Bruce A. Scoggins

The hypertensive effect of synthetic glucocorticoids in man: role of sodium and volume

In previous studies, administration of adrenocorticotrophin (ACTH; 0.5 mg i.m. b.d. for 5 days) to normal subjects produced an adrenally dependent rise in blood pressure (BP) of some 20 mmHg, accompanied by an increase in cardiac output and an increase in plasma volume. The BP and metabolic effects of ACTH (increase in plasma glucose, fall in eosinophils, increase in body weight and urine sodium retention) were reproduced by infusion of the glucocorticoid (GC) cortisol at rates (6-8 mg/h) which reproduced the blood concentrations of the steroid achieved with ACTH administration. Oral administration (hydrocortisone 200 mg daily) produced similar changes qualitatively, although the cortisol concentrations and increase in pressure (12 mmHg) were less. Plasma volume was increased. To determine the role of urine sodium retention and plasma volume expansion in the hypertension, we gave synthetic steroids to six normal subjects for 5 days, at doses which were calculated to be similar for GC activity, but which had little or no mineralocorticoid (MC) activity. Prednisolone (40 mg/day), methylprednisolone (32 mg/day), triamcinolone (40 mg/day) and dexamethasone (8 mg/day) all produced equivalent GC effects (increase in plasma glucose, increase in total white cell count, fall in direct eosinophil count). There were no MC effects with any of the steroids. Body weight did not increase and urinary sodium excretion increased rather than decreased. Plasma volume (125I human serum albumin) and haematocrit were unchanged. BP rose with all four steroids: systolic BP rose by 13 mmHg with prednisolone, by 9 mmHg with methylprednisolone, by 10 mmHg with triamcinolone, and by 6 mmHg with dexamethasone. Diastolic BP increases were 8, 11, 8 and 7 mmHg, respectively. Thus, neither MC activity nor an increase in plasma volume is essential for steroids to induce an increase in blood pressure. Therefore, screening of synthetic GCs to minimize MC activity will not prevent hypertensive complications.

Osmoregulatory thirst in sheep is disrupted by ablation of the anterior wall of the optic recess

Ablation of the organum vasculosum of the lamina terminalis (OVLT) and adjacent midline tissue in the anterior wall of the optic recess of the third ventricle resulted in greatly reduced water drinking to intracarotid infusion of hypertonic NaCl in sheep. Daily food and water intake and angiotensin II drinking were not consistently reduced by these lesions. Tissue in or close to the OVLT is probably involved in osmotically induced water-drinking.

Plasma nortriptyline and clinical response.

The relationship of plasma nortriptyline levels to the clinical response of 80 depressed patients was studied. Plasma nortriptyline levels were estimated 4 weeks after commencing treatment. Percentage change in the Hamilton Depression Rating Scale was used to measure clinical response. There was no simple relationship between these two measures. Twelve of the 80 patients were studied further. Clinical response to variations of plasma nortriptyline levels was studied. Calculation of regression coefficients showed a positive relationship between clinical change and plasma nortriptyline levels in all. Comparison of the regression coefficients showed that they differed significantly among themselves and were not related to age or sex.

Blood Pressure and Metabolic Effects of Cortisol and Deoxycorticosterone in Man

We have previously shown that ACTH administration (1 mg/day) for 5 days raises systolic blood pressure (BP) by some 20 mmHg in both normotensive and hypertensive subjects, accompanied by hypokalaemia, urinary Na retention, a rise in fasting blood glucose and a fall in plasma renin concentration (PRC). In the present study cortisol and deoxycorticosterone (DOC) were infused for 5 days in 7 and 6 subjects respectively at rates appropriate for conditions of ACTH stimulation to determine whether the effects of ACTH could be reproduced by either steroid. Cortisol infusion increased systolic BP from a control of 108 +/- 7 mmHg to 129 +/- 7 mmHg on day 5, p less than 0.001. Plasma [Na] increased from 137 +/- 1 to 139 +/- 1 mmol/l (p less than 0.01), plasma [K] fell from 3.8 +/- 0.1 to 3.6 +/- 0.1 mmol/l (p less than 0.05); blood glucose rose from 3.9 +/- 0.2 to 4.7 +/- 0.2 mmol/l (p less than 0.001); PRC fell from 26 +/- 7 to 12 +/- 3 mu iu /ml (p less than 0.05); renin substrate rose from 1629 +/- 140 to 2206 +/- 453 pmol AI/ml, (p less than 0.05); urine Na excretion fell from 93 +/- 19 to 41 +/- 10 mmol on day 2 (p less than 0.05) and rose to 209 +/- 31 mmol 48 hrs after infusion (p less than 0.001); urine output rose from 2.0 +/- 0.35 to 2.89 +/- 0.46 L on day 5, (p less than 0.01). Plasma cortisol levels were similar to those seen with ACTH treatment. DOC infusion was associated with a fall in diastolic BP (control 64.2 +/- 4.0 mmHg, day 5 57.0 +/- 4.2 mmHg, p less than 0.01). Urine Na excretion fell from 77 +/- 12 mmol/day to 49 +/- 8 mmol/day on day 1, (p = 0.06) and body weight rose from 76.0 +/- 5.8 kg to 76.8 +/- 5.9 kg day 5 (p less than 0.001). Thus in man, cortisol infusion (in contrast to DOC) at rates appropriate for conditions of ACTH stimulation reproduces both the BP and metabolic effects of ACTH. Whether cortisol acts to raise blood pressure by a classical glucocorticoid mechanism or by a hypertensinogenic mechanism is not known.

