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Biomedical subjects

P Minuz

Publications and source records attributed to P Minuz.

At least 37 records · Page 2Linked to original sources
PubMed1995

Antiaggregating and vasodilatory effects of a new nitroderivative of acetylsalicylic acid.

We studied in vitro the effects on platelet aggregation and vascular tone of a new nitrocompound (nitroxy-butyl-acetylsalicylate: NO-ASA). In order to elucidate any possible activity due to the release of nitric oxide or the inhibition of platelet cyclo-oxygenase we compared NO-ASA to acetylsalicylic acid. NO-ASA 1 mM inhibited arachidonic acid-induced platelet aggregation (basal 75.4 +/- 2.35%; NO-ASA 22 +/- 3.46%; M +/- SEM; P < 0.001; n = 6), but proved less active than acetylsalicylic acid (complete inhibition at 2 x 10(-5) M). NO-ASA also significantly reduced thrombin-induced (0.04-0.08 U/ml) platelet aggregation in acetylsalicylic acid-treated platelets (basal 70.5 +/- 1.7%; NO-ASA 35.4 +/- 2.2%; P < 0.001; n = 10; IC50 7 x 10(-5) M). Methylene blue reduced the effects of NO-ASA on thrombin-induced (NO-ASA 46.7 +/- 5.25%; NO-ASA+MB 59.1 +/- 4.3%; P < 0.01; n = 8), but not arachidonic acid-induced platelet aggregation. The inhibitory effects of NO-ASA on platelet aggregation were partially removed by oxyhaemoglobin. Platelet thromboxane A2 production (TXB2 concentration in the supernatant of the aggregate 35.38 +/- 7.81 ng/ml; n = 8), was totally abolished by acetylsalicylic acid (0.17 +/- 0.04 ng/ml; P < 0.001; n = 8) and reduced by NO-ASA (8.3 +/- 4.05 ng/ml; P < 0.01; n = 8). In vitro studies on isolated rat aortic rings showed NO-ASA 10(-3) M, but not ASA up to 10(-3) M, induce a dose dependent vasorelaxation (100% of epinephrine-induced contraction) both in intact and endothelium denuded arteries (IC50 5 x 10(-5) M). Addition of methylene blue reversed this relaxation. In conclusion these data demonstrate that NO-ASA acts through a double mechanism: a) by inhibiting cyclo-oxygenase and b) by releasing NO active on guanylyn cyclase both in platelets and in vascular smooth muscle cells.

Adult↗
PubMed1995

Amlodipine and haemodynamic effects of cyclo-oxygenase inhibition.

1. The haemodynamic effects of calcium antagonists could depend at least in part on the activity of vasoactive prostanoids. 2. We set out to study the effect of the cyclo-oxygenase inhibitor ibuprofen, 400 mg three times daily for 3 days, by a randomised cross-over study vs placebo in 12 mild to moderate essential hypertensive patients who had been treated for 1 month with amlodipine. 3. Blood pressure, heart rate and vascular resistances in the upper limb (Doppler ultrasound) were measured. Plasma renin activity and urinary aldosterone, as well as indices of renal function, were evaluated. Urinary 2,3-dinor-6-keto-PGF1 alpha and 2,3-dinor-TXB2, as well as 6-keto-PGF1 alpha and TXB2, were measured as indices of systemic and renal PGI2 and TXA2 synthesis. 4. Amlodipine normalised blood pressure and reduced upper limb vascular resistances; it did not affect urinary prostanoid excretion. Short-term combined administration of ibuprofen resulted in, by comparison with placebo, inhibition of systemic PGI2 (-80.5 ng 24 h-1, 95% CI -99.2, -61.4; P < 0.001) and TXA2 (-216.1 ng 24 h-1, 95% CI -276.5, -155.8; P < 0.001), together with an increase in systolic (+7.8 mm Hg, 95% CI +3.1, +12.3; P < 0.01) and diastolic (+3.9 mm Hg, 95% CI +1.2, +6.6; P < 0.01) blood pressure; it had no significant effect on regional vascular resistances (+4.7 mm Hg ml-1 s, 95% CI -5.6, +15.0). Effects of ibuprofen on renal prostanoid synthesis were less marked, and there was no change in indices of renal function or hydro-electrolytic balance.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1995

Oxidized LDL and reduction of the antiaggregating activity of nitric oxide derived from endothelial cells.

