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Biomedical subjects

A Semplicini

Publications and source records attributed to A Semplicini.

At least 55 records · Page 3Linked to original sources
PubMed1996

Improvement of insulin sensitivity by metformin treatment does not lower blood pressure of nonobese insulin-resistant hypertensive patients with normal glucose tolerance.

Nine hypertensive patients with body mass indexes between 24-27 kg/m2 and normal glucose tolerance with at least a postchallenge plasma insulin level greater than 360 pmol/L were recruited for a double blind, cross-over study with metformin (850 mg, twice daily) and placebo. Each treatment lasted 1 month. Before and after each treatment, hormone and substrate concentrations were determined, blood pressure was monitored over 24 h, and insulin sensitivity was measured by a euglycemic (4.7 mmol/L) hyperinsulinemic (450 pmol/L) clamp study. Renal cation excretion and erythrocyte membrane cation heteroexchange were measured. Metformin, compared to placebo, did not affect body weight (70 +/- 7 vs. 70 +/- 7 kg), fasting plasma glucose (4.8 +/- 0.1 vs. 4.8 +/- 0.1 mmol/L), total cholesterol (5.38+/0.33 vs. 5.48 +/- 0.38 mmol/L), or triglycerides (1.73 +/- 0.72 vs. 1.91 0.89 mmol/L). Nevertheless, after metformin treatment, the plasma high density lipoprotein cholesterol concentration increased (1.42 +/- 0.18 vs. 1.34 0.16 mmol/L), and the plasma insulin level dropped (62 +/- 10 vs. 88+/- 12 pmol/L; both P < 0.05). Insulin-mediated glucose disposal was higher after metformin treatment (26.1 +/- 2.4 vs. 19.3 +/- 2.3 micromol/min x kg; P < 0.01), whereas hepatic glucose production was completely suppressed. These positive metformin-induced metabolic effects were not associated with a significant change in mean daily blood pressure levels (141 +/- 6/89 +/- 3 vs. 142 +/- 7/90 +/- 3 mm Hg). Compared to placebo, metformin increased the excretion of sodium, potassium, and lithium by enhancing their glomerular filtration rate. Na+/Li+ countertransport was not affected by metformin. However, the apparent affinity for H+ of Na+/H+ exchange was increased, and the Hill coefficient was decreased. In conclusion, 1 month of metformin administration to patients with essential hypertension and normal glucose tolerance 1) reduces the basal plasma insulin concentration, 2) improves whole body insulin-mediated glucose utilization, and 3) improves plasma high density lipoprotein cholesterol levels. Despite these positive effects, metformin did not reduce arterial blood pressure.

Adult↗
PubMed1996

Posttranslational effects of protein kinase C and insulin on red cell membrane phosphorylation and cation heteroexchange in hypertension.

In the red blood cell membrane, sodium-proton exchange (NHE-1) exchanges intracellular H(+), Li(+), and Na(+) with extracellular Na(+). In hypertensives (HT), the maximal velocity of translocation (V max)of Na(+)/H(+) and of Na(+)/Li(+) exchange modes are higher, while apparent affinity for external Na(+) of Na(+)/Li(+) exchange and Hill's coefficient for H(+) activation of Na(+)/H(+) exchange are lower than in normotensive subjects (NT). We have therefore examined the effects of protein kinase C (PKC) and insulin on red blood cell membrane phosphorylation and on the kinetic properties of cation heteroexchange. In red cell from NT, PMA-induced activation of PKC reduced K(m) for H(+) of NHE but it did not affect V(max) and K(m) for Na(+). In red cell from HT, PMA-induced a greater PKC stimulation and membrane phosphorylation of band 3,4.1,4.9 than in NT and it did not significantly reduced K(m) for H(i). On the contrary, in HT PKC activation significantly increased Hill's coefficient of NHE. The larger activation of PKC in HT could be due to downregulation secondary to higher membrane calpain activity. Incubation of red cells with insulin decreases K(m) for external Na(+) and increases V(max) of Na(+)/Li(+) exchange. Therefore, we have examined the relationships between Na(+)-activation kinetics of Na(+)/Li(+) exchange and fasting insulin levels. Na(+)-stimulated Li(+) efflux was studied by raising Na(+)up to 300 mM isoosmotically to measure K(m) for Na(+) and V (max). Li(+) efflux saturated at 150 mM external Na(+)in NT but not in HT because in HT it exhibited a two fold higher Na(+) Km. V(max) was higher in HT than in NT. In hyperinsulinemic (fasting insulin > 10 mu U/ml) HT, V(max) and Na(+) Km were higher than in normoinsulinemic HT. In NT, hyperinsulinemia was not associated to abnormal kinetic properties of Na(+)/Li(+)exchange. Stepwise multiple regression analysis confirmed that the main determinants of a high Km were blood pressure and insulin. Our results show that posttranslational effects of PKC and insulin affect the kinetic properties of NHE-1 in red blood cells and suggest that the differences observed between hypertensives and normotensive subjects can be accounted for by PKC activation and insulin exposure.

