previously reported renal failure due to intra-renal vascular and glomerular sclerosis in one dysautonomic; in all, 9 patients whom we have followed up to 18 years of age or more have become uremic. In the present study, renal hemodynamcis were found to be consistently reduced in a group of dysautonomics who were studied at random.Among the 13 patients, aged 7 to 38 years, all had either persistent or episodic hypertension typical of dysautonomia. Glomerular filtration rates (CIN) ranged from 107 down to 20 ml/min/1.73m2 (x̄ = 70). Renal plasma flows (CPAH) were reduced to levels ranging from 560 to 72 ml/min/1.73m2 (x̄ = 350). Filtration fractions averaged 21%. Reductions in GFR and RPF increased with age. Decreased levels of PRA and aldosterone were found in 8 of 12 patients.We have documented depressed renal hemodynamics and progression to uremia in familial dysautonomia. Intermittent hypertension and failure of autoregulation resulting from renal denervation could expose the kidney to vascular and glomerular damage due to hydraulic stress. Dysautonomia may represent a model in man which depicts the key of hemodynamic factors in the causation of glomerular injury.

Responses of plasma renin activity, aldosterone, adrenocorticotropin, and cortisol to dermorphin, a new synthetic potent opiate-like peptide, in man.

This study was designed to investigate the effect of dermorphin (D), a new synthetic potent opiate-like peptide (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2), on PRA, plasma aldosterone (PA), plasma cortisol (PC), and plasma ACTH levels in normal men. D infusion (5.5 micrograms/kg X min for 30 min) significantly increased PRA (P less than 0.01) and decreased PC levels (P less than 0.02). D produced a small decrease in ACTH and a small increase in PA. Pretreatment with the opioid receptor antagonist naloxone (N) blunted the D-induced PRA increase and completely prevented the D-induced PC decrease, but enhanced PC and ACTH levels. These data indicate that the action of D is mediated through opioid receptors, and are consistent with the conclusion that 1) D, a new opioid peptide, increases PRA levels, perhaps via activation of the sympathetic nervous system, providing evidence that opioid peptides may exert an influence on renin secretion; and 2) D suppresses PC levels, perhaps by affecting ACTH secretion, corroborating previous observations that opioid peptides might affect the function of the pituitary-adrenocortical axis.

Glucocorticoid suppression enhances the 18-hydroxycorticosterone and aldosterone response to metoclopramide in man

18-Hydroxycorticosterone (18-OHB) is a precursor of aldosterone and is the only corticosteroid, other than aldosterone, that is synthesized predominantly in the zona glomerulosa. Administration of the dopamine antagonist, metoclopramide results in parallel rises in plasma 18-OHB and aldosterone levels without affecting the plasma levels of other aldosterone precursors. However, 18-OHB. is a product of the zona fasciculata as well as the glomerulosa. Thus, it is possible that metoclopramide may stimulate zona fasciculata secretion of 18-OHB. In order to more selectively examine dopaminergic regulation of zona glomerulosa secretion of 18-OHB we have examined the effect of glucorticorticoid suppression of the fasciculata on the 18-OHB and aldosterone responses to metoclopramide, 10 mg iv in 6 normal volunteers. Dexamethasone, 2 mg every 6 hours for 5 days, suppressed basal levels of cortisol, corticosterone, 18-OHB and aldosterone. Dexamethasone treatment had no effect on basal levels of PRA or PRA responses to metoclopramide. The 18-OHB and aldosterone responses to metoclopramide were enhanced (p<.05) by dexamethasone suppression. The results suggest that dopaminergic mechanisms selectively suppress glomerulosa production of 18-OHB. Endogenous ACTH may inhibit zona glomerulosa production of 18-OHB and aldosterone in response to the dopamine antagonist, metoclopramide.

The renin-angiotensin system in panhypopituitarism: dynamic studies and therapeutic effects in Sheehan's syndrome.