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% +/- 12.6, M +/- SD). This antiaggregating activity was reduced when slightly oxidized LDL 100 micrograms/ml (35.2% +/- 14.9, p < 0.001), but not native LDL 100 micrograms/ml (7.5% +/- 7.6), was added immediately before aggregation was induced. Incubation of endothelial cells with oxidized LDL 100 micrograms/ml for 1 h did not affect the antiaggregating capacity, unless oxidized LDL was present during aggregation (18.3% +/- 10.2 vs 35.8% +/- 9.6, p < 0.02). No significant direct effect of either oxidized or native LDL on stimulated platelet aggregation was observed. Our results indicate that slightly oxidized LDL can reduce the antiaggregating properties of the endothelium, probably by interaction with NO rather than through inhibition of its synthesis.

Aspirin↗
PubMed1993

Effects of imidazole-salicylate on renal function and the diuretic action of furosemide in cirrhotic patients with ascites.

Imidazole-salicylate is a non-steroidal anti-inflammatory drug with limited inhibitory effects on prostaglandin synthesis. The renal effects of this drug were investigated by a double-blind cross-over study in 10 patients with cirrhosis and ascites. Two therapeutic doses of imidazole-salicylate (750 mg each) were given at midnight and 08:00 h and 80 mg of furosemide were injected intravenously at 09:00 h. The same procedure was followed on another day but a placebo replaced imidazole-salicylate. Renal function (creatinine clearance, free water and electrolyte excretions) and urinary excretion of prostaglandin E, 6-keto-prostaglandin F1 alpha and thromboxane B2 were evaluated for 8 h after the first dose of the drug and for 2 h after furosemide injection. Platelet thromboxane production was also determined 9 h after the first administration of drug or placebo. Imidazole-salicylate did not affect renal function or inhibit kidney prostanoid production either under basal conditions or after the stimulating effect of furosemide. On the contrary, imidazole-salicylate significantly inhibited platelet thromboxane production (45.8 +/- 9 vs. 69.4 +/- 7.5 ng/ml, P < 0.05). These results suggest that imidazole-salicylate is an anti-inflammatory drug that can be given to patients with decompensated cirrhosis without risk of inhibiting kidney prostaglandin synthesis or the renal response to furosemide.

Adult↗
PubMed1991

Effect of picotamide on platelet aggregation and on thromboxane A2 production in vivo.

Effects of picotamide (900 mg in 3 oral administrations for 7 days) on ex vivo and in vivo platelet TxA2 production and on platelet aggregation were evaluated in 8 patients with peripheral arteriopathy and in 8 normal subjects. Picotamide significantly reduced ADP-induced platelet aggregation, but had no effect on that induced by arachidonic acid or the thromboxane analogue U46619. Though ex vivo platelet TxA2 production (TxB2 concentration after arachidonic-acid-induced aggregation) was reduced from 946 +/- 141 (mean +/- SD) to 285 +/- 91 ng/ml in controls and from 1515 +/- 673 to 732 +/- 420 ng/ml in patients with arteriopathy, there was no effect on urinary excretion of 2,3-dinor-TXB2 (in vivo indicator of platelet TxA2 production), or on in vivo PGI2 production (urinary excretion of 6-keto-PGF1 alpha and 2,3-dinor-6-keto-PGF1 alpha). In the same subjects, single-dose aspirin reduced ex vivo TxB2 production by at least 98% and 2,3-dinor-TxB2 excretion from 116.7 +/- 61.4 to 32.6 +/- 17.0 ng/g creatinine in control subjects, and from 156.3 +/- 66.1 to 59.1 +/- 19.2 ng/g creatinine in patients with peripheral arteriopathy. Our data suggest that inhibition of platelet TxA2 production in vivo may not be picotamide's main mechanism of action.

