PubMed Health⌕ Search

Biomedical subjects

M Pinzani

Publications and source records attributed to M Pinzani.

At least 91 records · Page 5Linked to original sources
PubMed1992

Thromboxane-receptor blockade increases water diuresis in cirrhotic patients with ascites.

This study was undertaken to investigate the role of increased renal thromboxane (TX) A2 production in modulating renal hemodynamics and sodium and water retention in cirrhotic patients with ascites. In a randomized, double-blind, placebo-controlled, crossover trial, 15 nonazotemic cirrhotic patients with ascites and elevated urinary TXB2 excretion received the thromboxane-receptor antagonist ONO-3708 (3 micrograms.kg-1.min-1) in a 4-hour continuous infusion. Administration of ONO-3708 significantly blocked TXA2 receptors; bleeding time showed a twofold increase (432 +/- 65 vs. 131 +/- 17 seconds; P less than 0.005), and platelet aggregation to U-46619 (an agonist of TXA2 receptors) was abolished in all patients studied. The drug induced a significant increase in free water clearance (3.06 +/- 0.70 vs. 1.72 +/- 0.57 mL/min; P less than 0.001) and diuresis (4.74 +/- 0.79 vs. 3.94 +/- 0.66 mL/min; P less than 0.05) compared with placebo, as well as a significant (14%) increase in renal plasma flow. The increases in both free water clearance and diuresis induced by ONO-3708 were directly related to basal urinary TXB2 excretion. These results suggest a role for renal TXA2 as a modulator of water handling in cirrhotic patients with ascites.

Aged↗
PubMed1992

Phenotypical modulation of liver fat-storing cells by retinoids. Influence on unstimulated and growth factor-induced cell proliferation.

In conditions of chronic liver inflammation, liver fat-storing cells (FSC) differentiate into 'myofibroblast-like cells'. This transition is characterized by a gradual loss of vitamin A stores, and previous studies suggest a possible relationship between the intracellular retinoid content and the proliferative potential of this cell type. In the present study, we further characterized this aspect of FSC biology by monitoring ultrastructural changes and growth characteristics during several serial passages in culture. Our observations suggest that the complete transition to the 'myofibroblast-like phenotype' is paralleled by a sudden and remarkable increase in the growth rate. At this stage, cell growth appears rather independent from the presence of mitogens in the culture medium, suggesting cell transformation. Accordingly, the mitogenic effects of platelet-derived growth factor and epidermal growth factor appears reduced when compared to those observed in FSC retaining the original 'storing' phenotype. Incubation of vitamin A-depleted FSC with retinol and retinoic acid resulted in the partial recovery of intracellular retinoid stores and in a significant reduction of basal growth rate and basal and growth factor-induced DNA synthesis. In summary, these in vitro observations suggest that intracellular retinoids play a central role in the control of unstimulated and growth factor-induced FSC proliferation and may help understand in vivo mechanisms leading to liver fibrosis.

Analysis of Variance↗
PubMed1992

Regulation of macrophage colony-stimulating factor in liver fat-storing cells by peptide growth factors.

Macrophage colony-stimulating factor (M-CSF) selectively promotes mononuclear phagocyte survival, proliferation, and differentiation. The production of this factor within the liver may be necessary to support the relatively long-term survival of circulating monocytes as they migrate into tissues and differentiate into macrophages. We studied the constitutive expression and the effects of platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), and epidermal growth factor (EGF) on M-CSF mRNA levels and secretion of M-CSF in murine liver fat-storing cells (FSC), vascular pericytes likely involved in the development of liver fibrosis. By Northern analysis, using a murine M-CSF cDNA, FSC constitutively express two major transcripts of 4.4 and 2.2 kb, similar to those detected in mouse L cells, used as a control. Exposure to 10 ng/ml PDGF or bFGF increased M-CSF mRNA levels. Peak effects were observed at 3 and 6 h for PDGF and bFGF, respectively, returning to baseline levels by 12 h. Under basal conditions, detectable amounts of M-CSF, measured by radioimmunoassay, were found in cell supernatants conditioned for 8 and 24 h. PDGF and bFGF markedly stimulated the release of M-CSF as early as 8 h, an effect persisting for at least 24 h. These findings suggest that liver FSC release M-CSF upon stimulation by PDGF and bFGF and may contribute to the activation of resident or infiltrating cells in inflammatory liver diseases.

Animals↗
PubMed1992

Fat-storing cells as liver-specific pericytes. Spatial dynamics of agonist-stimulated intracellular calcium transients.

Liver perisinusoidal fat-storing cells (FSC) show morphological and ultrastructural characteristics similar to pericytes regulating local blood flow in other organs. In the present study we have analyzed whether FSC respond to local vasoconstrictors such as thrombin, angiotensin-II, and endothelin-1 with an increase in intracellular free calcium concentration ([Ca2+]i) coupled with effective cell contraction. All agonists tested induced a rapid and dose-dependent increase in [Ca2+]i followed by a sustained phase lasting several minutes in confluent monolayers of Fura-2-loaded human FSC. Pharmacological studies performed using different Ca2+ channel blockers indicated that, at least for thrombin and angiotensin-II, the sustained phase is due to the opening of voltage-sensitive membrane Ca2+ channels. To analyze the temporal and spatial dynamics of Ca2+ release in response to these agonists, we performed experiments on individual Fura-2-loaded human FSC using a dual wavelength, radiometric video imaging system. The rise in [Ca2+]i was exclusively localized to the cytoplasm, particularly in the branching processes. Increases in [Ca2+]i more than four-fold were associated with a simultaneous and transient reduction of cell area indicating reversible cell contraction. Our results indicate that the Ca(2+)-dependent contraction of human FSC in vitro may reflect a potential role in regulating sinusoidal blood flow in vivo.

