E. Jungmann

Elevated endothelin-1 levels after cigarette smoking

The effect of short-term nicotine consumption on endothelin-1 (ET-1) levels was studied in 10 male healthy smokers. Volunteers smoked in random order on 3 separate days a low-tar cigarette or a high-tar cigarette, or were studied without having smoked (no-cigarette experiment). ET-1, corticotropin, and cortisol levels, heart rate, and blood pressure were determined before and 1, 3, 5, 10, 20, and 30 minutes after smoking. In contrast to results obtained after smoking a low-tar cigarette or not smoking, smoking a high-tar cigarette resulted in a significant increase in ET-1 levels within 10 minutes, followed by an increase in corticotropin levels within 20 minutes after smoking. Thirty minutes after smoking, cortisol levels were higher after a high-tar cigarette compared with a low-tar cigarette or no smoking. Increases in heart rate and systolic blood pressure were likewise higher after smoking a high-tar cigarette than after smoking a low-tar cigarette. In conclusion, it is tempting to speculate that ET-1 may indeed act as the long-searched-for link between vasopressin and corticotropin-releasing hormone (CRH) and thus play an essential role in the stimulation of the hypothalamic-pituitary-adrenal axis. In addition, these results suggest that the increase in the level of ET-1, a powerful vasoconstrictor and mitogen, may play an important part in the disease mechanisms of atherosclerosis arising from smoking.

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.

In vivo evidence that human atrial natriuretic factor-(99-126) (hANF) stimulates parasympathetic activity in man

SummaryIn a double-blind study 8 healthy male subjects received 100 µg human atrial natriuretic factor-(99-126) (hANF) and NaC10.9% in random order on different days.Following hANF injection a significant increase in cardiac beat-to-beat variation was observed (4.65% vs 5.95%).This shows that in vivo human atrial natriuretic factor stimulates cardiac parasympathetic activity in man.

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.

Human atrial natriuretic peptide in patients with type 1 diabetes mellitus: is it related to the development of diabetic nephropathy?

SummaryThere is controversy as to whether increased plasma levels of human atrial natriuretic peptide (hANP) in patients with type 1 diabetes mellitus may contribute to the development of diabetic nephropathy. Therefore, we decided to conduct two studies to examine the relationship of hANP levels to urinary albumin excretion and blood pressure. In a cross-sectional study, 83 randomly selected type 1 diabetic patients were investigated. 19 of the patients had increased urinary albumin excretion. 45 healthy volunteers served as controls. In a longitudinal study, 19 type 1 diabetic patients were examined for one year at monthly intervals. An increased risk of eventually developing diabetic nephropathy was identified in 7 out of these patients by repeatedly revealing increased urinary albumin excretion. On the average, hANP levels were increased in type 1 diabetic patients in comparison to controls (P < 0.001). In both studies, hANP levels were positively related (P < 0.05) to mean arterial blood pressure. There was no correlation between hANP levels and metabolic control. hANP levels lay within normal range irrespective of normal or elevated urinary albumin excretion provided that mean arterial blood pressure was normal. In the longitudinal study, increased urinary albumin and alpha-1-microglobulin excretion preceded the increase in both hANP levels and mean arterial blood pressure. Although hANP levels were evidently not related to the disease mechanisms of early diabetic nephropathy, it is tempting to speculate that hANP may contribute to the vicious circle connecting diabetic kidney disease to hypertension once that its levels are increased by elevated blood pressure.

Gallstones in acromegalic patients undergoing different treatment regimens.

SummaryThe frequency of gallstones during longterm treatment with the somatostatin analogue octreotide reported in different studies varies from 0% to 50%, the reason for this variation being unknown. Therefore, we examined 58 acromegalic patients undergoing different treatment regimens for the frequency of gallstones. Thirteen were treated with octreotide, 20 with bromocriptine, and 25 had no medical treatment after successful neurosurgery. Also, 58 patients without known gallbladder disease served as controls. The postprandial gallbladder contraction was also investigated in 27 acromegalic patients (10 with octreotide, 10 with bromocriptine, and 7 with no medical therapy). Ten of the 58 acromegalic patients were found to have gallstones, 4 of 25 receiving no medical treatment, 4 of 20 treated with dopamine agonists, and 2 of 13 treated with octreotide. In 9 of the 58 control patients, gallstones were detected. Although in the octreotide group the gallstones were newly formed under therapy, there was no difference in gallstone prevalence between the different treatment regimens and the control group. However, the postprandial gallbladder contraction was significantly more often inhibited during octreotide therapy, and this effect was most pronounced during the first hours following injection. Differences in the timing of injections therefore may be an explanation of the variable incidence of cholelithiasis in the different studies.

