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Biomedical subjects

C Patrono

Publications and source records attributed to C Patrono.

At least 163 records · Page 9Linked to original sources
PubMed1985

Prostaglandins and other arachidonic acid metabolites in the pathogenesis of clinical and experimental glomerulonephritis.

Isolated glomeruli, glomerular epithelial cells and mesangial cells contain the cyclooxygenase enzyme that converts arachidonic acid to prostaglandin (PG)-endoperoxides. Biologically active metabolites of the latter include PGE2, PGF2 alpha, PGI2 and Thromboxane (TX) A2. These substances modulate renal cortical functions, i.e. renin release, renal blood flow (RBF) and glomerular filtration rate. Acute glomerular injury (nephrotoxic serum nephritis) augments glomerular production of PGs and TXA2. Thromboxane A2 reduces glomerular function and inhibition of TXA2 synthesis preserves GFR and RBF in this disease model. Patients with chronic glomerulonephritis have a lower urinary excretion of 6-Keto-PGF1 alpha (the stable hydrolysis product of the vasodilator PGI2). In these patients, inhibition of PGI2 synthesis by a cyclooxygenase inhibitor leads to reductions in GFR and RBF inversely related to the basal urinary excretion of 6-Keto-PGF1 alpha. These findings suggest that in both acute and chronic glomerulonephritis, arachidonate metabolites may serve as pathophysiologic mediators of changes in glomerular function.

Acute Disease↗
PubMed1984

Effects of sulindac and ibuprofen in patients with chronic glomerular disease. Evidence for the dependence of renal function on prostacyclin.

We investigated whether the glomerular synthesis of prostacyclin modulates the renal blood flow and glomerular filtration rate in chronic glomerular disease. The urinary excretion of 6-keto-prostaglandin F1 alpha, a stable breakdown product of prostacyclin, was significantly (P less than 0.01) reduced in 20 women with chronic glomerular disease, as compared with 19 controls, whereas excretion of urinary prostaglandin E2 was unchanged. In 10 patients randomly assigned to one week of treatment with ibuprofen, excretion of urinary 6-keto-prostaglandin F1 alpha and prostaglandin E2 was reduced by 80 per cent, the level of serum creatinine was increased by 40 per cent, and creatinine and para-aminohippurate clearances were reduced by 28 and 35 per cent, respectively. The reduction of both clearances was inversely related (P less than 0.01) to the basal urinary excretion of 6-keto-prostaglandin F1 alpha but not of prostaglandin E2. No functional changes were detected in five healthy women, despite a similar suppression of renal prostacyclin synthesis by ibuprofen. In contrast, one week of treatment with sulindac did not affect renal prostacyclin synthesis or renal function in the other 10 patients, despite a marked inhibition of extrarenal cyclooxygenase activity. We conclude that in patients with mild impairment of renal function, the renal blood flow and glomerular filtration rate are critically dependent on prostacyclin production. In such patients sulindac may be a safe substitute for other nonsteroidal antiinflammatory drugs.

6-Ketoprostaglandin F1 alpha↗
PubMed1984

Leukotrienes in the rat central nervous system.

Leukotrienes C4, D4, and E4 were isolated after incubation of rat brain tissue in vitro with the ionophore A23187 and arachidonic acid. Identification of the compounds was carried out using high-performance liquid chromatography, radioimmunoassay, and bioassay. Average production of leukotrienes C4, D4, and E4 during 10 min of incubation was estimated to 25, 8, and 0.7 pmol per g of brain tissue (wet weight), respectively. Radioimmunoassay determinations indicated in vitro biosynthesis of leukotriene C4 in most regions of the brain, with the highest levels obtained in the hypothalamus and the median eminence. In slices from the caudate nucleus, ionophore A23187 caused a dose-dependent stimulation of leukotriene C4 formation with maximal effect at 5 microM. Leukotriene C4 synthesis of rat brain tissue was inhibited by 30 microM nordihydroguaiaretic acid. Finally, using the indirect immunofluorescence technique, nerve endings in the median eminence and cell bodies in the preoptic area reacting with antibodies raised against leukotriene C4 were observed.