Blood Pressure and Metabolic Effects of ACTH in Normotensive and Hypertensive Man

ACTH administration (0.5 mg Synacthen Depot I/M 12 hourly for 5 days) significantly increased systolic blood pressure in normotensive subjects (n=6) and mild essential hypertensives (n=6) but not in 2 Addisonian women, indicating that the pressure rise was adrenally dependent. ACTH administration was associated with urinary sodium retention, hypokalaemia, elevation of fasting blood glucose, lymphopaenia and eosinopaenia. Body weight was increased only in the normotensive subjects. Plasma renin concentration fell and renin substrate rose. Inactive renin fell in the hypertensive subjects only. Plasma cortisol, 11-deoxycortisol, corticosterone, deoxycorticosterone, 17 alpha-hydroxyprogesterone and 17-hydroxy, 20-dihydroprogesterone were all increased by ACTH treatment. Plasma aldosterone rose initially in the normotensives but then fell. ACTH administration in man produces metabolic and hormonal changes similar to those produced by ACTH in sheep but the rise in blood pressure is systolic only in man. The steroid(s) responsible for the blood pressure rise with ACTH in man have not been defined.

Adrenocorticotrophin-induced hypertension in the rat: haemodynamic, metabolic and morphological characteristics

Adrenocorticotrophin (ACTH) administration has been systematically studied in man and sheep. It raises systolic blood pressure (SBP) in the rat, but this has been little studied. ACTH was injected once daily at 0.5 mg/kg for 12 days in male Sprague-Dawley rats (n = 19). Sham-injected animals were studied in parallel (n = 15). ACTH increased SBP from 94 +/- 4 to 121 +/- 4 mmHg (P less than 0.001), significantly greater (P less than 0.02) than sham injection. The SBP of ACTH-treated rats was significantly higher than that of sham-injected rats when the same animals were measured by both the tail-cuff method (ACTH, 126 +/- 3 mmHg; sham, 99 +/- 3 mmHg) and direct arterial cannulation (ACTH, 137 +/- 2 mmHg; sham, 123 +/- 3 mmHg): P less than 0.005 and P less than 0.001, respectively. There was a loss of body weight, and increased water intake and urine output in ACTH-treated animals compared with both control (P less than 0.001) and sham treatments (P less than 0.02). ACTH increased plasma [Na] (sham, 140 +/- 1 mmol/l; ACTH, 145 +/- 1 mmol/l; P less than 0.001) and urinary Na excretion compared with control (P less than 0.01) and sham injection (P less than 0.05), and also decreased plasma [K] (sham, 4.6 +/- 0.2 mmol/l; ACTH, 3.3 +/- 0.8 mmol/l; P less than 0.01) and increased urinary K excretion (P less than 0.01) compared with control. SBP in adrenalectomized animals (n = 10) was unchanged by ACTH. ACTH increased adrenal, renal, cardiac and brain weights compared with sham injection (P less than 0.05). There were no significant changes in vascular morphology, although ACTH treatment increased glomerular epithelial cell droplets and abolished the adrenal zona glomerulosa.

Preoperative Lateralisation of Aldosterone-Producing Tumours in Primary Aldosteronism

Abstract A technique based on measurement of aldosterone in peripheral and left-adrenal venous plasma is described for the preoperative lateralisation of aldosterone-producing adenomas of the adren...

Renin, Angiotensin II, and Adrenal Corticosteroid Relationships during Sodium Deprivation and Angiotensin Infusion in Normotensive and Hypertensive Man

