Free calcium concentration in platelets of patients with essential hypertensio
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Research Interests: Endocrinology, Calcium, Medicine, Platelet, Humans, and 15 moreInternal Medicine, Hypertension, Epinephrine, Female, Male, Norepinephrine, Clinical Sciences, Middle Aged, Adult, Angiotensin II, Extracellular, Ouabain, Essential Hypertension, Blood platelets, and Cardiovascular medicine and haematology
Research Interests: Humans, Hypertension, Female, Male, Clinical Sciences, and 4 moreMiddle Aged, Adult, Erythrocyte Membrane, and Ouabain
Background—Oxidation of LDL produces a series of biologically active, oxidized lipids. Among them, isoprostanes, and in particular iPF2-III, seem to be crucial in mediating some of the key cellular events seen in myocardial... more
Background—Oxidation of LDL produces a series of biologically active, oxidized lipids. Among them, isoprostanes, and in particular iPF2-III, seem to be crucial in mediating some of the key cellular events seen in myocardial ischemia-reperfusion injury. Methods and Results—Minimally modified LDL (MM-LDL) triggers a dose-dependent, very rapid neutrophil adhesion to human fibrinogen. Rapid adhesion triggering correlates with degree of LDL oxidation
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Plasma from 37 essential hypertensive patients, from 11 subjects with primary aldosteronism and from 23 normotensive subjects was tested for ouabain-like activity. Despite a very substantial overlap, hypertensive patients (both essential... more
Plasma from 37 essential hypertensive patients, from 11 subjects with primary aldosteronism and from 23 normotensive subjects was tested for ouabain-like activity. Despite a very substantial overlap, hypertensive patients (both essential and secondary) showed significantly higher levels of a ouabain-like plasma factor compared to normotensive controls. No substantial differences could be detected, however, between the two forms of hypertension; in particular, no significant changes were observed in the low-PRA subgroup. Our results are hardly compatible with the hypothesis that this substance may be of crucial importance in the development either of essential hypertension or of primary aldosteronism.
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1. Despite the fact that numerous studies provide evidence for the existence of an endogenous inhibitor of the cell membrane Na(+)-K+ pump in plasma, little is known about the relationships between this factor and the main haemodynamic... more
1. Despite the fact that numerous studies provide evidence for the existence of an endogenous inhibitor of the cell membrane Na(+)-K+ pump in plasma, little is known about the relationships between this factor and the main haemodynamic parameters. 2. In order to shed some light on this, we attempted to correlate haemodynamic parameters, measured during heart catheterization in a group of 22 cardiopathic subjects, with plasma digitalis-like activity levels, determined by two different procedures. 3. The ability of plasma to inhibit a human renal Na(+)-K(+)-ATPase showed an inverse correlation with cardiac index and a direct correlation with peripheral resistance. Plasma cross-reactivity with digoxin antibodies correlated directly with left atrial pressure. 4. These results furnish confirmation of a number of theoretical assumptions which attribute to the digitalis-like factor the ability to modify the contractility of the cardiovascular system.
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The present study tested the effects of ox-low density lipoprotein (LDL) on nitric oxide (NO)-dependent decrease in agonist-stimulated [Ca2+]i. The effects of ox-LDL on platelet aggregation were also evaluated. Platelets loaded with FURA... more
The present study tested the effects of ox-low density lipoprotein (LDL) on nitric oxide (NO)-dependent decrease in agonist-stimulated [Ca2+]i. The effects of ox-LDL on platelet aggregation were also evaluated. Platelets loaded with FURA 2 AM (2 micromol/litre) were incubated with NO-donors for 2-10 min to obtain a 40-50% reduction in \[Ca2+]i and with NO-donors plus ox-LDL (100 microg of protein/ml). Thrombin (0.03 U/ml) was used as an agonist. In some experiments 8-Br-cGMP (0.5-1 mmol/l) was used to investigate the NO-dependent intraplatelet signalling system. Slightly oxidized LDL was obtained by leaving native LDL in the light at room temperature for at least 7 days. Ox-LDL did not cause any increase in thrombin-induced [Ca2+] (control: 215.4 +/- 44.3 nmol/l, ox-LDL 223.4 +/- 35.3 nmol/l, M +/- SEM; n = 8) and platelet aggregation (control: 78.7 +/- 4.9% , ox-LDL: 78.9 +/- 4.2% , n = 12). Ox-LDL antagonized the effects of NO-donors on platelet [Ca2+]i (NO-donor: 137.4 +/- 22.1 n...
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To ascertain the claimed links between peripheral insulin resistance and intracellular magnesium and calcium concentrations, we measured free intralymphocyte magnesium (Mg(i)) and calcium (Ca(i)) concentrations, as well as the rate... more
To ascertain the claimed links between peripheral insulin resistance and intracellular magnesium and calcium concentrations, we measured free intralymphocyte magnesium (Mg(i)) and calcium (Ca(i)) concentrations, as well as the rate constant of plasma glucose disappearance (K(itt)) after insulin injection (insulin tolerance test: ITT), in a group of 15 normotensive control subjects (NC) and 29 essential hypertensive subjects (EH). Mg(i) and Ca(i) were measured in triplicate by means of a fluorimetric technique based on the dyes furaptra and fura-2 respectively. K(itt) value were significantly reduced in hypertensive subjects as compared to control subjects (M +/- SD, EH: 4.54 +/- 1.31 vs 5.63 +/- 1.07; p < 0.02; 95% confidence limits: 0.22-1.96). Mg(i) and Ca(i) were not statistically different in hypertensive subjects as compared to control subjects (Mg(i), NC: 0.274 +/- 0.02 mmol/L; EH: 0.248 +/- 0.05 mmol/L; Ca(i), NC: 47.6 +/- 9 mmol/L, EH: 46.7 +/- 13.6 mmol/L). A statistical...