To gain insight in the influence of the pituitary gland on the renin-angiotensin system plasma renin substrate (PRS) and the response of PRA to stimulation were studied in a homogeneous group of 20 female patients with the same etiology and degree of pituitary failure, before treatment (group P), after hydrocortisone substitution (group F), and after hydrocortisone and thyroid hormone treatment (group F + T). All patients were studied before and after each treatment by response to two stimulatory tests, acting through two different pathways; orthostasis test (O-T) and the furosemide test (Furo-T). Results were compared between groups, each patient serving as her own control, and with those obtained in a 12 healthy women control group (group C). The diet contained about 85 meq Na/day. Compared to group C (O-T response, 5.97 +/- 0.54 ng ml-1 h-1; Furo-T response, 6.71 +/- 0.82 ng ml-1 h-1; mean +/- SEM), PRA response to both tests was blunted in group P (O-T: 2.48 +/- 0.46, P less than 0.001; Furo-T: 3.02 +/- 0.53, P less than 0.001) and remained so in F (O-T: 2.18 +/- 0.40, P less than 0.001; Furo-T: 2.52 +/- 0.28, P less than 0.001), In group F + T, the response to both tests was greater than in P and F (O-T, 6.61 +/- 1.19; Furo-T, 4.36 +/- 0.44; 0.001 less than P less than 0.05). However, whereas the response to orthostasis is entirely normalized, the response to a diuretic remained significantly smaller than in group C (P less than 0.01). These improvements were observed without significant change in PRS concentration which remained low. We conclude that panhypopituitarism is accompanied by an altered renin angiotensin system. Basal levels of PRS and PRA are low and unresponsive to adequate stimulation. Whereas glucocorticoid therapy alone is without effect on this hyporeninism, addition of thyroid hormones completely normalized the response to orthostasis and significantly improved furosemide response.

Catecholamine responses to central volume expansion produced by head-out water immersion and saline infusion.

To delineate plasma catecholamine responses to central volume expansion, four salt-replete healthy adults were subjected to 4 h of thermoneutral head-out water immersion (WI) and infusion of 2 liters normal saline (SI) over 4 h on two separate occasions. Each study was preceded and followed by a control hour. Both of these maneuvers resulted in significant increases in urinary sodium excretion and suppression of PRA and plasma aldosterone levels. During WI studies, plasma norepinephrine levels fell steadily from a prestudy value of 453 +/- 74 pg/ml to a nadir of 254 +/- 71 pg/ml (P less than 0.05) during the fourth immersion hour. In response to SI, plasma norepinephrine fell steadily from a prestudy level of 328 +/- 56 pg/ml to a nadir of 261 +/- 47 pg/ml during the fourth hour of infusion. Plasma dopamine levels rose and epinephrine levels were unchanged in response to WI as well as SI. When the mean urinary sodium excretion was plotted against the mean dopamine to norepinephrine ratio, there was a direct relationship in WI studies (r = 0.90) as well as SI studies (r = 0.92). These data suggest that plasma norepinephrine levels fall and plasma dopamine levels rise in response to volume expansion. These data also suggest that relative concentrations of dopamine vs those of norepinephrine may have a role in mediating natriuresis in response to volume expansion.

Altered dopaminergic modulation of 18-hydroxycorticosterone secretion in idiopathic edema: therapeutic effects of bromocriptine.

We have investigated dopaminergic mechanisms involved in the control of corticosteroid secretion in patients with idiopathic edema. The effects of treatment with the dopamine agonist bromocriptine (2.5 mg, three times a day for 5 days) on PRA, plasma cortisol, corticosterone, 18-hydroxycorticosterone (18-OHB), aldosterone, and PRL levels, and blood pressure responses to upright posture and isometric exercise were evaluated in nine patients with idiopathic edema and nine normal controls. Additionally, PRA and plasma cortisol, corticosterone, 18-OHB, aldosterone, and PRL responses to the dopamine antagonist metoclopramide were evaluated in both groups. Basal supine levels of PRA, cortisol, corticosterone, aldosterone, and PRL were similar in the two groups. However, plasma 18-OHB was considerably greater in the edema patients. Edema patients displayed greater orthostatic weight gain and greater 18-OHB and aldosterone responses to upright posture and isometric handgrip exercise. Bromocriptine treatment marke...