The responses of plasma renin activity, plasma angiotensin II, plasma aldosterone, cortisol, and corticosterone to sodium deprivation and to angiotensin II infusion (100 ng/min) were measured in 8 normotensive patients and in 17 patients with essential hypertension. Following sodium deprivations, plasma renin activity rose from 0.513 ± 0.100 to 1.029 ± 0.124 ng/ml hour−1 in normotensive patients and from 0.406 ± 0.077 to 0.629 ± 0.059 ng/ml hour−1 in hypertensive patients. Plasma angiotensin II did not parallel changes in plasma renin activity: in normotensive patients plasma angiotensin II was unchanged by sodium deprivation (31.8 ± 6.0 compared with 30.1 ± 4.6 pg/ml), but in hypertensive patients it rose from 22.2 ± 3.4 to 36.4 ± 5.1 pg/ml. Plasma aldosterone rose equally in both groups following sodium deprivation (5.8 ± 1.3 to 15.3 ± 2.4 ng/100 ml for normotensive patients and 5.9 ± 1.4 to 14.4 ± 1.6 ng/100 ml for hypertensive patients) and angiotensin infusion (5.8 ± 1.3 to 10.4 ± 2.1 ng/100 ml in sodium-loaded normotensive patients, 15.3 ± 2.4 to 19.6 ± 3.6 ng/100 ml in sodium-deprived normotensive patients, 5.9 ± 1.4 to 11.4 ± 2.7 ng/100 ml in sodium-loaded hypertensive patients, and 14.4 ± 1.6 to 22.2 ± 2.6 ng/100 ml in sodium-deprived hypertensive patients). However, changes in endogenous plasma angiotensin II did not correlate with the rise in plasma aldosterone caused by sodium deprivation, and, despite much larger increases in plasma angiotensin II during angiotensin II infusion, plasma aldosterone showed smaller rises than those accompanying sodium deprivation. Plasma renin activity fell during angiotensin II infusion, in both groups of patients during both sodium loading and sodium deprivation, and, hence, the infusion constitutes a potent feedback inhibition of renin release in normotensive and hypertensive man. Plasma cortisol and corticosterone were unaltered by sodium deprivation but fell significantly with the angiotensin II infusion.

[DES-ASP1] angiotensin II in the sheep: Blood levels and its effect on plasma renin concentration

Abstract The present study describes an improved method for measuring angiotensin III in arterial blood. This was accomplished by SE-sephadex column to separate angiotensin II from angiotensin III prior to radioimmunoassay. The arterial concentration of angiotensin III measured before and after 24 to 48 hours sodium depletion by acute cannulation of parotid gland was 12.4 ± 1.7 fmol/ml (SEM, n=7) and 49.8 ± 10.3 fmol/ml (SEM, n=7) respectively. The arterial concentration of Val 4 -angiotensin III obtained from continuous infusion of Val 4 -angiotensin III at rates of 24 and 48 nmol/h in sodium deficient sheep were 245 ± 32.5 fmol/ml (n=6) and 330 ± 11.4 fmol/ ml (n=7) respectively. The clearance rate of exogenous Val 4 -angiotensin III in sodium deficient sheep after correction for endogenous level was calculated to be 140 ± 13.6 L/h (SEM, n=13). This was in the same order as Ile 5 -angiotensin II and Ile 4 -angiotensin III reported earlier in sodium replete sheep. Prolonged intravenous infusion of Val 4 -angiotensin III at a rate of 48 nmol/h in sodium- deficient sheep suppressed plasma renin concentration to the same extent as equimolar infusions of angiotensin II. This suggests that angiotensin III may inhibit renin secretion by a similar mechanism to angiotensin II.

Angiotensin I, II, and III in sheep. A model of angiotensin production and metabolism.

SUMMARY The arterial and centra] venous concentrations of angiotensin I (AI), Val5-anglotensln II ([Val5]AII), and Val5-anglotensin III ([Val5]AIII(2-8)) were quantitatively determined in conscious sheep before and after sodium depletion. All three anglotenslns were elevated in blood with progressive sodium loss. During sodium deficiency the arteriovenous concentration ratios (A:V) of AI, [Val5]AII, and [Val5]AIII(2-8) were found to be 0.48 ± 0.03 (n - 9), 130 ± 0.05 (n - 16), and 1.52 ± 0.05 (n = 11) respectively. Intravenous infusion of [Val5]AII or [Val5]AIII(2-8) significantly elevated the A: V of respective angiotenslns, being 2.09 ± 0.28 (n - 5) for [Val5]AII and 2.2 ± 031 (n - 6) for [Val5]AIII(2-8). The blood clearance rates of exogenous [Val5]AII and [Vall]AIII(2-8) in sodium-depleted sheep were calculated to be 135 ± 15 liter/hr (n = 10) and 140 ± 13 liter/hr (n = 10) respectively. Based on these experimental data, a steady-state model of angiotensin metabolism was constructed.If it is assumed that endogenous arterial blood [Val5]AII and [Val5]AIII(2-8) cleared metabollcally at a similar rate as exogenous arterial blood angiotensins, it can be calculated that at steady-state 55% of the arterial [Val5]AII concentration was derived from the peripheral vascular bed. For [Val5]AIII(2-8), 63% of the arterial concentration was derived from the pulmonary circulation. The concentration of [Val5]AIII(2-8) in arterial blood was 42% of [Val5]AII.