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The effects of a single oral dose (100 mg) of the angiotensin-converting enzyme (ACE) inhibitor, captopril (SQ 14,224), on blood pressure (BP), plasma renin activity (PRA), plasma aldosterone (PA), and serum ACE were investigated in 18... more
The effects of a single oral dose (100 mg) of the angiotensin-converting enzyme (ACE) inhibitor, captopril (SQ 14,224), on blood pressure (BP), plasma renin activity (PRA), plasma aldosterone (PA), and serum ACE were investigated in 18 patients with essential hypertension (EH) and in 4 with renovascular hypertension (RVH). in most patients, SQ 14,225 caused a significant reduction of BP during the subsequent 6 h, particularly in RVH patients. A significant correlation between basal PRA levels and BP reduction was observed only by considering all the patients together. After ACE blockade, a significant increase of PRA was observed in RVH and in normal-renin EH patients, but not in EH patients with lower PRA. Maximal serum ACE inhibition (over 50%) occurred after 2 h but diminished after 4 h and 6 h, whereas the BP decrease persisted for 6 h. After 3-day treatment with indomethacin (six patients) captopril's antihypertensive action was blunted, despite a reduction of baseline PRA ...
Research Interests: Humans, Hypertension, Blood Pressure, Female, Male, and 4 moreProline, Middle Aged, Adult, and Captopril
It has been suggested that angiotensin-converting enzyme (ACE) inhibitors may also act through the renal prostaglandin (PG) system; moreover, it has been shown that nonsteroidal antiinflammatory drugs (NSAIDs) are capable of reducing the... more
It has been suggested that angiotensin-converting enzyme (ACE) inhibitors may also act through the renal prostaglandin (PG) system; moreover, it has been shown that nonsteroidal antiinflammatory drugs (NSAIDs) are capable of reducing the antihypertensive activity of ACE inhibitors. Sixteen essential hypertensive patients (WHO stages, I-II, eight on a low-sodium diet and eight on a high-sodium diet) were treated with enalapril, 20 mg/day per os, for 4 days. On days 3 and 4, ibuprofen, 1,200 mg/day per os, was also given. Enalapril reduced blood pressure, particularly in the group on the low-sodium diet. Urinary 6-keto-PGF1 alpha, an indicator of renal PGI2 production (determined by HPLC-RIA), increased in the first few hours after enalapril in the low-sodium group. Ibuprofen did not reduce the antihypertensive effect of enalapril, nor did it affect plasma renin activity or plasma aldosterone. Only a slight reduction in 6-keto-PGF1 alpha excretion was observed after enalapril plus ibu...
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Oxidized LDL has been observed to induce abnormalities in endothelial function which may be relevant for the progression of atherosclerotic lesions. We studied in vitro the possible effects of oxidized LDL on the antiaggregating activity... more
Oxidized LDL has been observed to induce abnormalities in endothelial function which may be relevant for the progression of atherosclerotic lesions. We studied in vitro the possible effects of oxidized LDL on the antiaggregating activity of endothelial cells, which is dependent on release of prostacyclin and nitric oxide. We used an experimental model in which cultured human endothelial cells were placed in the aggregometer in contact with human platelets, after blockade of cyclo-oxygenase by adding acetylsalicylic acid. In this way the antiaggregant effect of endothelial cells was dependent on the release of nitric oxide alone; prevention of antiaggregant activity by preincubation of endothelial cells with 300 microM L-NG-mono-methylarginine confirmed this. When this system was used, endothelial cells (2-7.5 x 10(5)/ml) almost completely inhibited thrombin-induced (0.02-0.08 U/ml) platelet aggregation (2 x 10(8) platelets/ml), measured according to Born (11.1% +/- 8.5 vs 68.6% +/- ...
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The effect on the electrolyte balance of a dopaminergic agonist (bromocriptine) and an antagonist (metoclopramide) and their effect on renal aldosterone and kallikrein excretion were investigated. Ten normotensive Wistar rats and ten... more
The effect on the electrolyte balance of a dopaminergic agonist (bromocriptine) and an antagonist (metoclopramide) and their effect on renal aldosterone and kallikrein excretion were investigated. Ten normotensive Wistar rats and ten spontaneously hypertensive rats (SHR-Wistar Kioto) were treated with BCR (4 mg/Kg weight b.i.d.) for 4 days; after a week of pharmacological wash-out they received MCP (0,5 mg/Kg weight b.i.d.) for 4 days. Before and after treatment and at the 2nd and 4th day of each treatment diuresis, urinary excretion of aldosterone, kallikrein, sodium, potassium and proteins were measured. During the 24-hour urine collections the rats were kept in separate metabolic cages with free access to food and water. Kallikrein urinary excretion was lower in SHR than in normotensive rats under basal conditions (p 0.05); urinary sodium, potassium, proteins and sodium/potassium rate were also reduced in SHR. After treatment with bromocriptine a further reduction in urinary kall...