Dopaminergic Control of 18-Hydroxycorticosterone Responses to Posture, Isometric Exercise, and Diuretic Administration in Normal Man

This study investigates dopaminergic mechanisms involved in the control of corticosteroid secretion in man. The responses of plasma 18-hydroxycorticosterone (18-OHB) and aldosterone levels to upright posture and isometric handgrip exercise and furosemide administration as well as PRA and catecholamine responses to posture and exercise were evaluated in six normal subjects with and without bromocriptine (BEC) treatment. To evaluate the role of PRL suppression by BEC in affecting corticosteroid responses, we evaluated the effect of BEC on plasma 18-OHB and aldosterone responses to 20 mg furosemide in two subjects with autoimmune hypoprolactinemia. BEC (2.5 mg, three times a day for 4 days) markedly suppressed basal levels of 18-OHB, but not aldosterone, in the six normal subjects as well as the two subjects with autoimmune hypoprolactinemia. BEC also suppressed the 18-OHB and aldosterone responses to upright posture, isometric exercise, and furosemide administration without altering electrolytes, PRA, or plasma cortisol levels. Additionally, BEC suppressed basal levels of PRL, norepinephrine, and epinephrine as well as norepinephrine and blood pressure responses to upright posture and isometric exercise in the normal subjects. These results offer additional evidence that dopaminergic mechanisms modulate the secretion of 18-OHB and aldosterone, perhaps indirectly via inhibitory effects of dopaminergic pathways on catecholamine secretion.

Effect of Prolonged Low Dose Infusion of Angiotensin II and Aldosterone on Rat Smooth Muscle and Adrenal Angiotensin II Receptors*

The present studies were designed to determine the effects of continuous alterations in angiotensin II (Ang II) blood levels on Ang II receptors of rat uterine myometrium and adrenal glomerulosa. These tissues were used in a radioreceptor assay for Ang II. Low dose infusion of Ang II for 7 days caused significant suppression of PRA, whereas plasma aldosterone was not increased above control levels. The Kd of uterine myometrium decreased to 29% of the control value, while the Kd of adrenal glomerulosa increased by 115%. No significant change in the number of receptors of uterine myometrium was observed in spite of the increased number of receptors in the adrenal glomerulosa. The observation that angiotensin infusion was associated with a decrease in uterine Kd and an increase in adrenal receptors suggests that receptor occupancy did not influence the affinity or concentration of sites under steady state conditions. Low levels of PRA and Ang II were achieved by continuous infusion of aldosterone with osmoti...

Vascular lesions and angiotensin in malignant hypertension in the absence of vasopressin.

1. Vasopressin deficient homozygous Brattleboro rats develop malignant renal hypertension following complete aortic-ligature between the renal arteries. 2. This form of hypertension is associated with high plasma renin activity (PRA) and plasma angiotensin II (AII) levels and a high incidence of the specific vascular lesions of fibrinoid necrosis in both Brattleboro and Long-Evans rats. 3. The levels of PRA and AII in the malignant hypertensive Brattleboro rats were not different from those in Long-Evans rats with malignant hypertension. 4. No compensation by the renin-angiotensin system therefore could be demonstrated for the lack of vasopressin in malignant hypertensive Brattleboro rats. 5. Vasopressin does not appear to be essential as a pressor hormone in the development of malignant renal hypertension and fibrinoid can occur in the absence of vasopressin.

Role of the sympathetic nervous system in blood pressure maintenance in obesity.

