K. Schöffling

Plasma Renin Aktivität und Aldosteronverhalten bei kritisch kranken Patienten

To investigate the influence of critical illness on plasma renin activity and aldosterone levels and to examine potential inhibitory effects of dopamine therapy on aldosterone responsiveness, we measured plasma renin activity, and potassium and creatinine in serum, as well as the responses of aldosterone, cortisol and prolactin levels to TRH 200 micrograms i.v. + Synacthen 0.25 mg i.v. in 63 unselected, critically ill patients (32 females, 31 males, aged 18-84 years). Of the patients 19 received dopamine treatment (3-13 micrograms/kg/min i.v.); 21 of the patients died in the further course of their disease. Plasma renin activity was increased in 66.7% of the patients and aldosterone levels were elevated in 90.5% of the patients. There were correlations (P less than 0.05) of lethality with plasma renin activity and cortisol levels and correlations (P less than 0.01) of aldosterone concentrations with plasma renin activity and cortisol levels. Whereas dopamine treatment had no inhibitory effect on aldosterone levels before and after stimulation, prolactin stimulation was decreased in dopamine-treated patients. Thus, dopamine does not generally lose its potency of hormone inhibition in critically ill patients, but has no influence on the secondary aldosteronism developing regularly in the early phase of critical illness, which is apparently mainly due to the stimulatory effect of ACTH (or ACTH-related pituitary peptides) and is considered an epiphenomen of the stress mechanisms acting upon the patients in this condition.SummaryTo investigate the influence of critical illness on plasma renin activity and aldosterone levels and to examine potential inhibitory effects of dopamine therapy on aldosterone responsiveness, we measured plasma renin activity, and potassium and creatinine in serum, as well as the responses of aldosterone, cortisol and prolactin levels to TRH 200 µg i.v. + Synacthen 0.25 mg i.v. in 63 unselected, critically ill patients (32 females, 31 males, aged 18–84 years). Of the patients 19 received dopamine treatment (3–13 µg/kg/min i.v.); 21 of the patients died in the further course of their disease. Plasma renin activity was increased in 66.7% of the patients and aldosterone levels were elevated in 90.5% of the patients. There were correlations (P<0.05) of lethality with plasma renin activity and cortisol levels and correlations (P<0.01) of aldosterone concentrations with plasma renin activity and cortisol levels. Whereas dopamine treatment had no inhibitory effect on aldosterone levels before and after stimulation, prolactin stimulation was decreased in dopamine-treated patients.Thus, dopamine does not generally lose its potency of hormone inhibition in critically ill patients, but has no influence on the secondary aldosteronism developing regularly in the early phase of critical illness, which is apparently mainly due to the stimulatory effect of ACTH (or ACTH-related pituitary peptides) and is considered an epiphenomen of the stress mechanisms acting upon the patients in this condition.

The inhibiting effect of trilostane on adrenal steroid synthesis: Hormonal and morphological alterations induced by subchronic trilostane treatment in normal rats

SummaryIn adult male rats the effect of a subchronic treatment with trilostane, a new, orally active, competitive inhibitor of 3β-hydroxysteroid dehydrogenase, on adrenal steroid production and morphology was studied. Rats were treated with 150 mg or 300 mg trilostane/kg/day for 7 or 14 days and with 150 mg trilostane/kg/day for 10 days in combination with 75 mg propranolol/kg/day or 1 mg indomethacin/kg/day. Trilostane leads to a dose-dependent increase in adrenal weight and to a rather uniform increase in nuclear volumes of zona glomerulosa and zona fasciculata cells. The basal secretion of aldosterone and corticosterone is not significantly altered. Trilostane increases the excretion of sodium and potassium in urine. The stimulating effect of trilostane on plasma renin activity and the adrenal enlargement are not inhibited by propranolol or indomethacin.We conclude that trilostane induces latent adrenal insufficiency. Increased renin and ACTH maintain normal basal steroid levels, and might impair the therapeutic effectiveness of trilostane.

Effect of human atrial natriuretic peptide on blood glucose concentrations and hormone stimulation during insulin-induced hypoglycaemia in healthy man

SummaryA double-blind placebo-controlled study using the double-dummy technique has been done to examine whether the responses of pituitary and adrenal hormones to insulin-induced hypoglycaemia were impaired by a pharmacological dose of human atrial natriuretic peptide (human ANF-(99-126), hANP).After an overnight fast eight male healthy volunteers (aged 23–40 years) received in random order i.v. bolus injections of insulin 0.125 U·kg−1 + placebo, hANP 100 µg + placebo, insulin + hANP, or both placebo preparations.In the insulin-only experiment, human growth hormone, adrenocorticotrophic hormone, cortisol, aldosterone, plasma renin activity, adrenaline, and noradrenaline were all stimulated by hypoglycaemia.In the hANP-only experiment there were no hormonal changes other than decreases in plasma renin activity and aldosterone concentration. In the insulin + hANP experiment the nadir of blood glucose was decreased to 1.3 from the 2.0 mmol·1−1 found in the insulin-only experiment. The exaggerated hypoglycaemia resulted in increased stimulation of human growth hormone, adrenocorticotrophic hormone and adrenaline when compared to the insulin-only experiment. The rise in the cortisol and aldosterone concentrations was only slightly increased, and the stimulation of plasma renin activity was blunted.Unexpectedly, hANP was found to enhance the hypoglycaemic action of insulin, most probably by inhibiting insulin degradation within the liver. There was no evidence of an inhibitory effect of hANP on the stimulation of pituitary or adrenal hormones during insulin-induced hypoglycaemia. The reduction in renin may indicate an inhibitory action of hANP on catecholaminergic effects within the kidney.