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The effects of prostaglandin synthetase inhibition by indomethacin on blood pressure and hormonal variations induced by captopril were studied in eight patients with essential hypertension and in six nonhypertensive subjects. Captopril... more
The effects of prostaglandin synthetase inhibition by indomethacin on blood pressure and hormonal variations induced by captopril were studied in eight patients with essential hypertension and in six nonhypertensive subjects. Captopril antihypertensive effect and captopril-induced plasma renin increase were almost totally abolished by a short-term administration of indomethacin (50 mg t.i.d.). These results support the hypothesis that prostaglandins contribute to the antihypertensive effects of ACE inhibitors. It may be of clinical importance that anti-inflammatory drugs that inhibit PG-synthetase can also blunt the antihypertensive action of ACE inhibitors.
Research Interests: Clinical Pharmacology, Humans, Blood Pressure, Female, Male, and 6 moreProline, Middle Aged, Adult, Captopril, Indomethacin, and Kinins
We studied in vitro the antiplatelet activity of a new nitroderivative chemically related to acetylsalicylic acid: 2 acetoxybenzoate 2-[1-nitroxy-methyl]-phenyl ester (NCX 4016), in order to identify any effects due to the release of... more
We studied in vitro the antiplatelet activity of a new nitroderivative chemically related to acetylsalicylic acid: 2 acetoxybenzoate 2-[1-nitroxy-methyl]-phenyl ester (NCX 4016), in order to identify any effects due to the release of nitric oxide and the blockade of cyclo-oxygenase. The effects of scalar doses of NCX 4016 on the early phase of platelet activation, platelet aggregation and thromboxane A2 production were investigated. We observed inhibitory effects of NCX 4016 on platelet adhesion (IC50 = 7.3 x 10(-5) M), platelet cytosolic calcium concentration, assayed by fluorescent probe Fura 2, and the expression of glycoprotein IIb/IIIa (CD41/alpha IIb beta 3) (IC50 = 3.4 x 10(-5) M) and P-selectin (CD62/GMP-140) (IC50 = 4.9 x 10(-5) M) measured by flow cytometry. NCX 4016 also prevented thrombin-induced platelet aggregation (IC50 = 3.9 x 10(-5) M). None of these parameters were affected by acetylsalicylic acid. These inhibitory activities of NCX 4016 were abolished by oxyhaemog...
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Variations in intracellular free calcium were measured in platelets from normal donors, incubated with plasma from hypertensive patients and from control subjects to test the hypothesis that a circulating factor might induce an increase... more
Variations in intracellular free calcium were measured in platelets from normal donors, incubated with plasma from hypertensive patients and from control subjects to test the hypothesis that a circulating factor might induce an increase in calcium concentration. Before incubation, plasma was heat-inactivated or ultrafiltered. Incubation both with heat-inactivated and ultrafiltered plasma failed to result in any significant modifications in intracellular free calcium. Similarly, no significant increase was observed after incubation with ouabain at concentrations ranging from 10(-7) to 10(-4) M. No significant differences were observed between platelets incubated with plasma from hypertensive as compared with control subjects. These findings are not consistent with the hypothesis that the increase in intracellular free calcium observed in platelets of hypertensive patients may be due to a plasma ouabain-like factor.
Research Interests: Calcium, Humans, Hypertension, Female, Male, and 4 moreClinical Sciences, Middle Aged, Adult, and Ouabain
Outward bumetanide-sensitive Na+-K+ cotransport was studied in the erythrocytes of 51 subjects, 24 normotensive subjects and 27 hypertensive patients, matched for sex and age. Three kinetic parameters of this cation transport system were... more
Outward bumetanide-sensitive Na+-K+ cotransport was studied in the erythrocytes of 51 subjects, 24 normotensive subjects and 27 hypertensive patients, matched for sex and age. Three kinetic parameters of this cation transport system were considered: velocity of efflux at saturating internal sodium (Nai) concentrations (Vmax.), apparent affinity for sodium (K 50%) and index of co-operativity among Nai sites (Hill's n). We correlated these values with clinical and laboratory data determined routinely in hypertension. There were no significant differences between normotensive and hypertensive subjects for the values considered and we did not find any significant correlations between co-transport and clinical data.
Research Interests: Kinetics, Adolescent, Humans, Hypertension, Diuretics, and 7 moreFemale, Male, Potassium, Middle Aged, Adult, Sodium, and Erythrocytes
We measured free intralymphocyte magnesium (Mgi) in 10 hypertensive subjects (HS) before and after treatment with atenolol (A) and in 16 normotensive control subjects (NC). We also carried out in vitro studies on human lymphocytes to test... more
We measured free intralymphocyte magnesium (Mgi) in 10 hypertensive subjects (HS) before and after treatment with atenolol (A) and in 16 normotensive control subjects (NC). We also carried out in vitro studies on human lymphocytes to test the effect of catecholamines and beta-antagonists on Mgi. Mgi in HS was not statistically different before and after the treatment with A (M +/- SD, basal: 227 +/- 31 + mumol/l; A: 236 +/- 47 mumol/l; NS). Mgi in NC proved not statistically different as compared to HS without treatment (M +/- SD, NC: 232 +/- 35 mumol/l; HS before treatment: 227 +/- 31 mumol/l; NS). The Mgi of the lymphocytes treated in vitro with noradrenaline (NA) significantly decreased in comparison with the control (M +/- SD, basal: 244 +/- 26 mumol/l; NA: 198 +/- 25 mumol/l; p = 0.0001), whereas it did not change after incubation with NA and propranolol (P) (M +/- SD, basal: 238 +/- 32 mumol/l; NA + P: 239 +/- 30 mumol/l; NS). On the other hand Mgi decreased significantly afte...
