A. Pala

Evidence for Cortisol as the mineralocorticoid in the syndrome of apparent mineralocorticoid excess

The hypothesis that Cortisol is the functioning mineralocorticoid in the syndrome of apparent mineralocorticoid excess was tested by suppressing its secretion with dexamethasone. The subjects were two siblings with the type 2 form of this syndrome in which the defect in the peripheral metabolism of Cortisol lies predominantly in ring A reduction but not in 11β-hydroxy dehydrogenation of Cortisol to cortisone. Low dosage dexamethasone improved the hypokalemia within several days and hypertension was corrected after 3 weeks of treatment. Mineralocorticoid manifestations remained in remission during 10 yr of therapy with the synthetic glucocorticoid during which normal growth and development were restored. The effectiveness of dexamethasone supports the hypothesis that Cortisol is the functioning mineralocorticoid in the AME syndrome.

In Vitro Action of Insulin on Erythrocyte Sodium Transport Mechanisms: Its Possible Role in the Pathogenesis of Arterial Hypertension

The effects of insulin on sodium and potassium metabolism have been well known for many years; clinical observation and laboratory experience showed different results about the insulin effect on the sodium-potassium pump. Moreover, studies about the insulin effect on the sodium-potassium cotransport are not available. Therefore, the effects of insulin on Na+,K+ pump and Na+,K+ cotransport were evaluated. Results show that insulin inhibits Na+,K+ pump, while Na+,K+ cotransport is markedly activated. The possible link between pathogenesis of arterial hypertension in hyperinsulinemic subjects and present data is examined.

Does kidney transplantation normalise cortisol metabolism in apparent mineralocorticoid excess syndrome

The syndrome of apparent mineralocorticoid syndrome (AME) results from defective 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2). This enzyme is co-expressed with the mineralocorticoid receptor (MR) in the kidney and converts cortisol to its inactive metabolite cortisone. Its deficiency allows the unmetabolized cortisol to bind to the MR inducing sodium retention, suppression of PRA and hypertension. Thus, the syndrome is a disorder of the kidney. We present here the first patient affected by AME cured by kidney transplantation. Formerly, she was considered to have a mild form of the syndrome (Type II), but progressively she developed renal failure which required dialysis and subsequent kidney transplantation. To test the ability of the transplanted kidney to normalise the patient’s cortisol metabolism, we gave, in two different experiments, 25 and 50 mg/day of cortisone acetate or 15 and 30 mg/day of cortisol after inhibition of the endogenous cortisol by synthetic glucocorticoid (methylprednisolone and dexamethasone). The AME diagnostic urinary steroid ratios tetrahydrocortisol+5αtetrahydrocortisol/tetrahydrocortisone and cortisol/cortisone were measured by gas chromatography/mass spectrometry. Transplantation resulted in lowering blood pressure and in normalization of serum K and PRA. After administration of a physiological dose of cortisol (15 mg/day), the urinary free cortisol/cortisone ratio was corrected (in contrast to the A-ring reduced metabolites ratio), confirming that the new kidney had functional 11β-HSD2. This ratio was abnormally high when the supra-physiological dose of cortisol 30 mg/day was given. After cortisone administration, the tetrahydrocortisol+5αtetrahydrocortisol/tetrahydrocortisone ratio resulted normalised with both physiological and supra-physiological doses, confirming that the hepatic reductase activity is not affected. As expected, the urinary free cortisol/cortisone ratio was normal with physiological, but increased after supra-physiological doses of cortisone. The described case indicates a normalisation of cortisol metabolism after kidney transplantation in AME patient and confirms the supposed pathophysiology of the syndrome. Moreover, it suggests a new therapeutic strategy in particularly vulnerable cohorts of patients inadequately responsive to drug therapy or with kidney failure.

Serum Insulin, Insulin Sensitivity, and Erythrocyte Sodium Metabolism in Normotensive and Essential Hypertensive Subjects with and Without Overweight

Increased insulin circulating levels and perturbations of intracellular sodium metabolism have been reported in essential hypertensive patients, leading to postulate their involvement in the pathophysiology of the disease. In-vitro studies have shown that insulin modulates the activity of some transmembrane sodium transporters. The aim of this investigation was to assess in subjects with essential hypertension and/or overweight, the levels of fasting serum insulin, the activity of sodium transporters and their possible relationships. In 18 lean normotensive, 12 overweight normotensive, 18 untreated lean essential hypertensive, and 16 untreated overweight essential hypertensive subjects, we measured the fasting levels of blood glucose and serum insulin, and calculated the glucose/insulin ratio as an index of sensitivity to insulin. In addition, in the red blood cells of these subjects, we evaluated the maximal rate of ouabain-sensitive Na/K pump, furosemide-sensitive outward Na/K cotransport, Nai/Lio countertransport, and the constant rate of passive permeability to Na. When compared to lean normotensive, overweight normotensive, lean hypertensive, and overweight hypertensive subjects exhibited significantly higher fasting insulin levels, with lower glucose/insulin ratio. No significant difference was found in the activity of Na/K pump, Na/K cotransport, and passive permeability to Na. The Nai/Lio exchange was significantly increased in both hypertensive groups. Mean blood pressure correlated positively and independently with body mass index and fasting insulinemia, and inversely with the glucose/insulin ratio. No relationships were found between blood pressure, fasting insulin levels or glucose/insulin ratio and the activity of sodium transport systems. We conclude that hyperinsulinemia and insulin resistance are associated with essential hypertension independently of overweight. These data lend support to the hypothesis that insulin is involved, concurrently with other factors, in the pathogenesis of essential hypertension in both lean and obese subjects.