Aged↗
PubMed1990

Selenium dependent glutathione peroxidase: a physiological regulatory system for platelet function.

In human platelets the selenoenzyme glutathione peroxidase (GSH-Px) acts as a scavenger of the peroxides generated during the burst of arachidonic acid (AA) metabolism. Such a mechanism inhibits the biosynthesis of both thromboxane A2 (TXA2) and lipoxygenase products. The same mechanism is not effective on the prostacyclin (PGI2) biosynthesis from cultured endothelial cells. In order to evaluate this effect in vivo, besides in vitro, we activated the enzyme in eight normal volunteers by increasing their daily Se intake for 8 weeks, monitoring: platelet GSH-Px activity, platelet aggregation induced by AA and U 44069, and concurrent malondialdehyde (MDA) and thromboxane B2 (TXB2) production, urinary excretion of renal and systemic TXA2 and PGI2 metabolites, platelet enzyme activities of the hexose monophosphate pathway and glutathione content, platelet adenine nucleotides, bleeding time, plasma Se concentration. We found: a) progressive platelet GSH-Px activation by Se paralleling an enhancement of platelet aggregation threshold values for AA, but not for U 44069; b) concurrent inhibition of platelet biosynthesis of TXA2 both in vitro and in vivo while the biosynthesis of systemic prostacyclin was unaffected; c) a progressive increase in the bleeding time, unmodified by aspirin. In conclusion, we believe that Se-dependent GSH-Px represents a physiological mechanism regulating the biosynthesis of prostanoids with implications in platelet function and that a Se dietary supplement might be considered in the prevention of arterial thrombosis.

Adult↗
PubMed1990

Sodium homeostasis and hormonal responses during dopaminergic blockade in normal humans.

Six normal subjects were submitted to 2 h water immersion (WI) with and without pharmacological dopaminergic (DA) blockade with metoclopramide (MCP). Urinary sodium excretion showed a marked increase during WI alone while it was blunted during WI plus DA blockade. Plasma aldosterone was significantly suppressed by WI alone but remained unchanged during WI plus MCP. Plasma atrial natriuretic factor showed similar augmentation during WI alone and during WI plus MCP. The reduced sodium and 6-keto-PGF1 alpha excretion, observed during WI plus MCP administration, suggests that dopamine might induce prostacyclin synthesis in the kidney during WI.

Adult↗
PubMed1990

Effects of non-steroidal anti-inflammatory drugs on prostacyclin and thromboxane biosynthesis in patients with mild essential hypertension.

1. The effects of non-steroidal anti-inflammatory drugs (NSAID) on prostacyclin and thromboxane biosynthesis and on blood pressure were determined in 46 patients with mild essential hypertension. Patients who had abstained from antihypertensive therapy for 2 weeks before study were treated with either aspirin, ibuprofen, sulindac or placebo for 7 days. 2. Excretion rates of 2,3-dinor-6-oxo-prostaglandin (PG) F1 alpha, 6-oxo-PGF1 alpha, 2,3-dinorthromboxane (TX) B2 and TXB2 were measured as indices of prostacyclin and TXA2 biosynthesis. Samples were assayed using immunoaffinity chromatography and gas chromatography/electron capture chemical ionisation mass spectrometry. 3. Aspirin and ibuprofen reduced urinary excretion of all prostacyclin- and thromboxane-derived products. Sulindac inhibited excretion of 2,3-dinor-6-oxo-PGF1 alpha, 6-oxo-PGF1 alpha and 2,3-dinor-TXB2, but had no significant effect on TXB2. 4. Systolic blood pressure increased in the ibuprofen-treated group when compared with the placebo group. There were no other significant changes in systolic or diastolic pressure in any of the treatment groups. Among the patients as a whole, there was a significant negative correlation between change in blood pressure and change in excretion of the prostacyclin-derived but not of the thromboxane-derived products. 5. We conclude that, in patients with mild essential hypertension, neither sulindac nor aspirin (in the doses used) selectively spares prostacyclin biosynthesis by the kidney. The significant relationship between increase in blood pressure and reduction in prostacyclin biosynthesis favours the possibility that in individuals who become hypertensive, prostacyclin biosynthesis determines, in part, the severity of the hypertensive state.