Research Interests: Calcium, Humans, Magnesium, Hypertension, Female, and 6 moreMale, Norepinephrine, Adult, Propranolol, Lymphocytes, and Atenolol
Intracellular platelet pH was studied by the BCECF fluorescent pH-sensitive intracellular indicator method in 52 patients with essential hypertension and 42 control subjects of similar age and sex. In 40 hypertensive patients studied by... more
Intracellular platelet pH was studied by the BCECF fluorescent pH-sensitive intracellular indicator method in 52 patients with essential hypertension and 42 control subjects of similar age and sex. In 40 hypertensive patients studied by oral glucose tolerance test (standard OGTT) 23 presented with pathological blood glucose and plasma insulin values. Intracellular pH was on average higher in hypertensives (7.415 +/- 0.114, mean +/- SD) than in controls (7.348 +/- 0.109, P < 0.05), although there was a considerable overlap in values. In the group of hypertensive patients, no difference was observed between those with normal and those with pathological OGTT. There was also no significant correlation between intracellular pH and blood glucose, plasma insulin after OGTT, plasma cholesterol and triglycerides, age, BP or body mass index. These data are consistent with an anomaly of intraplatelet pH, perhaps owing to alteration of Na+/H+ exchange in essential hypertension, but do not in...
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Enhanced Na+/H+ exchange has been reported to be increased in patients with essential hypertension. However, early variations of intracellular pH, although influenced by the antiport, are only partially dependent on the exchange. In this... more
Enhanced Na+/H+ exchange has been reported to be increased in patients with essential hypertension. However, early variations of intracellular pH, although influenced by the antiport, are only partially dependent on the exchange. In this study, we measured the initial platelet pH response to agonists in a group of untreated subjects with essential hypertension (EH, n = 24) and in a group of age- and sex-matched normotensive control subjects (CS, n = 24). Intracellular pH was measured with the specific fluorescence indicator 2'7'bis(carboxyethyl)-5,6-carboxyfluorescein. Measurements were performed on platelets in the presence or absence of extracellular calcium, in a carbonate-free medium. Intracellular calcium was measured by the Fura 2 method. Mean pH values were slightly higher in the platelets of EH (7.469 +/- 0.017 U) compared with CS (7.423 +/- 0.012 U, P < .05), although there was a substantial overlap. When stimulated with physiologic agonists ADP and thrombin and ...
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Our group have described a group of patients with primary aldosteronism which is characterized by significantly decreased intralymphocyte ionized magnesium concentration. Some models of experimental hyperaldosteronism are characterized by... more
Our group have described a group of patients with primary aldosteronism which is characterized by significantly decreased intralymphocyte ionized magnesium concentration. Some models of experimental hyperaldosteronism are characterized by cardiovascular fibrosis but despite this fact the link between a negative magnesium balance and fibrosis is lacking. Consequently, to shed some light on the relationships between magnesium and tissue fibrosis we tested the in vitro effects of incubating human fibroblasts in low magnesium medium on mRNA collagen I and III gene expression by northern blot analysis. Both collagen I and III mRNA gene expression were increased by magnesium deprivation. The increase in collagen expression was similar for both collagen I and III. These data are in favour of a potential link between magnesium homeostasis and collagen synthesis. A physiopathologic mechanism linking magnesium homeostasis to the state of collagen turnover may have important clinical correlate...
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NCX4016 (2 acetoxy-benzoate 2-(2-nitroxymethyl)-phenyl ester, NicOx S.A., France) is an antithrombotic agent chemically related to acetylsalicylic acid (ASA). We hypothesised that NCX4016, being able to release nitric oxide (NO) and to... more
NCX4016 (2 acetoxy-benzoate 2-(2-nitroxymethyl)-phenyl ester, NicOx S.A., France) is an antithrombotic agent chemically related to acetylsalicylic acid (ASA). We hypothesised that NCX4016, being able to release nitric oxide (NO) and to inhibit cyclo-oxygenase, might inhibit the prothrombotic function in human monocytes. The effects of NCX4016 and ASA on the release of thromboxane (TX) B2 and tissue factor expression and activity were compared using adherent human monocytes. The tested drugs were added before stimulation with 10 Kg/ml LPS and incubation lasted 6 hours. TXB2 concentration was measured by RIA in the supernatant of cultured cells. Immunoreactive tissue factor (TF) concentration was determined by enzyme-linked immunoassay and TF activity was assayed by measuring the peptidyl activity of the tissue factor/ factor VII complex. Both ASA and NCX4016 10-300 Kmol/L dose-dependently reduced TXB2 release. NCX4016 activity was comparable to that of equimolar ASA. Part of the acti...