Cations↗
PubMed1995

Ouabain-inhibiting activity of aldosterone antagonists.

It has been suggested that endogenous substances (known as ouabain-like factors, OLF), secreted from the central nervous system in response to salt and water retention, inhibit the cell membrane Na+/K+ pump in the renal tubules and reduce sodium reabsorption. However, by also acting upon vascular smooth muscle cells, they may induce cell Na+ and Ca++ accumulation, vasoconstriction and systemic hypertension. Recently, an endogenous Na+/K+ pump inhibitor was isolated from human plasma; this inhibitor is indistinguishable from the cardiac glycoside ouabain based on biochemical and immunological criteria. Its plasma concentration is close to the therapeutic range for ouabain (around 0.4 nmol/L). Since plant ouabain promotes natriuresis, vasoconstriction, and hypertension; endogenous ouabain may therefore control extracellular fluid volume and blood pressure. The highest plasma concentrations of endogenous ouabain and OLF were found in congestive heart failure, aldosterone producing adenoma, human and animal models of volume expanded hypertension (reduced renal mass and DOCA-salt hypertension), and in Milan hypertensive rats (MHS). Aldosterone antagonists (canrenone and canrenoate) exert both agonist and antagonist effects on the digitalis receptor site of the Na+/K+ pump. They are effective antihypertensive agents in animal models of hypertension sustained by OLF (reduced renal mass-Na+ and DOCA-salt hypertension in rats). Moreover, in a subgroup of essential hypertensives, 4 weeks of canrenoate administration reduced blood pressure, heightened red blood cell Na+/K+ pump activity, and antagonized ouabain-induced vasoconstriction. None of these effects was seen in the other hypertensives. These data suggest that aldosterone antagonists stimulate the Na+/K+ pump inhibited by endogenous ouabain and exert their antihypertensive action at least in part through this mechanism.

Animals↗
PubMed1995

Immunoreactive endogenous ouabain in primary aldosteronism and essential hypertension: relationship with plasma renin, aldosterone and blood pressure levels.

OBJECTIVE: To investigate the role of ouabain in human hypertension and to establish whether immunoreactive endogenous ouabain is secreted by the adrenal gland under the influence of dopaminergic regulation. METHODS: We measured plasma levels of endogenous ouabain by immunoassay, together with other variables, including plasma renin activity and aldosterone levels, in 91 clinically selected hypertensives and 19 healthy volunteers. We also measured endogenous ouabain in adrenal venous blood and the effect of DA2 dopaminergic receptor blockade and stimulation. After a thorough clinical evaluation, 64 patients were diagnosed with essential hypertension and 24 with primary aldosteronism. RESULTS: Plasma levels of endogenous ouabain were higher in essential hypertensives than in controls. Multiple regression analysis showed a significant relationship of mean blood pressure with plasma endogenous ouabain, age and body mass index, but not with other measured parameters. The plasma levels of endogenous ouabain were more than two standard deviations above the mean value for normotensives in 45% of patients with essential hypertension in whom plasma renin activity was normal. Higher plasma levels of endogenous ouabain were found in patients with aldosterone excess, specifically affecting 56% of 17 patients with surgically confirmed adrenal cortical adenoma and one (14%) of seven patients with idiopathic causes. Removal of adenomas lowered blood pressure in half of the patients in whom plasma levels of endogenous ouabain normalized after surgery. Plasma endogenous ouabain levels were similar in venous blood from the adrenal and inferior vena cava, and plasma levels were not influenced by DA2 dopaminergic blockade and stimulation. CONCLUSION: Approximately half of Caucasian patients with essential hypertension and with hyperaldosteronism exhibit elevated circulating levels of endogenous ouabain. The latter do not appear to be secondary to hypertension, are unrelated to plasma renin activity, and may not involve adrenal type-2 dopaminergic receptors.

