Renal extraction of atrial natriuretic peptide in unilateral renal artery stenosis.

1. Elevated peripheral atrial natriuretic peptide (ANP) levels were observed in 12 patients with unilateral renal artery stenosis (U-RAS). 2. Renal extraction of ANP was higher across the affected than the unaffected kidney in U-RAS, provided the glomerular filtration rate in the affected kidney was not severely reduced (> 12 mL/min). As ANP is a high clearance compound, reduced flow on the affected side may result in increased renal extraction of ANP. 3. When glomerular filtration rate (GFR) in the affected kidney was severely reduced (< 12 mL/min), renal extraction of ANP was also reduced, possibly contributing to increased circulating ANP levels in this subgroup. 4. Overall, renal extraction of ANP was inversely correlated to peripheral ANP levels in patients with U-RAS. This might be explained by progressive sodium retention as GFR falls leading to volume expansion and increased ANP secretion.

Ageing and blood pressure regulation: dose-response relationships for angiotensin, blood pressure, atrial natriuretic peptide and aldosterone in normal subjects of varying ages.

1. Infusion of increasing doses of angiotensin II (AII) in normal subjects sequentially increased blood pressure, aldosterone and atrial natriuretic peptide (ANP) levels. 2. The slope of ANP response to AII was positively correlated with basal ANP and with the slope of blood pressure response to AII (pressor slope) but not with age. 3. This is consistent with the response of ANP to AII being mediated partly by the rise in blood pressure, independent of ageing. 4. As expected in a selected normotensive population, there was no correlation between basal blood pressure and age, but pressor slope was positively correlated with age. 5. Thus, dose-response relationships may be an index of age-induced alterations in pressure regulatory mechanisms.

Familial hyperaldosteronism type II: five families with a new variety of primary aldosteronism.

1. Thirteen patients from five families had Familial Hyperaldosteronism Type II (FH-II), a new variety of familial primary aldosteronism not suppressible with dexamethasone that often involves adrenocortical adenoma formation. 2. Five patients had solitary aldosterone-producing adenomas, three had bilateral autonomous overproduction of aldosterone, and in five the subtype is yet to be determined. 3. Comparing FH-II patients with 88 patients with primary aldosteronism of other causes revealed no differences in mean age at presentation or at onset of hypertension, sex incidence, lowest recorded serum potassium, plasma aldosterone, plasma renin activity or adenoma size. 4. Analysis of DNA in peripheral blood of patients with FH-II, their affected and unaffected relatives, and in removed tumours is in progress in order to determine the underlying genetic defect(s) in FH-II, perhaps an abnormality in the P-450aldo gene (CYP11B2). 5. It is recommended that hypertensive relatives of patients with primary aldosteronism should have measurements of the aldosterone/renin ratio.

Inappropriately elevated levels of atrial natriuretic peptide may contribute to the pathophysiology of orthostatic hypotension.

1. Overnight recumbent and upright plasma atrial natriuretic peptide (ANP) levels were markedly elevated (P less than 0.001) in patients with orthostatic hypotension (OH). 2. Overnight urinary clearance of ANP was significantly lower (P less than 0.01) in patients with OH, and was inversely correlated with plasma ANP levels (r = -0.94, P less than 0.01). The same negative correlation (r = -0.87, P less than 0.01) was seen in normal subjects. 3. Reduced urinary clearance of ANP may be associated with reduced filtered load and increased binding of ANP to the neutral endopeptidase 24.11 receptor binding sites in the proximal renal tubule. 4. ANP may be involved in the pathophysiology of orthostatic hypotension.

Subpressor calcium infusion increases isovolumic left ventricular relaxation time and atrial natriuretic peptide in humans.