Adult↗
PubMed1990

Prostacyclin and thromboxane biosynthesis in mild essential hypertension.

The possibility that prostacyclin or thromboxane biosynthesis is abnormal in patients with established mild essential hypertension was investigated in 46 patients. These eicosanoids have opposing effects both on vascular smooth muscle and on platelets. An imbalance in their biosynthesis could therefore influence both vascular tone and predisposition to thrombosis. We studied the relation between blood pressure and the biosynthesis of prostacyclin and thromboxane A2 by measuring urinary excretion rates of stable breakdown products of prostacyclin (6-oxo-prostaglandin F1 alpha and 2,3-dinor-6-oxo-prostaglandin F1 alpha) and of thromboxane A2 (thromboxane B2 and 2,3-dinor-thromboxane B2) using immunoaffinity chromatography and gas chromatography/electron capture mass spectrometry. Excretion rates of both of the prostacyclin-derived products ranged from less than 5 to more than 100 ng/g creatinine; each was significantly negatively correlated with blood pressure (r = 0.36-0.45). A reduction of 2,3-dinor-6-oxo-prostaglandin F1 alpha excretion of 100 ng/g creatinine was associated with an increase in arterial pressure of 14 mm Hg (systolic) and 8 mm Hg (diastolic) in patients who had been without antihypertensive medication for 2 weeks. The same reduction in 6-oxo-prostaglandin F1 alpha excretion was associated with an increased pressure of 19 mm Hg (systolic) and 12 mm Hg (diastolic) (2p less than 0.05 for diastolic pressure and 2p less than 0.01 for systolic pressure in each case). There were similar correlations between the excretion rates of these products and blood pressure in the same patients while they were receiving antihypertensive therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Increased urinary 6-keto-PGF1 alpha excretion during water immersion is blunted by metoclopramide in normal man.

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.

6-Ketoprostaglandin F1 alpha↗
PubMed1989

Increased platelet aggregation and intracellular calcium in hypertensive patients: effects of cyclo-oxygenase blockade.

Increased platelet aggregation induced by ADP and arachidonic acid was observed in 12 patients with essential hypertension compared with 12 control subjects, but not after pretreatment with acetylsalicylic acid. The increase in intracellular calcium induced by ADP was also greater in the hypertensive patients, and again this difference disappeared after cyclo-oxygenase blockade. Urinary excretion of 2,3-dinor-thromboxane B2, the main metabolite of platelet thromboxane A2, was slightly, but not significantly increased in the hypertensive patients. These data suggest that thromboxane system activity is increased in the platelets of hypertensive patients.

Adenosine Diphosphate↗
PubMed1989

High plasma levels of a ouabain-like factor in normal pregnancy and in pre-eclampsia.

Recent reports have described high levels of one or more substances which cross-react with digoxin antibodies in the serum of women with pre-eclampsia. We measured plasma ouabain-like activity and intraerythrocyte sodium and potassium concentrations, in addition to performing routine hypertensive laboratory tests, in 13 normotensive non-pregnant subjects, 15 normotensive pregnant women and 16 pre-eclamptic women (gestational age: 33-36 weeks). Plasma ouabain-like activity, measured as plasma-induced variations in ouabain binding to human erythrocytes, proved significantly higher in both groups of pregnant subjects as compared to normotensive non-pregnant women, and a significant difference was also found between pre-eclamptic and normotensive pregnant women, the former exhibiting higher plasma ouabain-like activity. No differences in intracellular sodium and potassium levels were detected among the three groups studied. Though there is reason to believe that the high plasma levels found both in normal and hypertensive pregnancy may depend on placental production, we are not in a position to define with any degree of certainty what the mechanism or mechanisms are that regulate ouabain-like factor production.