Impaired renal responsiveness to human atrial natriuretic peptide (hANP) in normotensive patients with type 1 diabetes mellitus.

SummaryPotential impairment of the efficacy of human atrial natiuretic peptide (human ANF-(99-126), hANP), the most potent endogenous natriuretic agent in healthy subjects, was examined in eight male normotensive patients with uncomplicated type 1 diabetes mellitus (aged 22–37 years). After giving informed consent, patients and eight male control subjects (aged 22–28 years) received in a random double-blind study design i.v. bolus injections of 100 µg hANP (Bissendorf peptide) or placebo. At base-line, patients differed from controls in elevated creatinine clearance (P<0.05) and in mild postprandial hyperglycemia. Whereas the responses of urinary cyclic guanosine monophosphate, the second messenger of hANP, were found to be normal in patients, the diuretic and natriuretic effects of hANP were grossly impaired when compared to controls (P<0.01); hANP resulted in increased plasma protein concentrations only in controls (P<0.05 vs patients). In both groups, creatinine clearance remained uninfluenced by hANP. There were similar decreases in plasma renin activity, aldosterone, levels, and blood pressure (systolic more than diastolic) in both groups (P<0.05 vs placebo). Heart rate and blood glucose remained unchanged. Thus, there is evidence for a decreased responsiveness to hANP exclusively of renal fluid, sodium, and chloride excretion in uncomplicated type 1 diabetes mellitus. The mechanisms responsible for this phenomenon remain obscure, neither a down regulation at the hANP receptor sites nor an hANP-induced shift from intra- to extravascular fluid volume are likely to be involved in its probably diabetes-specific pathogenesis.

Morphologische Veránderungen nach Biopsie oder Aspirationspunktion des Hodens bei der Ratte

Cambios morfológicos del testiculo de rata luego de biopsia o puncion aspiradora:

The effect of metoclopramide and haloperidol on plasma renin activity and aldosterone levels in rats.

SummaryTo gain further information on dopaminergic inhibition of renin release and aldosterone secretion, we studied the effect of 0.1, 1.0, or 5.0 mg metoclopramide or haloperidol/kg body weight i.p. on plasma renin activity (PRA) and aldosterone concentration in serum, and of furosemide pretreatment or dietary sodium restriction (14 days) on PRA and aldosterone responses to 1.0 and 5.0 mg haloperidol/kg b.wt. i. p. in groups of eight male Spargue-Dawley rats.Aldosterone levels in serum were increased very similarly by 0.1 and 1.0 mg metoclopramide and haloperidol/kg. Whereas PRA and aldosterone were unaffected by 5.0 mg metoclopramide/kg, both were maximally stimulated by 5.0 mg haloperidol/kg. Furosemide pretreatment increased PRA and aldosterone concentration and blunted the aldosterone response to haloperidol. PRA response to 5.0 mg haloperidol/kg was not changed. After sodium restriction, aldosterone concentration was inappropriately high and did not respond to 1.0 mg haloperidol/kg. However, PRA and aldosterone response to 5.0 mg haloperidol/kg was magnified.Our study confirms both dopaminergic inhibition of PRA and stimulation of aldosterone secretion by dopamine antagonists in rats. A feedback regulatory mechanism becomes conceivable which comprises aldosterone secretion, sodium turnover, volume homeostasis, and dopaminergic activity.

Aspartic acid at position 57 of the HLA-DQβ chain is protective against future development of insulin-dependent (Type 1) diabetes mellitus

SummaryInsulin-dependent (Type I) diabetes mellitus is a chronic autoimmune disease. From studies in discordant twins and multiplex families a long prediabetic period has been reported. In a population-based program started in 1983, fifteen individuals at possible risk for future Type I diabetes were followed for up to 74 months. Two individuals (13%) developed Type I diabetes. These probands were characterized by the presence of high-level cytoplasmic islet cell antibodies (ICA), complement-fixing ICA, and an impaired first-phase insulin response after intravenous glucose load. Both were homozygous for a high-risk immunogenetic marker of Type I diabetes, i.e., non-Asp at codon 57 of the HLA-DQΒ chain. In all other subjects studied, the immunogenetic marker that confers “dominant resistance”, aspartic acid at codon 57, was found.On the basis of our data we conclude that a combination of assays which determine ICA, first-phase insulin release, and HLA-DQB1 polymorphisms will identify individuals with a high probability of developing Type I diabetes at the population level. Conversely, HLA haplotypes positive for aspartic acid seem to confer resistance to the disease.