1. Subpressor calcium infusion for 1 h, which raised calcium levels to the upper limit of normal in normal subjects, increased plasma and urinary levels of atrial natriuretic peptide (ANP). 2. Heart rate fell, presumably due to carotid baroreflex stimulation (supported by the fall in noradrenaline) and the resultant fall in cardiac output prevented the expected rise in blood pressure due to the rise in total peripheral resistance (TPR). Thus the increase in ANP was not explained by an increase in blood pressure or noradrenaline. 3. There was no evidence for increased atrial stretch (no increase in atrial area or early velocity of left ventricular filling) as a mechanism for increased ANP. 4. Isovolumic left ventricular relaxation time increased, early velocity of ventricular filling decreased and TPR increased, consistent with increased tone in left ventricular and arteriolar muscle. 5. This suggests a direct effect of calcium on the atrial myocyte, stimulating ANP either through contractile or secretory mechanisms.

Prostaglandins and systolic blood pressure, but not angiotensin II, independently affect atrial natriuretic peptide levels in man.

1. Two hours after a single dose of indomethacin (INDO), plasma renin activity (PRA) and atrial natriuretic peptide (ANP) levels decreased, which is consistent with an effect of lowering prostaglandins (PG). 2. After 48 h of INDO, PRA remained low but ANP had increased, which is consistent with the known effect of prostaglandin inhibitors to cause sodium retention, with a resulting volume expansion. 3. Infusions of angiotension II (AII), which raises diastolic blood pressure (BP) 20 mmHg or more, consistently raised ANP levels. The ANP response to AII infusion was reduced 48 h after INDO, which is consistent with an important role for PG in AII-stimulated ANP release. 4. After PG were blocked with INDO, the stimulating effect of AII on ANP at doses that increased diastolic BP less than 20 mmHg was insignificant, whereas before INDO it was significant. 5. In dose-response studies, INDO increased the systolic BP response but decreased the ANP response to AII, which is consistent with a direct effect of PG on ANP that is independent of systolic BP. 6. Prostaglandins and BP are important in the ANP response to AII infusion in normal subjects, but AII itself appears to have little direct effect on ANP.

Clinical and pathological diversity of primary aldosteronism, including a new familial variety.

1. Of 93 patients with primary aldosteronism seen during a 20 year period, 52 had an aldosterone-producing adenoma (APA) removed (five more await surgery), 14 had bilateral adrenal hyperplasia (BAH), three had glucocorticoid-suppressible hyperaldosteronism (GSH), one had adrenal carcinoma and 18 are yet to be categorized. 2. Seventy-three presented with hypertension and hypokalaemia. Others had markedly suppressed renal venous plasma renin activity (PRA) or elevated plasma aldosterone (PA)/PRA ratio, in new or resistant hypertensives. 3. The PA/PRA ratio was the most reliable screening test. 4. Diagnosis depended on the failure of suppression of aldosterone by salt loading and fludrocortisone. 5. Differentiation of BAH from APA depended on adrenal venous sampling comparing adrenal and peripheral venous PA/cortisol ratios. 6. A new familial variety of primary aldosteronism is described, with two affected members in each of three families. 7. Primary aldosteronism should be looked for in resistant and low-renin hypertension as well as in hypertension with hypokalaemia, and other family members should have PA/PRA measured if they are hypertensive.

Sodium and volume dysregulation after apparently normal pregnancy is suggested by abnormal levels of atrial natriuretic peptide, renin and aldosterone.

1. Plasma atrial natriuretic peptide (ANP), renin activity, aldosterone, sodium, potassium and serum total protein and albumin during and after 14 normal pregnancies were compared with age-matched controls. 2. None developed toxaemia and all delivered healthy babies. 3. During pregnancy, plasma renin activity and aldosterone were significantly (P less than 0.01) higher and potassium, total protein and albumin significantly lowew (P less than 0.01) than in controls, while ANP was not different from the control level. 4. At 6-13 weeks postpartum, a significant (P less than 0.01) suppression of renin and aldosterone was accompanied by significant (P less than 0.01) elevation of atrial natriuretic peptide when compared with controls. 5. The hormonal changes are consistent with 'effective plasma volume' reduction during pregnancy and persistent volume expansion after pregnancy, perhaps due to a renal glomerular lesion sustained late in pregnancy. In contrast, levels of potassium, total protein and albumin are consistent with haemodilution during pregnancy and its correction postpartum. 6. Measurements available in seven women 40-120 weeks postpartum showed normal renin and aldosterone levels in most, but ANP was still elevated. 7. Pregnancy may have a protracted effect on volume regulation.

