Dose-response relationship between plasma ACTH and serum cortisol in the insulin-hypoglycaemia test in 25 healthy subjects and 109 patients with pituitary disease.

OBJECTIVE: The insulin hypoglycaemia test (IHT) is believed to be the most reliable test for evaluating the entire hypothalamo-pituitary-adrenal (HPA) axis. The lower limit for the normal peak serum cortisol response has been reported to be between 500 and 580 nmol/l. Reference levels for a normal plasma ACTH response have not been reported recently. DESIGN AND PATIENTS: We performed the IHT in 25 healthy subjects and in 109 patients with proven or suspected pituitary disorders with serial measurements of serum or plasma cortisol and of plasma ACTH, in order to establish reference levels and to study the dose-response relationship between ACTH and cortisol in this test. In most patients, other pituitary hormonal axes were evaluated in addition. RESULTS: With the cortisol kit from Diagnostic Products Corporation (DPC), serum cortisol was about 13% lower than plasma (EDTA) levels with an excellent correlation between serum and plasma (r = 0.976; P<0.001). In the normals, the lower limit of the cortisol response (mean cortisol peak level minus 2 SD.) was 570 nmol/l for plasma and 500 nmol/l (calculated) for serum, while the lower limit of the ACTH response was 17.6 pmol/l (80 ng/l). In normals, the cortisol response was independent of the magnitude of the ACTH response. Seventeen out of 30 patients with ACTH responses to levels < 8.8 pmol/l (< 40 ng/l) had subnormal cortisol responses. However, 38 of the patients with pituitary disease had normal cortisol responses in spite of subnormal ACTH responses (group 2), while 47 patients had completely normal IHT results (group 1). Patients in group 2 had more often additional pituitary hormone deficiencies than those of group 1. The dose-response relationship between ACTH and cortisol in the patients resembled a dose-response curve that had been set up previously in normal subjects who received incremental doses of subcutaneous human ACTH (1-39). CONCLUSIONS: The normal increment of plasma ACTH in the IHT is greater than necessary for stimulating serum cortisol to levels > 500 nmol/l. Patients with a subnormal ACTH but normal cortisol response in the IHT have a decreased ACTH secretory reserve. It is unlikely that they are at increased risk of developing an adrenal crisis perioperatively or in other stressful situations unless pituitary function deteriorates. The ACTH-cortisol relationship in the IHT performed in patients with pituitary disease shows no sharp dividing line between normality and disease, and whether a patient needs permanent glucocorticoid substitution is a discretionary decision.

The role of atrial natriuretic factor [alpha-human ANF-(99-126)] in the hormonal and renal adaptation to sodium deficiency.

Atrial natriuretic factor (ANF) inhibits renin and aldosterone secretion and enhances natriuresis in short term experiments. For studying the role of ANF in the chronic hormonal and renal adaptation to sodium restriction, we infused alpha-human ANF iv at a low dose (0.15-0.2 microgram/min) for 6 days into five normal male volunteers on a low sodium diet (LS; 15 mmol Na+/day) to mimic ANF levels observed in a preceding high sodium period (HS; 250 mmol/day). Endocrine (ANF, PRA, and aldosterone) and renal parameters (urine volume and urinary sodium) and plasma and urinary cGMP were measured and compared to sodium restriction without ANF infusion. At the end of HS and LS periods, the response of plasma aldosterone to angiotensin-II infusion was tested. ANF infusion prevented the fall in plasma ANF from a mean of 17.7 on HS to 7 pmol/L on LS by raising the level to 16.1 pmol/L. Cumulative negative sodium balance and the rise in renin activity and aldosterone were almost identical in both parts of the experiment. There was a transient diuretic and mild hypotensive effect of ANF. Plasma and urinary cGMP rose only transiently during ANF infusion despite constantly elevated ANF levels, suggesting that the effect of ANF was blunted under long term conditions by receptor down-regulation or other mechanisms inhibiting cGMP formation. Chronic ANF infusion did not blunt the enhanced aldosterone response to angiotensin-II in the LS state. ANF does not seem to play a major role in the long term renal and hormonal adaptation to dietary sodium restriction.

Effects of atrial natriuretic factor on the renin-aldosterone system: in vivo and in vitro studies.

We investigated the effect of high physiological plasma levels of human varies; is directly proportional to atrial natriuretic factor (ANF) on renin and aldosterone secretion in normal sodium deplete men. In short term infusion studies (2 or 8 h duration), ANF plasma levels as observed after sodium loading (50-70 pg/ml) lowered basal renin (PRA) and aldosterone, but had only a marginal effect on angiotensin II-stimulated aldosterone secretion. Preliminary results of a study with long term infusion (6 days) of ANF during a period of dietary sodium depletion argue against a significant tonic inhibitory effect of ANF on the renin-aldosterone system in the preceding period of sodium repletion: the plasma aldosterone response to sodium depletion was similar with and without ANF infusion. The second messenger of ANF for the direct inhibition of aldosterone secretion from zona glomerulosa cells is still unknown. To test the hypothesis, that cGMP is the second messenger of ANF, we produced a rise in intracellular cGMP in rat and rabbit zona glomerulosa cells using the unspecific phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) and the more cGMP specific phosphodiesterase specific inhibitor M + B2948 (Zaprinast). Both inhibitors simulated the action of ANF in suppressing steroid secretion and elevating cGMP levels. The results are compatible with the view that cGMP is of importance as a second messenger for ANF in adrenal zona glomerulosa cells. Selective inhibition of phosphodiesterases in combination with endopeptidase inhibition may be an interesting principle to enhance the action of endogenous and exogenous ANF.

Role of atrial natriuretic factor in changes in the responsiveness of aldosterone to angiotensin II secondary to sodium loading and depletion in man.

1. Sodium loading blunts the response of aldosterone to infusion of angiotensin II, whereas sodium depletion leads to an enhanced response. The hypothesis was tested that these changes in responsiveness of the zona glomerulosa are mediated in part by changes in plasma atrial natriuretic factor levels. 2. To this end, plasma renin activity and plasma aldosterone were measured in the upright and recumbent position and during incremental infusions of angiotensin II (1, 3 and 6 ng of angiotensin II amide min-1 kg-1 for 1 h each dose) after 6 days of sodium loading (study 1), after 5 days of sodium depletion (study 2) and after sodium depletion plus infusion of atrial natriuretic factor (0.13 microgram/min for 8 h) on the test day (study 3). Six normal young males were investigated. 3. Plasma atrial natriuretic factor levels were around 5 pmol/l in study 2, 15 pmol/l in study 1 and 15 pmol/l in study 3 during infusion of atrial natriuretic factor. Two hours after the onset of atrial natriuretic factor infusion, plasma renin activity and plasma aldosterone (recumbent) were markedly and significantly lower in study 3 than in study 2, but still significantly higher than in study 1. The increase in plasma aldosterone after infusion of angiotensin II was slightly, but not significantly, blunted by infusion of atrial natriuretic factor in study 3 compared with study 2. The overall increase in plasma aldosterone was still significantly greater in study 3 than in study 1.(ABSTRACT TRUNCATED AT 250 WORDS)