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ABSTRACT Am J Hypertens (2000) 13, 157A–157A; doi:10.1016/S0895-7061(00)00652-X C004: In vitro effects of cathecolamines on intracellular free magnesium in human lymphocytes P. Delva1, C. Pastori1, M. Degan1, G. Covi1 and A. Lechi11Dept... more
ABSTRACT Am J Hypertens (2000) 13, 157A–157A; doi:10.1016/S0895-7061(00)00652-X C004: In vitro effects of cathecolamines on intracellular free magnesium in human lymphocytes P. Delva1, C. Pastori1, M. Degan1, G. Covi1 and A. Lechi11Dept Biomedic and Surgical Sciences, University of Verona, Verona, Italy
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Despite the fact that numerous studies have been published regarding the possible presence in plasma of an endogenous Na-K pump inhibitor with a digitalis-like structure in essential hypertension, very little is known about this factor in... more
Despite the fact that numerous studies have been published regarding the possible presence in plasma of an endogenous Na-K pump inhibitor with a digitalis-like structure in essential hypertension, very little is known about this factor in heart disease in general, and in situations characterized by low cardiac output. We measured the ability of plasma obtained from the femoral vein to inhibit a human renal Na(+)-K+ ATPase before and immediately after percutaneous transluminal coronary angioplasty (PTCA) in 6 patients suffering from angina pectoris and severe coronary stenosis. Intraerythrocyte sodium and potassium concentrations were also measured simultaneously. Na(+)-K+ ATPase inhibition proved significantly greater after angioplasty as compared to basal activity (percentage inhibition: 31.5 +/- 7.8 vs 16.1 +/- 12.2). No significant changes in intraerythrocyte sodium and potassium were detected. Though we are not in a position to define the mechanism underlying the increase in the digitalis-like factor, a plausible hypothesis may be that the reduction in cardiac output during PTCA by raising cardiac pressures may stimulate the production of a factor of compensatory inotropic significance.
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Platelet function and levels of vascular adhesion molecule-1 (VCAM-1) were investigated in 24 patients with peripheral arterial disease at Fontaine stage II undergoing a 2 weeks treatment with iloprost (0.5-2 ng/kg/h i.v. infused, 6... more
Platelet function and levels of vascular adhesion molecule-1 (VCAM-1) were investigated in 24 patients with peripheral arterial disease at Fontaine stage II undergoing a 2 weeks treatment with iloprost (0.5-2 ng/kg/h i.v. infused, 6 h/day) or a 2 weeks supervised physical training, randomly assigned. Patients were studied before (T0) and after (T14) treatments and 10 days later (T24). The adhesion of washed platelets to fibrinogen coated microwells was reduced after treatment both with iloprost (1.9+/-0.4 vs 6.8+/-0.7%; T24 vs T0; M+/-SEM; p&amp;amp;amp;amp;lt;0.05) and physical exercise (3.0+/-1.0 vs 6.7+/-0.7; p&amp;amp;amp;amp;lt;0.05) while adhesion to human plasma coated microwells was reduced only after treatment with iloprost (1.9+/-0.8 vs 5.8+/-0.9; p&amp;amp;amp;amp;lt;0.05). The expression of fibrinogen receptor (glycoprotein IIb/IIIa) on platelets, measured by flow-cytometry was also reduced after iloprost treatment (17.1+/-1.5 vs 31.8+/-4.8 AU; p&amp;amp;amp;amp;lt;0.05) and physical exercise (14.6+/-1.5 vs 34.0+/-3.3; p&amp;amp;amp;amp;lt;0.05). Theurinaryexcretion of platelet thromboxane A2 metabolite 2,3-dinor-thromboxane B2 decreased only in patients treated with iloprost (154.7+/-97.9 vs 256.2+/-106.4 pg mg creatinine(-1); p&amp;amp;amp;amp;lt;0.05). Similarly plasma VCAM-1 was lower in patients who were treated with iloprost (827.7+/-77.4 vs 999.0+/-83.8 ng ml(-1); p&amp;amp;amp;amp;lt;0.05). In conclusion, both iloprost and physical exercise seem to act on reversible phenomena such as the expression of adhesion molecules or ex vivo adhesion, whereas only iloprost reduces thromboxane A2 biosynthesis in vivo. This anti-platelet activity seems to be extended in time and to be associated with an improvement in vascular function.
Research Interests: Flow Cytometry, Life Sciences, Treatment Outcome, Fibrinogen, Humans, and 16 moreBlood Glucose, Blood Pressure, Cholesterol, Male, P-glycoprotein, Exercise, Vascular endothelium, Platelet activation mechanism, Platelet function, Triglycerides, Aged, Middle Aged, Physical Exercise, Physical Training, Biochemistry and cell biology, and Peripheral artery disease
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Despite the importance of the adrenergic activity and of the metabolism of magnesium in some important cardiovascular pathologies, very little is known about how intracellular ionized magnesium (Mgi2+) is regulated by catecholamines. We... more
Despite the importance of the adrenergic activity and of the metabolism of magnesium in some important cardiovascular pathologies, very little is known about how intracellular ionized magnesium (Mgi2+) is regulated by catecholamines. We made an in-vitro study of the variations in the concentration of ionized magnesium in human lymphocytes using the fluorescent probe furaptra in response to different catecholamines. We also made an ex-vivo study of the changes in intracellular ionized magnesium in lymphocytes in 20 subjects with essential arterial hypertension, 10 treated with 120 mg/d of propranolol and 10 with placebo. Norepinephrine and isoproterenol significantly decrease Mgi2+ and this effect is blocked by beta-blockers but not by alpha-blockers. The EC50 of the effect of norepinephrine is within the range of concentrations physiologically present in plasma. The substitution of extracellular sodium with choline blocks the decrease in intracellular ionized magnesium induced by norepinephrine, which leads us to suppose that the magnesium-reducing effect of catecholamines is a result of the activation of a Na+-Mg2+ exchanger. We were not able to demonstrate any change in intracellular ionized magnesium after 1 and 17 days of active treatment in essential hypertensives. The impossibility of demonstrating ex vivo the mechanism of catecholamine-mediated regulation that is evident in vitro is perhaps due to our experimental conditions or to substances which in vivo inhibit the action of the catecholamines on magnesium, such as insulin and/or glucose.