Does urinary atrial natriuretic peptide reflect plasma levels in humans?

1. Saline infusion produced concurrent mean increases over basal in plasma and urinary atrial natriuretic peptide (ANP) of approximately 100%. 2. Subpressor calcium infusion also produced concurrent increases in plasma and urinary ANP of 38 and 60% respectively. 3. Urinary ANP appeared to be as responsive to the dynamic stimulation of saline and calcium infusion as plasma levels. 4. Urinary ANP may be useful when an integrated estimation of ANP secretion and metabolism is required. Further studies are required to assess clinical utility in a variety of settings, for example during endopeptidase 3.4.24.11 inhibition.

Biochemical correction in the syndrome of hypertension and hyperkalaemia by severe dietary salt restriction suggests renin-aldosterone suppression critical in pathophysiology.

1. Plasma potassium and chloride concentrations were raised and plasma renin activity, aldosterone, bicarbonate and arterial pH were reduced in two brothers with the syndrome of hypertension and hyperkalaemia with normal glomerular filtration rate (Gordon's syndrome), on unrestricted or moderately restricted sodium diets. 2. These abnormalities were corrected in both patients within 10 days of severe sodium restriction. 3. Pressor sensitivity to cold and angiotensin II decreased on low sodium diet, associated with a fall in blood pressure. 4. Increasing distal tubular sodium delivery by infusion of normal saline increased fractional excretion of potassium when aldosterone had been stimulated by severely restricted sodium diet, but not when aldosterone levels were low on unrestricted sodium diet. 5. These findings are consistent with excessive sodium reabsorption as the primary renal lesion in Gordon's syndrome, leading to volume expansion and suppression of renin and aldosterone. Severe dietary sodium restriction leading to volume contraction, by stimulating renin and aldosterone and promoting kaliuresis, corrects the abnormalities.

Suppressor calcium infusion raises plasma atrial natriuretic peptide concentrations in humans.

1. Calcium was infused in normal subjects in subpressor dosage to examine the effects of raised calcium levels on atrial natriuretic peptide (ANP) concentrations. 2. Calcium infusion progressively raised serum ionized and total calcium concentrations significantly, without raising mean arterial pressure or heart rate. 3. Plasma ANP concentrations increased significantly by 5 min of infusion and increased further by 15 min (approximately 40%) to levels which were maintained to 60 min. 4. Urinary sodium excretion increased by 140% during calcium infusion. 5. Calcium may affect secretory as well as contractile functions of the atrial myocyte.

A renin-secreting tumour sensitive to changes in central blood volume (presumably via sympathetics) but not to circulating angiotensin II.

1. A 17 year old female presented with severe hypertension, hypokalaemia and elevated levels of plasma renin activity due to a renin-secreting tumour. 2. Renin was responsive to posture, low sodium diet, saline infusion and frusemide, but relatively unresponsive to raising or lowering circulating levels of angiotensin II. 3. Renal venous renin levels lateralized to the side of the tumour with good contralateral suppression when measured with control of posture and avoidance of prior stimulation, with and without angiotensin converting enzyme inhibition. 4. Levels of atrial natriuretic peptide were elevated and responsive to posture, saline infusion and angiotensin infusion. 5. The tumour was evident on computerized tomography, but not on intravenous pyelography or renal angiography. 6. Responsiveness of renin secretion to normal stimuli in reninoma may make diagnosis difficult, and renal vein sampling under controlled conditions is necessary.

Reduced adrenal secretory mass after unilateral adrenalectomy for aldosterone-producing adenoma may explain unexpected incidence of hypotension.