Aldosterone↗
PubMed1995

Sodium-lithium countertransport has low affinity for sodium in hyperinsulinemic hypertensive subjects.

We recently reported that incubation of red blood cells with insulin markedly decreases the affinity for external Na+ and increases the maximal transport rate (Vmax) of Na(+)-Li+ countertransport. The association of hypertension with insulin resistance and its compensatory hyperinsulinemia led us to investigate the relationship between insulin levels in vivo and the Na+ activation kinetics of this antiporter. We studied normotensive (n = 28) and hypertensive (n = 25) subjects after they had fasted overnight and determined their plasma glucose and insulin concentrations. Insulin levels were higher in the hypertensive subjects (11.7 +/- 1.5 microU/mL, mean +/- SEM) than in the normotensive subjects (8.2 +/- 1.2 microU/mL), but glucose levels were similar and within normal limits. Antiporter activity was measured as sodium-stimulated Li+ efflux by a new procedure that uses isosmotic conditions to raise external Na+ to 280 mmol/L. In normotensive subjects, Vmax was reached between 50 and 100 mmol/L Na+, whereas in most hypertensive subjects, Na+ concentrations higher than 150 mmol/L were needed. This different kinetic behavior was because the Na+ concentration for half-maximal activation (Km) was twofold higher in hypertensive subjects (58.9 +/- 5.3 mmol/L) than in normotensive subjects (29.8 +/- 2.6 mmol/L, P < .001). Hypertensive subjects with fasting insulin levels greater than 10 microU/mL (n = 12) had a higher Km for Na+ than subjects with insulin levels less than 10 microU/mL (n = 13) (73.4 +/- 8.7 versus 45.6 +/- 3.9 mmol/L, respectively, P < .01) and similar Vmax (0.57 +/- 0.05 versus 0.41 +/- 0.05 mmol.L-1.h-1).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

[The treatment of hypertension in patients with a metabolic disorder].

Life expectancy has increased significantly in the last decades in many Western populations, due to the fall of total and cardiovascular death rates. However, morbidity for cardiovascular diseases has decreased to a smaller extent due to the still unsatisfactory improvement in the overall population risk profile. This is true for blood pressure control (with only 20% of hypertensive patients achieving normotension with antihypertensive drugs), hypercholesterolemia (with borderline-high serum cholesterol levels in 50% of the population), and smoking habits. Since hypertension, hypercholesterolemia, hyperglycemia and insulin resistance are frequently associated, further improvement in cardiovascular risk can be obtained only with a comprehensive approach to the hypertensive patients, including dietary and life style modifications and the use of antihypertensive drugs with beneficial effects on lipid and glucose metabolism. It has to be noted in fact that some antihypertensive drugs have divergent effects on lipid and glucose metabolism. Long-term diuretic administration may reduce glucose tolerance, increase serum glucose and cholesterol. Beta-adrenergic blockers with no sympathomimetic activity raise triglycerides and decrease HDL cholesterol. ACE-inhibitors improve insulin sensitivity, while calcium entry blockers are neutral on both glucose and lipid metabolism. Recent reports suggest that alpha-1 adrenoceptor blockers may reduce total and LDL cholesterol while alleviating insulin resistance and increasing HDL cholesterol.

Arteriosclerosis↗
PubMed1995

Kinetic properties of erythrocyte Na+-Li+ and Na+-H+ exchange in hypertensive patients.