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Cardiovascular disease is the major cause of mortality in patients with rheumatoid arthritis. This work studied the presence of impaired forearm haemodynamics, arterial stiffness and microcirculatory reactivity in young women with... more
Cardiovascular disease is the major cause of mortality in patients with rheumatoid arthritis. This work studied the presence of impaired forearm haemodynamics, arterial stiffness and microcirculatory reactivity in young women with rheumatoid arthritis. Sixty-five women aged 41-52 years, with rheumatoid arthritis, were screened for the absence of common cardiovascular risk factors. They underwent laser Doppler study on the hand at rest and after ischaemia, endothelium-dependent dilation with colour Doppler ultrasound and pulsewave velocity (PWV). Forty healthy subjects were also examined. Microcirculatory flux at rest with laser Doppler was reduced in rheumatoid arthritis patients (112 +/- 45 versus 220 +/- 65 perfusion units (PU, arbitrary units); P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.005), post-ischaemic peak flow was lower in rheumatoid arthritis patients (235 +/- 65 versus 329 +/- 76 PU; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05); percentage increase in peak flow was higher in rheumatoid arthritis patients compared with healthy subjects (153 +/- 12 versus 65 +/- 18%; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.005). Time to peak flow was longer in rheumatoid arthritis patients (12.7 +/- 8 versus 6.2 +/- 2 s; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.005). Higher microcirculatory resistance was detected in rheumatoid arthritis patients (0.656 +/- 0.011 versus 0.358 +/- 0.009 mmHg/PU; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). Endothelium-dependent dilation was impaired in rheumatoid arthritis patients (increase in artery dilation 8.2 +/- 2 versus 11.5 +/- 3%; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05) and correlated directly with actual C-reactive protein. PWV was higher in rheumatoid arthritis patients (9.3 +/- 0.2 versus 8.4 +/- 0.4 m/s; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05) and correlated directly with the duration of disease. District resistance by the arm was higher in rheumatoid arthritis patients (1098 +/- 190 versus 661 +/- 55 mmHg/l per minute; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.005). Female rheumatoid arthritis patients present with impaired microcirculatory reactivity, endothelial dysfunction and increased arterial stiffness. Alterations in the vascular bed are extended and may explain the increased incidence of cardiovascular events in these patients.
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Several authors have described increased Na(+)-H+ exchanger activity in essential hypertension, and an increase in activity of this transport system has also been postulated in situations of hyperinsulinism, such as obesity and essential... more
Several authors have described increased Na(+)-H+ exchanger activity in essential hypertension, and an increase in activity of this transport system has also been postulated in situations of hyperinsulinism, such as obesity and essential hypertension. We measured Na(+)-H+ exchanger activity in a group of 37 subjects with essential hypertension (18 obese, 19 non-obese), in a group of nine normotensive obese subjects and in a control group of 16 healthy volunteers. Plasma insulin and glucose values during an oral glucose tolerance test were evaluated, together with other variables such as plasma aldosterone, plasma renin activity and plasma potassium. Na(+)-H+ exchanger system activity did not appear to be abnormally raised in the hypertensive subjects, but was significantly increased in the normotensive obese group. Upon dividing the hypertensive subjects into two subgroups on the basis of body mass index, it was noted that, whereas the non-obese hypertensives showed Na(+)-H+ exchanger activity patterns similar to those in controls, the obese hypertensive subjects exhibited increased activity of the transport system. Na(+)-H+ activity correlates with body mass index and shows a significant inverse correlation with plasma potassium. No correlations were found between Na(+)-H+ exchanger activity and the sum of plasma insulin values during the oral glucose tolerance test. Na(+)-H+ exchanger overactivity appears to be characteristic in overweight subjects, but would not appear to be a specific feature of essential hypertension. The increased Na(+)-H+ exchanger activity observed in obese subjects may be postulated to be related to the hypermineralocorticoidism characteristic of this condition.