Hyperinsulinemia and hypertension: Do intestinal hormones play a role?

Gastric inhibitory polypeptide (GIP) is one of the strongest insulinotropic gut factors. Its secretion is induced by oral (but not intravenous) glucose and it has been implicated in the pathogenesis of hyperinsulinemic states (NIDDM, obesity). To determine its relevance to hypertension, 54 subjects were studied: 26 normotensives (12 with and 14 without family history of essential hypertension), and 28 essential hypertensive subjects. Plasma glucose, serum insulin (IRI), and GIP were evaluated after a mixed meal containing a total of 82 g of carbohydrates, and 2 g sodium chloride. Venous blood was collected at baseline and every 15 min during a 3-h period. Baseline levels of glucose, IRI, and GIP were comparable in the three groups. At 30 min, however, IRI and GIP were higher in normotensives with a family history of hypertension and in established hypertensive versus control subjects. Both in normotensive and in hypertensive groups, glucose, IRI, and GIP responses to the meal were significantly correlated. Our data suggest the contribution of altered GIP secretion in the pathogenesis of hyperinsulinemia in essential hypertension.

Effects of ketanserin on transmembrane sodium transport in erythrocytes

Ketanserin, an antagonist of 5-HT2-serotonergic and α1-adrenergic receptors, has come into use for the therapy of mild to moderate arterial hypertension. Quite recent observations have shown changes in trans-membrane sodium (Na) transport after the acute administration of high doses of this drug to normal subjects. It is well known that some of these transport systems have an altered activity in essential hypertension. We evaluated the effects of long-term (3 months) administration of ketanserin (40–80 mg/day) on Na and potassium (K) intracellular concentrations and transmembrane fluxes in red blood cells (RBCs) from 12 essential hypertensive patients. In addition the present study describes the in vitro effects of two different concentrations of the drug (5 × 10−8 and 5 × 10−7 M) on erythrocytes in normal subjects. In the first study, both systolic and diastolic blood pressure were significantly lowered by the treatment with ketanserin (from 165/103 to 143/89; p < 0.001). Na and K intraerythrocyte concentrations fell markedly during ketanserin administration (both p < 0.001). A marked decrease in Na, K-pump activity (p < 0.001) and an increase in Na,lithium(Li)-countertransport function (p < 0.001) were observed. Na outward cotransport, Na leak, and K leak were not modified by the therapy. Direct correlation was found between the fall in mean blood pressure and in Na and K intraerythrocyte concentration (respectively, p < 0.01 and p < 0.05). In the second, in vitro study, ketanserin induced a dose-dependent activation of Na,Li countertransport (p < 0.05) and a decrease in the activity of the Na,K pump (p < 0.05). Our observations show that ketanserin influences both the number and activity of some monovalent cation transmembrane carriers placed on the cell surface. These effects might be involved in the hypotensive action of the drug.

Evidence for a direct and non-receptor-mediated action of 5HT2 antagonists on transmembrane cation transport systems

SummaryChanges in transmembrane sodium fluxes have been reported in normotensive and in hypertensive subjects after ketanserin administration. In this study, the effects of the serotonergic system on transmembrane sodium transport mechanisms have been investigated in vitro. In erythrocytes drawn from ten healthy subjects, we studied the effects of serotonin (5HT) on the Na/K pump, Na/K cotransport, Na/Li countertransport, and passive permeability of Na. No significant changes were found. A direct, non-receptor-mediated action of ketanserin was then suspected, and the effects of two concentrations of ketanserin (5×10-8 and 5×10-7 M) were evaluated in erythrocytes from 12 normal volunteers. Both concentrations of ketanserin significantly decreased the activity of the Na/K pump and increased the activity of Na/Li countertransport. Na/K cotransport and passive permeability were not affected. Indirect evidence of the action of ketanserin on sodium transmembrane fluxes came from other experiments. In the red blood cells taken from five normal subjects and incubated for 2 hours in a plasma pool, we evaluated the changes in intracellular sodium concentration induced by the presence of 5HT or ketanserin. A significant decrease in intracellular sodium concentration occurred only with ketanserin. This study indicates that ketanserin has a direct influence on transmembrane sodium fluxes. If this action were also present in other cells, it might contribute to the actions of the drug at vascular, nervous, and renal tubular levels.