OBJECTIVE: To ascertain the relationships between the kinetic properties of erythrocyte Na+-H+ exchange [maximum kinetic energy (Vmax), Michaelis constant (Km) for internal H+ and Hill's coefficient], Na+-Li+ (Vmax and Km for external Na+), and metabolic parameters in normotensive controls and hypertensive subjects. MATERIALS AND METHODS: Na+-H+ exchange was measured as the Na+ influx driven by intracellular H+, and Na+-Li+ exchange as the Li+ efflux driven by extracellular Na+, in erythrocytes from normotensive (n = 59) and hypertensive (n = 93) subjects. RESULTS: In comparison with normotensives, the hypertensives had a higher Vmax for Na+-Li+ and Na+-H+ exchange, a higher Km for external Na+ for Na+-Li+ exchange and a lower reduced Hill's number for Na+-H+ exchange. Vmax values for Na+-Li+ and Na+-H+ exchange were significantly correlated, as were Km values for internal H+ for Na+-H+ exchange and Km for external Na+ for Na+-Li+ exchange. Insulin resistance and beta-cell function indices were higher in the hypertensives than the normotensives. Upon stepwise multiple regression analysis, Vmax for Na+-Li+ exchange was correlated significantly and independently with Km for external Na+ and with the insulin resistance index, while Km for external Na+ was correlated with Km for internal H+, Vmax for Na+-H+ exchange and mean blood pressure. Vmax and Hill's coefficient for Na+-H+ exchange were correlated only with mean blood pressure. CONCLUSIONS: The demonstration of functional correlations between the kinetic properties of Na+-H+ and Na+-Li+ exchange provides further evidence that erythrocyte Na+-Li+ exchange is a functioning mode of Na+-H+ exchange, which is affected by insulin resistance.

Adult↗
PubMed1994

Fish oils and their possible role in the treatment of cardiovascular diseases.

The multifactorial origin of arteriosclerotic cardiovascular diseases is well recognized. It recently has been shown that n-3 fatty acids (FA), contained in fish oils, may correct some of the most important cardiovascular risk factors and may interfere with key steps in the formation of the atherosclerotic plaque. These findings have raised such interest that many reports have been published with somewhat conflicting results. In hypertensive patients, randomized controlled studies have confirmed that n-3 FA may reduce systolic blood pressure by 5 mmHg and diastolic by 4 mmHg. The decrease in pressure, which could be larger if dietary sodium restriction is added, is probably due to the shift of balance between vasoconstrictive and vasodilator eicosanoids toward vasodilatation. n-3 FA correct endogenous hypertriglyceridemia, but the effects on low-density lipoprotein and high-density lipoprotein cholesterol are less clear cut, since an increase in low-density lipoprotein and a decrease in high-density lipoprotein may be observed in selected patients. As far as the glucose metabolism in patients with diabetes mellitus is concerned, inhibition of the beta cell by n-3 FA has been reported. n-3 FA reduce platelet aggregation, blood viscosity, plasma levels of fibrinogen, PF4 and beta-thromboglobulin and increase capillary flow and red cell membrane fluidity, but their long-term effects on cardiovascular mortality are largely unknown. Medium-term studies, however, have shown a decreased risk of myocardial reinfarction and of restenosis after percutaneous transluminal coronary angioplasty with n-3 FA supplementation. Pure, highly concentrated triglycerides and ethyl esters of n-3 FA are available and will allow further investigations on the dose-response ratio in humans.

Animals↗
PubMed1994

Abnormal erythrocyte and renal frusemide-sensitive sodium transport in idiopathic calcium nephrolithiasis.

1. Anomalous transmembrane anion transport has been observed in erythrocytes of patients with idiopathic calcium nephrolithiasis. 2. To verify whether cation transport is also abnormal, we investigated the frusemide-sensitive Na+ efflux from Na(+)-loaded erythrocytes and the natriuretic response to acute intravenous frusemide administration in calcium oxalate renal stone formers. 3. Frusemide administration induced a statistically significant smaller increase in the fractional excretion of Na+ in patients than in control subjects. Abnormal kinetic properties of erythrocyte Na(+)-K(+)-2Cl- cotransport were observed in approximately 60% of stone formers. The Km for Na+ of Na(+)-K(+)-2Cl- co-transport correlated with urinary Ca2+ excretion. 4. The abnormal kinetic properties of Na(+)-K(+)-2Cl- co-transport may be relevant for stone formation, hampering renal Ca2+ reabsorption in the distal nephron and determining critical physicochemical conditions for calcium/oxalate crystallization.