Research Interests: Obesity, Humans, Hypertension, Female, Male, and 5 moreClinical Sciences, Middle Aged, Adult, Body Weight, and Erythrocytes
Research Interests: Aging, Life Sciences, Calcium, Insulin Resistance, Humans, and 19 moreMagnesium, Blood Glucose, Hypertension, Insulin, Blood Pressure, Cholesterol, Female, Male, Regression Analysis, Statistical Significance, Body Mass Index, Triglycerides, Clinical Sciences, Adult, Multivariate Regression, Lymphocytes, Fasting Insulin, Confidence Limit, and Biochemistry and cell biology
To define the changes in variability of heart rate and of blood pressure during vasodilation in a group of hypertensive patients treated with an angiotensin II type I (AT1) receptor inhibitor. Losartan (50 mg/day at 0800 h) or placebo... more
To define the changes in variability of heart rate and of blood pressure during vasodilation in a group of hypertensive patients treated with an angiotensin II type I (AT1) receptor inhibitor. Losartan (50 mg/day at 0800 h) or placebo were administered for 3 weeks according to a single blind, crossover, randomized protocol, to 18 hypertensive patients (16 men and two women, mean age 42 + 3.6 years). Continuous ECG recording and beat-to-beat blood pressure monitoring were carried out with subjects in the supine position and during a head-up tilt test, as well as after sublingual administration of trinitroglycerine. The elaboration of ECG traces in the frequency domain, was carried out using an autoregressive method and measured using the autoregressive moving average technique. Orthostatic stimulus, both during treatment with losartan and with placebo, caused a significant decrease in the heart rate high frequency power; on the other hand, the low frequency power appeared unchanged after placebo and was significantly reduced with losartan. Five minutes after the administration of trinitroglycerine, the low frequency power with placebo showed a significant increase (817 -+ 221 versus 465 + 101 ms2, P &lt; 0.03). No change was recorded in total power nor in low frequency or high frequency power during losartan therapy. The ratio of low frequency to high frequency powers showed a sympathetic prevalence during vasodilation only during placebo treatment, whereas a mainly unchanged balance was maintained during losartan treatment Blood pressure variability showed a sympathetic prevalence after upright and trinitroglycerine stimulation only in placebo-treated subjects. Our study demonstrated that vasodilation is not able to evoke an unbalancing of the autonomic modulation in hypertensive patients treated with an AT1 receptor inhibitor, but permits the maintenance of a significant vagal component, thus highlighting the favorable profile of this drug in the autonomic control of circulation.
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Despite the claimed disregulation of extracellular matrix synthesis and the increased proliferation rate of different cell types in experimental models of hypertension, very few data are available on collagen synthesis and the... more
Despite the claimed disregulation of extracellular matrix synthesis and the increased proliferation rate of different cell types in experimental models of hypertension, very few data are available on collagen synthesis and the proliferation rate of fibroblasts in essential hypertensive patients. We measured collagen I, collagen III, histone H3 mRNA gene expression, collagen protein concentration and thymidine incorporation in fibroblasts from 17 essential hypertensive patients (EH) and 13 healthy normotensive control subjects (NC). A Northern blot analysis was performed on fibroblasts in culture obtained from skin biopsies. Collagen protein concentration and DNA synthesis were measured by means of incorporation of tritiated proline and tritiated thymidine, respectively. In cultivated fibroblasts from hypertensives, the expression of collagen III mRNA after addition of fetal calf serum was significantly increased in comparison with that of normotensive-derived cells. After addition of fetal calf serum, collagen protein was statistically increased in cultures from EH patients as compared to NC. In hypertensives, the expression of histone H3 mRNA as well as tritiated thymidine incorporation were both increased as compared to normotensives. Our data suggest that cultivated fibroblasts from essential hypertensive patients are characterized by an increased expression of type III collagen mRNA and collagen protein synthesis in response to fetal serum, as compared to normotensive-derived cells. Cells from hypertensives are characterized by an increased rate of proliferation after addition of fetal serum, as ascertained by increased thymidine incorporation and increased histone H3 mRNA gene expression, as compared to normotensive-derived cells. This phenotype could be genetically determined and may have an important role in the pathogenesis of essential hypertension.
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As suggested by findings of abnormal responses to posture in patients with normal-tension glaucoma (NTG), cardiovascular autoregulation may also be defective in primary open-angle glaucoma (POAG). Both 24-hour ambulatory blood pressure... more
As suggested by findings of abnormal responses to posture in patients with normal-tension glaucoma (NTG), cardiovascular autoregulation may also be defective in primary open-angle glaucoma (POAG). Both 24-hour ambulatory blood pressure monitoring and the head-up tilt test were performed in 17 subjects with NTG and in 13 subjects with high-tension POAG (ht-POAG). These groups were compared with 17 age-matched healthy individuals. Subjects undergoing cardiovascular therapy were excluded. No significant differences in diurnal and nocturnal blood pressure and heart rate were found between the groups. A significant reduction in diurnal heart rate variability was found in NTG (12.1 +/- 2.8 bpm) compared with the ht-POAG (15.0 +/- 2.4 bpm, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01) and control groups (15.8 +/- 3.0 bpm, P = 0.01]). Nocturnal diastolic blood pressure variability was also reduced in NTG (6.9 +/- 2.2 mm Hg) compared with controls (8.6 +/- 2.3 mm Hg, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05]) as was heart rate variability (6.3 +/- 1.4 vs 8.3 +/- 2.6 in ht-POAG, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05), suggesting blunted blood pressure and heart rate modulation in NTG subjects. Spectral analysis of short-term heart rate variability showed a significant reduction of total power in the supine position (1064 +/- 600 in NTG vs 1688 +/- 889 ms2 in controls, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05]). This was not accompanied either by a physiological reduction in total power or in a high-frequency component during the passive orthostatic stimulus. These differences tend to become more prominent in the clinically more severe forms of NTG (as identified by scores based on the extent of optic disk excavation, visual field damage, and progression of disease). This would suggest a correlation between the extent of autonomic disorder and severity of glaucoma. The alpha index (root-square of low-frequency heart rate to low-frequency blood pressure ratio) was lower in the supine position in NTG subjects (8.1 +/- 3.1 vs 10.6 +/- 3.3 ms/mm Hg in controls, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05), confirming the reduced baroreflex sensitivity. The results confirm the hypothesis that dysfunction of autonomic control of the cardiovascular response may be a contributing pathogenetic factor in NTG, inducing a chronic ischemia of the optic nerve.