Animals↗
PubMed1984

Differential effects of dazoxiben, a selective thromboxane-synthase inhibitor, on platelet and renal prostaglandin-endoperoxide metabolism.

Pharmacologic inhibition of thromboxane (TX) synthase can result in redirection of prostaglandin (PG) endoperoxide metabolism, possibly affecting platelet, vascular and renal function. This study explores the in vitro, ex vivo and in vivo effects of dazoxiben, an orally active TX-synthase inhibitor, on platelet and renal TXB2 production and associated changes in PG-endoperoxide metabolism. Dazoxiben inhibits TXB2 production in clotting human whole blood with an IC50 of 0.3 micrograms/ml and causes parallel enhancement of PGE2 greater than PGF2 alpha greater than 6-keto-PGF1 alpha production. Similar redirection of PG-endoperoxide metabolism is observed ex vivo, after the oral administration of 1.5 and 3.0 mg/kg to six healthy volunteers. Plasma 6-keto-PGF1 alpha ranges between less than 4 and 8 pg/ml during the first 3 h. Urinary TXB2 excretion, a reflection of renal TXA2 production, is significantly reduced by 30% with no evidence of redirection of renal PG-endoperoxide metabolism. In vitro inhibition of TXB2 production in rat kidney glomeruli requires significantly higher dazoxiben concentration (IC50 = 1.60 micrograms/ml) than in rat whole blood (IC50 = 0.32 micrograms/ml) and is not associated with changes in PGE2, PGF2 alpha and 6-keto-PGF1 alpha production. These results demonstrate quantitatively and qualitatively diverse effects of dazoxiben in different TXA2-producing cells and suggest the possibility of developing tissue-selective TX-synthase inhibitors.

Adult↗
PubMed1983

Release of prostacyclin into the coronary venous blood in patients with coronary arterial disease.

Voluntary patients with a history of myocardial infarction and with typical effort angina underwent catheterization of the coronary sinus and a brachial artery. Healthy young males, serving as controls, were subjected to the same procedure. Arterial and coronary venous blood was drawn at rest and during atrial pacing to angina (patients) or to a heart rate of 140 beats/min (healthy volunteers) for analysis of 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) and prostacyclin-like activity (PILA). 6-Keto-PGF1 alpha levels were measured using radioimmunoassay; PILA in the blood was assayed by rapid preparation of platelet-rich plasma followed by determination of the ADP-induced platelet aggregation. Increased arterial levels of PILA and of radioimmunoactive 6-keto-PGF1 alpha (RIA-6-keto-PGF1 alpha) were observed in the patients at rest as well as during pacing. No obvious release of RIA-6-keto-PGF1 alpha occurred at rest, either in the patients or in the controls. However, during pacing, increased amounts of RIA-6-keto-PGF1 alpha appeared in the coronary venous blood of the patients. The results demonstrate that an increased cardiac prostacyclin formation prevails in patients with signs of impaired coronary flow and suggest that ischemic heart disease is characterized by an insufficient vascular response to this vasodilator prostaglandin rather than by its insufficient endogenous production.

6-Ketoprostaglandin F1 alpha↗
PubMed1983

Release of two vasodilators, adenosine and prostacyclin, from isolated rabbit hearts during controlled hypoxia.