Adult↗
PubMed1994

Red blood cell sodium heteroexchange in familial primary hypertrophic cardiomyopathy.

The hallmark of primary hypertrophic cardiomyopathy is an inappropriate myocardial hypertrophy, linked to myofibril disarray of the left ventricle. Its variable clinical expression may be due to genetic heterogeneity and variable penetrance. Since we have recently shown that abnormalities of cation transport in the erythrocytes are associated with cardiac hypertrophy in essential hypertensives and insulin-dependent diabetics, we have investigated the relationship between cardiac anatomy and function and red cell Li+/Na+ and Na+/H+ exchange in 33 relatives of a patient who died of cardiac failure and was found to have a primary hypertrophic cardiomyopathy at autopsy. According to echocardiographic examination, 11 members of the family also had a hypertrophic cardiomyopathy, with a family distribution compatible with autosomal dominant genetic transmission and variable penetrance. Red cell Li+/Na+ and Na+/H+ exchange were not significantly different in the affected members as compared to the unaffected, but in the former, after correction for potentially confounding variables, interventricular septum thickness was positively correlated to Na+/H+ exchange and diastolic function (Area E/Area A and Vmax E/Vmax A) negatively correlated to Li+/Na+ exchange. Since a generalized overactivity of the cell membrane Na+/H+ exchange, reflected by increased Na+/H+ and Li+/Na+ exchanges in the red cells, could favour cellular growth and diastolic dysfunction, our data suggest that abnormalities of cell membrane cation transport could play a role in the phenotypic expression of hypertrophic cardiomyopathy.

Adolescent↗
PubMed1994

[Pressure and metabolic effects of terazosin in essential hypertension].

To assess the efficacy and safety of different doses of the alpha-1 blocker terazosin on long-term therapy, 12 essential hypertensives (7 males, 5 females, aged 27-61) were investigated. The study was conducted according to the Latin square design and each patient underwent 4 periods of treatment with 2, 5, 10 mg/day terazosin and placebo, in a double-blind, randomized order. Each treatment lasted 4 weeks. In comparison to placebo, a fall in diastolic pressure was observed already with the 2 mg/daily dose, with a decrease > 10 mmHg in 7 patients (responders). Body weight increased in a dose dependent manner, while atrial natriuretic peptide, serum glucose and insulin during oral glucose tolerance test, total cholesterol, HDL and LDL cholesterol, triglycerides were unaffected. It is concluded that terazosin is effective and safe in essential hypertensives already at 2 mg daily dose. Further reduction in blood pressure at higher doses is likely to be counteracted by salt and water retention.

Adrenergic alpha-Antagonists↗
PubMed1994

Interactions between insulin and sodium homeostasis in essential hypertension.

It has been proposed, therefore, that hyperinsulinemia may favor the development of hypertension through sodium retention, sympathetic nervous system activation, and vascular hypertrophy. In insulin-resistant hypertensive subjects, insulin infusion during euglycemic clamp promotes a transient sodium retention by stimulating proximal tubular Na+ reabsorption, but chronic hypertension usually is not associated with extracellular fluid and plasma volume expansion. In essential hypertensive subjects, intracellular potassium is decreased and intracellular sodium increased, which is consistent with insulin resistance. The latter is also associated with high red blood cell Li+/Na+ exchange, and chronic insulin treatment in insulin-dependent diabetics induces a slight increase in Li+/Na+ CT. This is a functioning mode of the Na+/H+ exchange, and its increase may reflect either an increased number of transport units or abnormal kinetic properties. Experiments in vitro and in vivo suggested that any change in insulin concentration and insulin sensitivity may affect Li+/Na+ and Na+/H+ counter-transport. High Li+/Na+ and Na+/H+ CT are associated with a significant cardiac and vascular remodeling in essential hypertension, insulin-dependent diabetes, and familiar hypertrophic cardiomyopathy. Reduced insulin sensitivity is associated with salt-sensitive hypertension. Finally, insulin potentiates the effects of other agonists (eg, thromboxane A2, angiotensin II) on vascular contraction and cell growth. These data indicate that insulin may play a role in the pathogenesis of hypertension and its major complications by amplifying the effects of sodium, vasoconstrictors, and growth factors.