Adult↗
PubMed1988

Altered excretion of prostaglandin and thromboxane metabolites in pregnancy-induced hypertension.

The renal and systemic metabolites (the latter as 2,3-dinor derivatives) of prostacyclin and thromboxane A2 were measured, along with renal prostaglandin E2 and kallikrein, in the urine of 15 patients with pregnancy-induced hypertension, 15 normotensive pregnant women matched for both age and gestational age, and 15 normotensive nonpregnant control women. Urinary excretion of all prostaglandin and thromboxane metabolites studied proved significantly higher in normotensive pregnant women than in controls. Prostaglandin E2, 6-keto-prostaglandin F1 alpha, and 2,3-dinor-6-keto-prostaglandin F1 alpha were significantly lower in pregnancy-induced hypertensive women than in normotensive pregnant women, whereas thromboxane B2 and 2,3-dinor-thromboxane B2 showed no significant differences in the two groups. A significant negative correlation (r = -0.636, p less than 0.01) was found between urinary 2,3-dinor-6-keto-prostaglandin F1 alpha and mean blood pressure in the two groups of pregnant women taken as a whole. These data indicate that, in pregnancy-induced hypertension, there is an imbalance between vasodilator and vasoconstrictor factors, not only in the kidneys, but also at the systemic vascular level. This imbalance, which may in itself produce vasoconstriction, may also potentiate the hypertensive effect of catecholamines and angiotensin II.

6-Ketoprostaglandin F1 alpha↗
PubMed1987

Reduced excretion of vasodilator prostaglandins in preeclampsia.

The role of prostaglandin (PG) system in preeclampsia (pre-E) was investigated. Urinary excretion of PGE2,6-keto PGF1 alpha,2,3 dinor 6-keto PGF1 alpha, TxB2 and 2,3-dinor-TxB2 and kallikrein were determined in 10 normotensive pregnant women and 14 with pre-E. 6-keto PGF1 alpha and 2,3-dinor 6-keto PGF1 alpha (the main renal and extrarenal metabolites of vasodilator PGI2) and PGE2 excretion was lower in pre-E. TxB2 metabolites in urine were similar in the two groups of women. Our data are consistent with the hypothesis of an imbalance between vasodilator and vasoconstrictor PGs in pre-E.

6-Ketoprostaglandin F1 alpha↗
PubMed1987

Antihypertensive activity of enalapril. Effect of ibuprofen and different salt intakes.

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 ibuprofen. It is suggested that the effect of enalapril on urinary 6-keto-PGF1 alpha excretion is largely dependent on factors such as sodium intake.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Effect of carprofen and indomethacin on gastric function and the content of prostaglandins E2 and F2 alpha in human gastric juice.

The effect of indomethacin (2 X 50 mg daily) and carprofen (2 X 150 mg daily) on gastric secretion and the generation of prostaglandins PGE2 and PGF2 alpha in gastric juice, was investigated in a single blind cross-over study in eight healthy volunteers lasting one week. We observed no statistically significant change in basal and pentagastrin-stimulated gastric secretory parameters (outputs of gastric acid, N-acetyl-neuraminic acid and pepsin) before and after treatment with indomethacin and carprofen. However, an inhibitory effect was found on the output of PGE2 and PGF2 alpha after pentagastrin stimulation. While both drugs diminished the output of PGF2 alpha to a similar extent, carprofen exerted a markedly weaker inhibitory effect on the output of PGE2 than did indomethacin. It is suggested that the gastric tolerability of non-steroidal anti-inflammatory drugs (NSAIDs) is related to their inhibitory potency on PGE2 formation, in the sense that weak inhibitors of PGE2 cause less damage to the gastric mucosa than do strong inhibitors.

Adult↗