Verhalten der renalen Funktionsreserve von Typ I Diabetikern: Einfluß der Konversionshemmung

Renal functional reserve capacity was evaluated in 19 normotensive type I diabetics without microalbuminuria. All patients had normal basal renal function as assessed by 24-hour creatinine clearances higher than 120 ml/min. PAH, inulin, and creatinine clearances were carried out every hour before, during, and after infusion of an amino acid (AA) solution. The same experiment was repeated after ACE inhibition with captopril (25 mg). Two groups of patients were found: Group A (responders) showed a significant rise in GFR after AA infusion (inulin clearances from 117 +/- 8 to 138 +/- 10 ml/min) (p less than 0.05), whereas in Group B (non-responders) no significant change in GFR was observed. Groups were comparable in age, duration of diabetes, metabolic control, and mean arterial blood pressure. Group B, however, had a significantly higher basal inulin clearance (167 +/- 17 ml/min) than Group A (117 +/- 8 ml/min). In Group A ACE inhibition completely blocked the AA-induced rise in GFR, while basal GFR in Group B was significantly reduced (167 +/- 17 to 148 +/- 8 ml/min) after captopril administration. In both groups renal plasma flow was enhanced by ACE inhibition. A rise in glucagon was observed in all patients during AA infusion. It is concluded that type I diabetics with normal basal renal function already have reduced (Group A) renal functional reserve capacity, which is completely abolished (Group B) when concomitant hyperfiltration occurs. ACE inhibition reduces hyperfiltration and is capable of blocking the AA-induced rise in GFR in these patients.SummaryRenal functional reserve capacity was evaluated in 19 normotensive type I diabetics without microalbuminuria. All patients had normal basal renal function as assessed by 24-hour creatinine clearances higher than 120 ml/min. PAH, inulin, and creatinine clearances were carried out every hour before, during, and after infusion of an amino acid (AA) solution. The same experiment was repeated after ACE inhibition with captopril (25 mg). Two groups of patients were found: Group A (responders) showed a significant rise in GFR after AA infusion (inulin clearances from 117±8 to 138±10 ml/min) (p<0.05), whereas in Group B (non-responders) no significant change in GFR was observed. Groups were comparable in age, duration of diabetes, metabolic control, and mean arterial blood pressure.Group B, however, had a significantly higher basal inulin clearance (167±17 ml/min) than Group A (117±8 ml/min).In Group A ACE inhibition completely blocked the AA-induced rise in GFR, while basal GFR in Group B was significantly reduced (167±17 to 148±8 ml/min) after captopril administration. In both groups renal plasma flow was enhanced by ACE inhibition.A rise in glucagon was observed in all patients during AA infusion.It is concluded that type I diabetics with normal basal renal function already have reduced (Group A) renal functional reserve capacity, which is completely abolished (Group B) when concomitant hyperfiltration occurs. ACE inhibition reduces hyperfiltration and is capable of blocking the AA-induced rise in GFR in these patients.

Modification of the responses of endothelin-1 to exhaustive physical exercise under simulated high-altitude conditions with acute hypoxia

To assess whether acute alveolar hypoxia leads to the release of endothelin-1 (ET) in vivo, ET, cortisol (CORT), and lactate (LA) levels were determined in 15 healthy subjects at rest and during exhaustive incremental cycle ergometry on two separate test days. The subjects were to breathe a gas mixture with reduced O2 content ([H] fraction of inspired O2, 0.14) on one day and normal air on the other (N). Modified responses of LA and CORT to exhaustive incremental cycle ergometry on the H day indicated elevated anaerobic tissue metabolism and increased physical stress. With acute alveolar hypoxia, the response of ET to exhaustive physical labor was found to be augmented.