Homeostasis↗
PubMed1993

Effects of canrenoate on red cell sodium transport and calf flow in essential hypertension.

The effects of potassium canrenoate (100 mg/day, orally for 1 month) on blood pressure, calf blood flow at rest and after ouabain (0.5 mg intravenous bolus), and red cell Na homeostasis were investigated in 15 patients (7 men, 8 women, aged 18 to 63) with essential hypertension and without peripheral vascular diseases. On placebo, acute intravenous ouabain administration significantly and transiently reduced calf flow and increased calf vascular resistance without affecting blood pressure. Canrenoate significantly decreased blood pressure (from 159 +/- 21/105 +/- 9 mm Hg to 141 +/- 14/94 +/- 10, P < .05) and the rise of calf resistance after intravenous ouabain bolus. The latter effect was variable, since it was inhibited almost completely in 8 patients and unaffected in the others. In the patients in whom exogenously administered ouabain was antagonized, canrenoate diminished blood pressure through vasodilation and heightened the red cell Na/K pump. None of these parameters changed significantly in the other patients. Thus these data suggest that the fall in vascular resistance induced by canrenoate is mediated, in part, by the antagonism of endogenous ouabain-like factors.

Adult↗
PubMed1993

Red blood cell Li+/Na+ exchange in patients with diabetic nephropathy and essential hypertension: therapeutic implications.

Patients who develop diabetic nephropathy, one of the leading causes of end-stage renal diseases in Western communities, have an increased red cell Li+/Na+ countertransport (CT). Li+/Na+ CT is a membrane function which exchanges intracellular Li for extracellular Na in vitro. High Li+/Na+ CT reflects abnormal kinetic properties of red cell membrane Na/H exchange. A widespread abnormality of Na/H exchange could play a major role in the pathogenesis of diabetic nephropathy as well as of cardiovascular diseases since Na/H exchange is involved in the regulation of cell pH and cell volume; in the cellular response to hormones, mitogens, and growth factors; and in the renal reabsorption of Na and bicarbonate. Li+/Na+ CT is under genetic control and raised in a subgroup of patients with essential hypertension. Among these patients, high Li+/Na+ CT is associated with increased glomerular filtration rate, filtration fraction, proximal fractional Na reabsorption, microalbuminuria, plasma renin activity, and kidney and cardiac volume. Increased Li+/Na+ CT is often associated with hyperlipidemia, hyperuricemia, reduced insulin sensitivity, and obesity. The whole of these observations may explain why patients with diabetes or essential hypertension and increased Li/Na CT are at risk of early renal and cardiac impairment.

Adult↗
PubMed1992

Perindopril versus captopril: efficacy and acceptability in an Italian multicenter trial.

The aim of this 3-month, double-blind, double-dummy, parallel group study was to compare the antihypertensive efficacy and acceptability of perindopril (4-8 mg/day) in 54 patients (30 males, 24 females, 25-68 years of age) and captopril (50-100 mg/day) in 54 patients (39 males, 15 females, 29-66 years of age) in the treatment of essential hypertension. In a subgroup of 38 patients a complete echocardiographic study was performed. The two groups had similar (ANOVA) blood pressure (BP), heart rate (HR), body mass index, and duration of hypertension. Supine and standing BP was significantly reduced by both drugs, without differences between them. Owing to poor control of BP, hydrochlorothiazide (25 mg/day) was added to 27% of patients on perindopril and to 41% of patients on captopril (p less than 0.05). Normalization of supine diastolic BP (less than or equal to 90 mm Hg) was obtained in 67% of patients on perindopril and in 47% of patients on captopril (p less than 0.01). No change in HR was detected. Only mild untoward effects were recorded. Left ventricular mass was significantly reduced by either drug, with no change in systolic function. In conclusion, perindopril and captopril, at these doses, were both well tolerated and on average reduced BP to a similar extent; however, treatment with perindopril showed that fewer patients needed the addition of a thiazide and BP became normal in a larger number of patients.

Adult↗