A group of 10 borderline hypertensive obese subjects had higher (P less than 0.05) supine plasma norepinephrine (NE), epinephrine, and PRA levels as well as greater (P less than 0.05) NE responses to upright posture and isometric handgrip exercise than 12 nonobese controls. Plasma NE as well as mean arterial pressure (MAP) responses to posture and handgrip in the obese patients demonstrated a significant decrement at week 2 after the onset of a low calorie diet. Decrements in plasma NE and MAP responses to posture were correlated (r = 0.61; P less than 0.05) throughout an 8-week period of weight loss in these borderline hypertensive obese subjects. In 15 normotensive obese subjects as well as in the 10 borderline hypertensive obese subjects, weight reduction associated with a very low calorie intake was accompanied by a reduction in supine plasma NE, epinephrine, and MAP 2 weeks after the onset of dieting. PRA decreased after 8 weeks of dieting in both obese groups, and these PRA decrements were correlated with reductions in MAP and decrements in plasma NE. We conclude that enhanced sympathetic activity may play a role in the maintenance of elevated blood pressure in obese individuals. Decreases in PRA and blood pressure associated with weight loss in both normotensive and hypertensive obese individuals occurs, in part, secondary to reductions in plasma NE levels.

Abnormal relationship between sodium intake and sympathetic nervous system activity in salt-sensitive patients with essential hypertension

To examine the mechanisms underlying the sensitivity to sodium intake in a subset of patients with essential hypertension, we studied the effects of different sodium intake (10, 100, 200 mEq/day) on blood pressure, the function of the renin-angiotensin-aldosterone system, and on blood levels of catecholamines in 20 patients with essential hypertension and 10 normal subjects. Mean blood pressure (MBP) was not different in hypertensive and normal subjects during low sodium diet. But, with high sodium intake, MBP increased by at least 10% in 12 patients (salt-sensitive), whereas in the remaining 8 patients (salt-resistant) and in normal subjects, MBP did not change significantly. This phenomenon cannot be attributed to differences in sodium retention because the percent change in body weight ad the urinary sodium excretion in the salt-sensitive patients was not different than it was in salt-resistant patients or in normal subjects. The observed difference in blood pressure response to high sodium intake in salt-sensitive patients is also not dependent on an impaired suppressibility of the renin-angiotensin-aldosterone system because there were no significant differences in the basal levels of PRA and aldosterone between the groups, and because the orthostatic increments in PRA were significantly lower in salt sensitive than they were in the salt-resistant patients and in normal subjects. Plasma norepinephrine (NE) levels were not significantly different between normal subjects or hypertensive patients while on low sodium intake. But during high sodium intake, they decreased significantly (P less than 0.05) in normal subjects (from 22 +/- 3.4 to 12 +/- 2.3 ng/dl) and in salt-resistant patients (from 17 +/- 4.5 to 13 +/- 2.4 ng/dl) but not in salt-sensitive patients (from 20 +/- 1.9 to 22 +/- 3.2 ng/dl). Furthermore, the majority of salt-sensitive patients displayed inappropriately high plasma NE in relation to their urine excretion of sodium during high sodium intake. Finally, the increments in plasma NE after 5 min of standing were significantly greater in salt-sensitive patients than they were in salt-resistant patients and normal subjects during both low or high sodium intake. These data indicate that a subset of patients with essential hypertension may have impaired suppressibility of plasma NE during high sodium intake, which suggests hyperactivity of the sympathetic nervous system in these patients. These aberrations may be responsible for the increase in MBP in the salt-sensitive patients during high sodium intake.

Exchangeable sodium, plasma renin activity and blood pressure changes during the development of 2 kidney 1 clip hypertension, and after subsequent contralateral nephrectomy.