Effects of nifedipine on renal responses to human atrial natriuretic peptide in healthy subjects and normoglycemic patients with type 1 diabetes mellitus

SummaryWe examined renal responses to a pharmacological dosage of human atrial natriuretic peptide (hANP) and the potential interference of nifedipine administration with the effects of hANP on kidney function in healthy subjects and normoglycemic patients with type 1 diabetes mellitus. Ten healthy volunteers (age, 28±1 years) and ten patients (age, 33±2 years; diabetes duration; 14±3 years; HbAI 7.2%±0.2%) were studied. According to a double-blind, randomized, placebo-controlled trial design, three experiments were performed in each subject using the doubledummy technique: placebo only, hANP only, and nifedipine+hANP. As i.v. bolus injection 100 µg hANP was given; nifedipine was applied buccally, at a dose of 10 mg 90 min before and at a dose of 5 mg together with hANP injection. At base-line and in the placebo only experiment, patients did not differ from controls. In the hANP only experiment, in both groups hANP resulted in increased urinary volume and both sodium and chloride excretion (P<0.05 vs placebo only experiment). In patients, hANP-induced increase in electrolyte excretion was greater than in controls (P<0.05). In the nifedipine + hANP experiment, hANP-induced changes in renal indexes were enhanced in controls (P<0.05 vs hANP only experiment) but not in patients. Thus, diuretic response to nifedipine + hANP in patients was decreased in comparison with controls (P<0.05). In patients, however, nifedipine administration decreased the hANP-induced increase in urinary albumin excretion (P<0.05 vs hANP only experiment). Creatinine clearance was uninfluenced throughout the experiments.There were similar decreases in blood pressure in patients and controls after nifedipine administration (P<0.05 vs placebo only experiment). The increase in heart rate after nifedipine was more pronounced in patients than in controls (P<0.05). Conversely, plasma renin activity was stimulated by nifedipine only in controls (P<0.05 vs placebo only experiment). In this study hANP had no effect on heart rate, blood pressure, or plasma renin activity. There was a short-term increase in hANP levels in plasma after nifedipine administration in controls (P<0.05 vs placebo only experiment) but not in patients. In contrast to a previous study, where renal responses to the same pharmacological dosage of hANP were decreased in patients with type 1 diabetes mellitus with HbAI exceeding the normal range, there is no impairment of renal responsiveness to an i.v. bolus of hANP in patients with HbAI within the normal range. Nifedipine and hANP have synergistic effects on kidney function in healthy subjects. It remains to be studied, however, by which mechanism(s) this synergism could be obscured in diabetes patients. Moreover, the increase in hANP levels after nifedipine administration exclusively in controls merits further investigation.

The role of adrenal medulla in endogenous dopaminergic inhibition of aldosterone secretion.

SummaryEvidence has accumulated that aldosterone secretion is under endogenous dopaminergic inhibition. To examine potential sources of the dopamine thus inhibitorily acting in the adrenal zona glomerulosa, the responsiveness of aldosterone, plasma renin activity, prolactin, and plasma catecholamines to haloperidol, a dopaminergic antagonist, was studied in rats 6 weeks after unilateral adrenalectomy (Group B), 6 weeks after unilateral adrenal demedullation followed by contralateral adrenalectomy 5 days later (Group C), and in controls without any pretreatment (Group A). In Group C, there were increases in basal levels of norepinephrine (P < 0.01), prolactin (P < 0.02), and aldosterone (P < 0.01). Basal plasma renin activity was also increased (P < 0.05), epinephrine concentrations were decreased. Two hours after haloperidol 1 mg/kg b.wt. i.p., aldosterone levels were increased in Groups A + B (P<0.01) but unresponsive in Group C. Haloperidol-induced stimulation of prolactin and norepinephrine was not impaired by the surgical procedures. Epinephrine levels were increased by haloperidol only in groups A + B (P < 0.002). In none of the groups were plasma renin activity or dopamine levels influenced by haloperidol. It is concluded that dopaminergic inhibition of aldosterone production is brought about neither by circulating dopamine nor by potential dopaminergic nerves accompanying arterial blood supply of the adrenal cortex but by dopamine originating directly in adrenal medulla.

PREVALENCE OF HLA-DQ BETA CHAIN NON-ASP ALLELES IN TYPE I (INSULIN-DEPENDENT) DIABETICS WITH YOUNG AND OLDER AGES OF ONSET

SummaryParticular HLA-DQβ chain alleles were reported as immunogenetic markers of type I diabetes mellitus with young onset of the disease. In a homogenous German population, we studied HLA-DR specificities and HLA-DQβ chain alleles in young-onset (<21 years of age;n=185) and adult-onset (>40 years of age;n=48) insulin-dependent diabetics. In both cohorts of type I diabetics, the HLA-DR3 and -DR4 specificities were significantly increased. The presence of an HLA haplotype with an amino acid other than aspartic acid at position 57 of the DQβ chain was significantly associated with type I diabetes in both cohorts (etiologic fraction:93% and 73%). We conclude that the presence of DNA sequences coding for an amino acid other than aspartic acid at the 57th position of the DQβ chain provides a molecular risk marker for type I diabetes of both and adult onset.