The release of two locally formed vasodilators, adenosine and prostacyclin (PGI2), from hearts subjected to different degrees of hypoxia was investigated. Isolated rabbit hearts were perfused according to Langendorff with Tyrode solution, saturated with gas mixtures containing 8-95% O2 and 5% CO2 in N2. Coronary flow rate, O2 extraction and uptake, and cardiac production of lactate, purines and 6-keto-PGF1 alpha (the stable metabolite of PGI2) were determined. During perfusion of the hearts with a solution saturated with 95% O2, release of lactate, 6-keto-PGF1 alpha and purines was very low: lactate was liberated at a rate of about 5 mumol/100 g . min, purine release corresponded to 2% of the total adenosine nucleotide content of the heart per hour and the release of 6-keto-PGF1 alpha was about 150 mumol/100 g . min. During hypoxia there was a graded release of lactate and purines from the heart, as well as a liberation of 6-keto-PGF1 alpha. Mild hypoxia (60% O2 in the gas mixture) elicited a 160% increase in the formation of lactate and a 40% increase in the release of purines. During severe hypoxia (8% O2 in the gas mixture) the release of lactate and purines increased by more than 2000%. In contrast, the release of 6-keto-PGF1 alpha never increased more than 80% at any degree of hypoxia, neither did it correlate to the severity of the hypoxia. From these data we conclude that of the two vasodilating agents formed in the heart, adenosine and prostacyclin, the former is probably more important in the regulation of coronary flow.

6-Ketoprostaglandin F1 alpha↗
PubMed1983

Reduced platelet thromboxane formation in uremia. Evidence for a functional cyclooxygenase defect.

A qualitative platelet abnormality and a bleeding tendency are frequently associated with renal failure and uremia. We demonstrated previously that uremic patients display an abnormal platelet aggregation to arachidonic acid and reduced malondialdehyde production in response to thrombin and arachidonic acid. The objectives of this investigation were: (a) to compare platelet prostaglandin (PG) and thromboxane (TX) production in whole blood and in platelet-rich plasma (PRP) of 21 uremic patients and 22 healthy subjects; (b) to evaluate the concentration and activity of platelet PG- and TX-forming enzymes; (c) to assess the functional responsiveness of the platelet TXA(2)/PGH(2) receptor; (d) to explore the hemostatic consequences of partially reduced TXA(2) production.Platelet immunoreactive TXB(2) production during whole blood clotting was significantly reduced, by approximately 60%, in uremic patients as compared to age- and sex-matched controls. Exogenous thrombin (5-30 IU/ml) failed to restore normal TXB(2) production in uremic platelets. Uremic PRP produced comparable or slightly higher amounts of TXB(2) than normal PRP at arachidonate concentrations 0.25-1 mM. However, when exposed to substrate concentrations >2 mM, uremic PRP produced significantly less TXB(2) than normal PRP. To discriminate between reduced arachidonic acid oxygenation and altered endoperoxide metabolism, the time course of immunoreactive TXB(2) and PGE(2) production was measured during whole blood clotting. The synthesis and release of both cyclooxygenase-derived products was slower and significantly reduced, at all time intervals considered. Furthermore, PGI(2) production in whole blood, as reflected by serum immunoreactive 6-keto-PGF(1alpha) concentrations, was significantly reduced in uremic patients as compared with healthy subjects. PGH synthase levels, as determined by an immunoradiometric assay, were not significantly different in platelets from uremic patients as compared to control platelets. A single 40-mg dose of aspirin given to five healthy volunteers reduced their serum TXB(2) to levels found in uremic patients. This was associated with a significant increase of threshold aggregating concentrations of ADP and arachidonic acid and prolongation of bleeding time. Substantially similar threshold concentrations of U46619, a TXA(2) agonist, induced aggregation of normal and uremic platelets. Prostacyclin induced a significant elevation of uremic platelet cyclic AMP, which was suppressed by U46619, further suggesting normal responsiveness of the TXA(2)/PGH(2) receptor. WE CONCLUDE THAT: (a) an abnormality of platelet arachidonic acid metabolism exists in uremia, leading to a reduced TXA(2) production; (b) the characteristics of this abnormality are consistent with a functional cyclooxygenase defect; (c) reduced TXA(2) production may partially explain the previously described abnormality of platelet function in uremia.

Adult↗