In a prospective study of 37 patients who had unilateral adrenalectomy for an aldosterone-producing adenoma, five of 33 (15%) were symptomatically hypotensive after at least 1 year, and eight of 29 (28%) who were observed 3, 6, 12, 18 and 24 months after the operation showed 2-year blood pressures below the fifth percentile for age- and sex-matched controls. Postoperatively, plasma aldosterone was lower, and plasma renin activity higher than in controls, these differences being more marked in the hypotensive group. Pre-operatively elevated atrial natriuretic factor fell to levels lower than in controls. These serial changes in volume-regulatory hormones are consistent with chronic hypovolaemia, due to relative hypoaldosteronism. Plasma cortisol was lower 6 months after the operation and plasma adrenaline levels fell by half. A reduced adrenocortical (aldosterone and cortisol) and adrenomedullary (adrenaline) secretory mass may play a role in the hypotension observed after unilateral adrenalectomy.

Levels of atrial natriuretic peptide are not always consistent with atrial pressure: is there alternative regulation as evidenced in Gordon's and Bartter's syndromes?

1. In Bartter's syndrome, atrial pressures were low, consistent with volume contraction, while atrial natriuretic peptide (ANP) levels were unexpectedly elevated. Infusion of normal saline increased both right atrial pressure (RAP) and ANP levels, while administration of prostaglandin inhibitors raised RAP, probably due to volume expansion, but ANP levels fell paradoxically. 2. In Gordon's syndrome, atrial pressures were unexpectedly low or normal despite volume expansion, while ANP levels were normal. Pressor infusions of angiotensin II either raised right and left atrial pressures (LAP) without increasing ANP, or increased ANP without increasing atrial pressures. 3. In these two syndromes, atrial pressures and ANP levels were poorly correlated, leading to the proposal that other regulators of ANP may be important.

Effects of altitude on atrial natriuretic peptide: the Bicentennial Mount Everest Expedition.

1. Overnight recumbent atrial natriuretic peptide levels were significantly elevated in all ten subjects of the Australian Bicentennial Mount Everest Expedition during the first week at 5400 m, during acclimatization. 2. Twenty-four hour urine volume and urine sodium increased markedly at altitude. 3. Plasma renin activity and plasma aldosterone levels decreased significantly at altitude. 4. No significant changes in plasma cortisol, plasma sodium or potassium, body temperature, systolic or diastolic blood pressure or heart rate were observed. 5. Although it was impossible to control or measure salt and water intake during the study, results suggest that atrial natriuretic peptide may be important in the reduction in renin and aldosterone levels and in the diuresis and natriuresis necessary to adapt to hypoxia at altitude.

Unexpected incidence of low blood pressure 2 years after unilateral adrenalectomy for primary aldosteronism.

1. Serial observations of blood pressure after unilateral adrenalectomy for aldosterone-producing adenoma revealed an incidence of hypotension (systolic BP less than fifth percentile for age- and sex-matched normal population) of 27% at 2 years, more than 5 times that predicted. 2. Serial observations of volume regulatory hormones showed significantly raised mean levels of plasma renin activity consistent with hypovolaemia. Significantly reduced mean aldosterone levels despite significantly raised mean plasma renin activity levels may reflect reduced responsiveness of the remaining adrenal. 3. Reduction of significantly elevated preoperative ANP levels to significantly reduced levels postoperatively is also in keeping with postoperative hypovolaemia. 4. A 50% reduction in plasma adrenaline after unilateral adrenalectomy might contribute to reduced noradrenergic activity (prejunctional beta-receptor) and reduced blood pressure, but plasma noradrenaline did not fall significantly postoperatively. 5. Postoperative levels of renin, aldosterone, adrenaline and noradrenaline were not significantly different between those who did, and those who did not, become hypotensive.

Effects of volume expansion and contraction on plasma levels of atrial natriuretic peptide in man.

1. Effects of saline infusion and blood removal on atrial natriuretic peptide (ANP) in normal subjects were examined in order to better define the magnitude of acute central volume regulatory influences on ANP. 2. Plasma ANP levels increased progressively during volume expansion with saline infusion, increasing by 18% after 30 min and by 93% after 120 min, and did not change during recumbency alone. 3. Plasma ANP levels immediately after a standard blood donation performed semirecumbent were significantly lower than before blood donation; they fell by 18%. 4. The magnitude of the fall in ANP induced by blood donation correlated significantly with basal plasma ANP. 5. In man, ANP responds to both increases and decreases in central blood volume, consistent with a role for ANP in blood volume homeostasis.