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Erythrocyte sodium-lithium countertransport was evaluated in three adult patients with Bartter&#39;s syndrome, diagnosed on clinical and histopathological basis and on laboratory tests. As compared with age-matched control subjects,... more
Erythrocyte sodium-lithium countertransport was evaluated in three adult patients with Bartter&#39;s syndrome, diagnosed on clinical and histopathological basis and on laboratory tests. As compared with age-matched control subjects, lithium effluxes to both sodium medium and to sodium-free medium were high in two patients and Na+-Li+ countertransport was significantly greater in all three patients. The relationship between increased Na+-Li+ countertransport and the proposed primary disorder of Bartter&#39;s syndrome (i.e., a primary tubular defect of chloride reabsorption) is not apparent. However, this finding favours the hypothesis of a generalized cellular membrane dysfunction of ion transport in Bartter&#39;s syndrome.
Research Interests: Lithium, Humans, Female, Male, Clinical Sciences, and 4 moreAdult, Sodium, Erythrocytes, and Hyperaldosteronism
ABSTRACT Urinary excretion of 6-keto-PGF1 alpha and 2,3 dinor-6-keto-PGF1 alpha, as indices of the renal and systemic production of prostaglandins, was measured during water immersion in a group of 6 healthy volunteers both in the... more
ABSTRACT Urinary excretion of 6-keto-PGF1 alpha and 2,3 dinor-6-keto-PGF1 alpha, as indices of the renal and systemic production of prostaglandins, was measured during water immersion in a group of 6 healthy volunteers both in the presence and absence of dopamine blockade by the dopamine receptor antagonist, metoclopramide. Urinary flow rate and excretion of both sodium and 6-keto-PGF1 alpha increased during water immersion, while plasma renin activity and plasma aldosterone were reduced. Urinary kallikrein and 2,3 dinor-6-keto-PGF1 alpha also tended to increase during water immersion. Administration of metoclopramide significantly reduced 6-keto-PGF1 alpha and sodium excretion during water immersion, but produced no changes in plasma renin activity or in 2,3 dinor-6-keto-PGF1 alpha. Plasma aldosterone concentrations after metoclopramide were similar to those observed in the pre-immersion period. An increased synthesis of the vasodilator and natriuretic prostacyclin in the kidney might play a role in the response to water immersion. The reduced sodium and 6-keto-PGF1 alpha excretion observed after metoclopramide administration suggests that dopamine might induce prostacyclin synthesis in the kidney during water immersion.
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Research Interests:
ABSTRACT Objective: The aim of this prospective study was to establish whether or not there is any relationship between activation of the prostaglandin system and changes in systemic and uteroplacental hemodynamics in pregnancy. Methods:... more
ABSTRACT Objective: The aim of this prospective study was to establish whether or not there is any relationship between activation of the prostaglandin system and changes in systemic and uteroplacental hemodynamics in pregnancy. Methods: Urinary excretion of prostaglandin E2 (PGE2) and the main metabolites of prostacyclin (PGI2) and thromboxane A2 (TXA2) was determined, and indices of the vascular resistance of the uteroplacental bed were measured in 10 normotensive women studied in each trimester of pregnancy and in 15 women with pregnancy-induced hypertension in the third trimester. None of these subjects presented renal insufficiency or coagulation disorders, and all were monitored up to delivery to assess the outcome of pregnancy. Urinary excretion of prostanoids was measured by radioimmunoassay after purification of samples with high-pressure liquid chromatography. Blood pressure was measured and vascular resistance indices were calculated, using ultrasonography to measure the amplitude of systolic and diastolic blood flow at the arcuate artery level. Results: Inverse correlations were observed between increased systemic PGI2 synthesis and reductions in blood pressure and uteroplacental vascular resistance in normotensive pregnancy. Positive correlations were found between increased uteroplacental vascular resistance, increased blood pressure, and indices related to the outcome of pregnancy; but no relationship with reduced PGI2 synthesis was detected in women with pregnancy-induced hypertension. Conclusions: We conclude that PGI2 appears to play a role in the regulation of systemic and uteroplacental hemodynamics, particularly in the course of normal pregnancy, and seems to be related to the development of pregnancy-induced hypertension. No evidence emerged to suggest that TXA2 plays a role in inducing hemodynamic changes in either normotensive or hypertensive pregnancy.
ABSTRACT Urinary excretion of calcium, sodium, creatinine, proteins and renal prostaglandins (PGE2, 6kPGF1α) and serum levels of calcium, sodium, creatinine and albumin were determined in 10 normotensive pregnant women throughout... more
ABSTRACT Urinary excretion of calcium, sodium, creatinine, proteins and renal prostaglandins (PGE2, 6kPGF1α) and serum levels of calcium, sodium, creatinine and albumin were determined in 10 normotensive pregnant women throughout pregnancy and in 30 normotensive pregnant women (NTP) and 30 women with pregnancy-induced hypertension or preeclampsia (HTP) and intact kidney function in the third trimester in comparison with 13 nonpregnant control subjects (C). Urinary excretion of calcium was found to be significantly reduced in the HTP group and was correlated with PGE2 excretion (p &lt; 0.01). A weak correlation was detectable in the NTP group, which, however, as in the HTP and C groups, showed a close correlation between urinary calcium and sodium values (p &lt; 0.05). In the NTP group, there was a significant increase in calcium excretion, which might reasonably be regarded as related to increased renal PG activity.