Sequential changes in exchangeable sodium, fluid intake, blood pressure and plasma renin activity were measured in 2K1C hypertensive rats during the development of severe hypertension. Exchangeable sodium was measured by the equilibration of the rats' exchangeable sodium with radioactive saline. In rats drinking saline, both PRA and exchangeable sodium levels increased as hypertension developed, and captopril induced large falls in blood pressure. Subsequent removal of the contralateral kidney reduced PRA, but did not alter exchangeable sodium or blood pressure. Captoril had no effect on blood pressure. It is concluded that the rise in PRA in 2K1C hypertension depends on the presence of the contralateral kidney, but occurs in the absence of sodium depletion.

Response of plasma catecholamine and PRA to i.v. injection of glucagon in upright posture after furosemide injection in essential hypertension (author's transl)

To investigate the pathogenic role of the sympathetic nervous system and the renin-angiotensin system in essential hypertension, we evaluated plasma catecholamine and PRA levels after glucagon stimulation and during one hour in upright posture after i.v. injection of furosemide. In nine normal and high renin essential hypertensive (NHRH) subjects, i.v. injection of 1000 micrograms of glucagon caused rapid and significant increases in plasma epinephrine(E) concentration. Both the 5 min. level after glucagon injection (314 +/- 30 pg/ml, mean +/- S.E., p less than 0.05) and peak value (358 +/- 87 pg/ml, p less than 0.05) were significantly higher than the basal level(170 +/- 25 pg/ml). Plasma norepinephrine(NE) concentration of the peak value(1065 +/- 231 pg/ml) was significantly higher than the basal(357 +/- 50 pg/ml, p less than 0.02). PRA levels increased in 4 out of 9 patients. In seven patients with low renin essential hypertension(LRH), there was an impaired PRA response to glucagon, E also failed to increase at any time after glucagon injection, but peak value of NE(1212 +/- 274 pg/ml) was significantly higher than the basal level(391 +/- 77 pg/ml, p less than 0.01). NE level of NHRH during one hour in upright posture after i.v. injection of 40 mg of furosemide were higher than LRH. Particularly at 10 min. level, the NE level of NHRH(895 +/- 115 pg/ml) was significantly higher than LRH(523 +/- 91 pg/ml, p less than 0.05). These results suggest that the sympathetic-adrenomedullary function in LRH is diminished, and the renin secreting ability of JG cells is also diminished in LRH. The glucagon stimulation test is useful to assess renin secreting ability of JG cells.

Hemodynamic effects of [Sar1, Ile8] AII, an angiotensin II analog, in the renin subgroups of essential hypertension.

Hemodynamic effects of [Sar1, Ile8] AII, an angiotensin II analog, were studied in 30 patients with essential hypertension, who were subdivided into 11 low renin, 10 normal renin and 9 high renin groups according to low, normal and high PRA values both before and after furosemide administration (80 mg, orally) plus 4 h of ambulation, respectively. [Sar1, Ile8] AII infusion (600 ng/kg/min) produced significant increases in mean blood pressure (MBP) and total peripheral resistance index (TPRI) in normal renin and low renin groups and significant decreases in MBP and TPRI in high renin group, while the cardiac index and heart rate remained unchanged during the infusion in these three groups. Change in MBP at 30 min of [Sar1, Ile8] AII infusion correlated significantly with alteration in TPRI in 23 patients with essential hypertension, who completed the 30-min infusion. The response of both MBP and TPRI to [SAR1, Ile8] AII also correlated significantly with basal PRA. These results suggest that blood pressure response to [SAR1, Ile8] AII in essential hypertension is primarily due to alteration in total peripheral resistance and that direction and amplitude of the response of both MBP and TPRI are practically dependent on basal PRA levels.

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.

Inactive renin and prostaglandin E2 production in hyporeninemic hypoaldosteronism.

To ascertain whether inactive renin (IR) might predominate in the syndrome of hyporeninemic hypoaldosteronism (HH) and whether the production of prostaglandin E2 (PGE2), a potent stimulus for renin release, might be decreased, we measured PRA, active renin (AR), and IR by the acid activation method and urinary PGE2 in 10 patients with HH. In contrast to uniformly low levels of PRA (0.6 +/- 0.2 ng/ml . h) and AR (2.7 +/- 0.6), IR was either normal or elevated (14.7 +/- 2.2 in HH; 11.8 +/- 1.1 in 28 normal subjects) and the IR to AR ratio was markedly increased (8.5 +/- 2.0 vs. 3.4 +/- 0.5; P < 0.05). Urinary PGE2 was decreased in 4 patients but was in the normal range in 5 other patients with HH. In 16 human volunteers, PG inhibition with indomethacin led to a significant decrease in AR (P < 0.05) but not in IR, and the IR to AR ratio increased 2-fold (P < 0.02). The data suggest that HH is a disease involving the defective conversion of IR to AR rather than impaired total renin production. In some patients, PG deficiency may contribute to the development of HH.

Mineralocorticoid biosynthesis in patients with hyporeninemic hypoaldosteronism.

Aldosterone and several of its steroid precursors were measured in patients with hyporeninemic hypoaldosteronism to examine adrenal biosynthesis in this disorder. Five hyperkalemic patients with diabetes mellitus and mild to moderate renal insufficiency and six controls were studied on both 120- and 10-meq sodium diets. Plasma levels of aldosterone (PA), 18- hydroxycorticosterone (18-OHB), corticosterone (B), H-deoxycorticosterone (DOC), 18-hydroxydeoxycorticosterone (18-OHDOC), cortisol, and PRA were measured on both sodium diets and after a 4-h infusion of ACTH. PAand 18-OHB levels were also measured during angiotensin II infusion. Mean PRA (1.1 ± 0.2 ng⁄ml-h) and PA (2.8 ± 0.8 ng⁄dl) were low and failed to increase after sodium restriction and ACTH administration in all patients. However, the levels of 18-OHB, B, DOC, 18-OH-DOC, and cortisol were within the normal range on both sodium diets and responded normally to ACTH administration. A 30-min angiotensin II infusion failed to increase PA levels but produced normal increments in plasma 18-OHB. The normal levels of DOC, B, and cortisol indicate intact adrenal 21- and 11-hydroxylase activities in hyporeninemic hypoaldosteronism. Likewise, the normal levels of 18-OH-DOC and cortisol imply normal integrity of adrenal zona fasciculata 18-hydroxylase activity in this disorder. The lack of accumulation of 18- OHB in our patients differs from the findings in patients with inborn errors in aldosterone biosynthesis (corticosterone methyl oxidase defect, type 2) and could suggest intact zona glomerulosa function in hyporeninemic hypoaldosteronism. However, the normal levels of 18-OHB in the face of suppressed PRA levels in our patients could be interpreted as a partial enzymatic blockade in the conversion of 18-OHB to aldosterone. The normal 18-OHB response to angiotensin II accompanied by subnormal aldosterone responses further supports an adrenal zona glomerulosa biosynthetic defect in hyporeninemic hypoaldosteronism. Although our results cannot exclude that chronic renin suppression may also contribute to the subnormal aldosterone response, the findings do point out a possible adrenal abnormality in addition to the proposed defects in the renin-angiotensin system in this disorder.

Renal vein renin measurements in normotensive children

Renal venous PRA was measured in 49 normotensive children without renal disease undergoing routine cardiac catheterization. PRA levels did not differ significantly between both renal veins and were significantly higher in the renal veins than in the IVC. There was a constant mean ratio of 1.21 between the renal veins and the IVC at low, intermediate, and high absolute PRA levels. Three patients had a renal venous PRA ratio greater than 1.4 and the highest ratio observed was 1.55. This fidning supports 1.5 as an acceptable upper limit of normality for the interpretation of renal vein PRA ratios in the investigation of patients with suspected renal hypertension. In four patients, PRA in the renal veins was significantly lower than in the IVC. The possibility of renin removal by these kidneys is discussed.