Angiotensin II↗
PubMed1991

Peptide growth factors stimulate macrophage colony-stimulating factor in murine stromal cells.

Bone marrow stromal cells influence hematopoiesis through cell-cell interaction and release of hematopoietic growth factors. Macrophage colony-stimulating factor (M-CSF) is constitutively produced by several murine and human stromal cell lines and is induced by inflammatory mediators such as interleukin-1 alpha or tumor necrosis factor-alpha (TNF-alpha) in a variety of mesenchymal cells. Other potentially important regulatory molecules such as platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF), released by activated monocytes in response to inflammation, stimulate the growth of human stromal cells. However, the effect of these peptide mitogens on M-CSF expression in stromal cells has not been explored. In this study, we used TC-1 murine bone marrow-derived stromal cells that constitutively secrete M-CSF to determine the effect of PDGF and bFGF on cell proliferation and M-CSF gene expression. PDGF and bFGF, but not TNF-alpha, were potent mitogens for the TC-1 cells. Similar to mouse L cells, TC-1 murine stromal cells constitutively expressed two major mRNA transcripts of 4.4 and 2.2 kb that hybridized to a murine M-CSF cDNA. PDGF, bFGF, and TNF-alpha markedly stimulated the steady-state expression of M-CSF mRNA with different time-course kinetics. The increased expression of M-CSF mRNA was associated with enhanced secretion of M-CSF as determined by radioimmunoassay. These findings suggest that PDGF, bFGF, and TNF-alpha may regulate hematopoiesis indirectly through release of M-CSF by stromal cells and may modulate, at least in part, the hematopoietic response to inflammation.

Animals↗
PubMed1991

Mitogenic signals for platelet-derived growth factor isoforms in liver fat-storing cells.

Platelet-derived growth factor (PDGF), a key mitogen for liver fat-storing cells (FSC), is a dimeric molecule that occurs as homodimers or heterodimers of related polypeptide chains (PDGF-BB, -AB, and -AA). In chronic inflammation of the liver lobule, any of the three dimeric forms of PDGF derived from multiple sources could potentially interact with FSC. We explored the effects of the three different PDGF isoforms on DNA synthesis and early signal transduction pathways potentially related to PDGF mitogenicity in rat liver FSC. PDGF-BB homodimer and -AB heterodimer induced a marked increase in DNA synthesis, whereas the effect of PDGF-AA homodimer was considerably lower. Moreover, the mitogenicity of each isoform proportionally correlated with their effects on phosphoinositide turnover and intracellular Ca2+. Both the PDGF-BB and -AB dimers likely interact with the PDGF-beta-receptor, although PDGF-AB requires at least one alpha-receptor. The low responsiveness to PDGF-AA could not be accounted for by downregulation of the PDGF-alpha-receptor because FSC expressed very low levels of PDGF-A- and B-chain mRNAs and did not secrete detectable amounts of PDGF activity in the conditioned media. In addition, preincubation of FSC with suramin, a potent inhibitor of PDGF binding to its receptor, failed to increase PDGF-AA-induced DNA synthesis. These results are consistent with a predominant expression of PDGF-beta-receptor in liver FSC, that is linked to phospholipase C activation.

Animals↗
PubMed1991

Evidence for alpha 1-adrenoreceptor hyperresponsiveness in hypotensive cirrhotic patients with ascites.

Cirrhosis with ascites is often characterized by arterial hypotension associated with increased plasma norepinephrine levels. Clinical evidence suggests a decreased sensitivity to norepinephrine in this clinical setting, indicating a potential derangement of alpha 1 adrenoreceptors. The aim of the present study was to evaluate the reactivity of the alpha 1-adrenoreceptor, using phenylephrine, a selective alpha 1 receptor agonist. First, we evaluated the pupillar response to the intraconjunctival administration of the agonist. Hypotensive cirrhotic patients showed a trend to a more marked and prolonged response, compared with age-matched healthy controls. Second, we studied the response of alpha 1-adrenoreceptors in the peripheral vasculature by administering iv phenylephrine to a similar group of patients. A significantly greater and longer lasting pressor response was observed in hypotensive cirrhotic patients (p less than 0.0001 vs. healthy controls). Our results indicate that in this group of patients, there is a rather peculiar situation, characterized by alpha 1-adrenoreceptor hyperresponsiveness in the presence of high levels of circulating norepinephrine. This finding could be related to biochemical abnormalities within the peripheral sympathetic nervous system endings.

Adult↗
PubMed1991

Platelet-derived growth factor expression in mesangial proliferative glomerulonephritis.

Proliferation of mesangial cells and expansion of mesangial matrix are common histologic features of proliferative glomerular disease, a frequent cause of renal failure. Proliferation of glomerular mesangial cells occurs in response to platelet-derived growth factor (PDGF), and these cells release PDGF and express PDGF A and B chain mRNAs. However, all studies relating PDGF to potential changes in glomerular structure and function to date have been performed in vitro. To explore the role of PDGF in proliferative glomerulonephritides, we studied the expression of PDGF in vivo in two animal models of IgA nephropathy with different histologic patterns of glomerular injury: either predominant mesangial proliferation or expansion of mesangial matrix. Increased expression of PDGF and PDGF B-chain mRNA in whole kidneys from diseased mice was demonstrated by immunohistochemical techniques and by solution hybridization assay, respectively. Immunohistochemically, PDGF was localized primarily within the mesangial area of glomeruli and to a much lower extent in interstitium. The increased PDGF expression correlated with the degree of hypercellularity and clinical features of the disease. In addition, PDGF expression was increased in some forms of human glomerulonephritis, characterized by mesangial proliferation. These findings suggest that PDGF may be a major contributor to mesangial cell proliferation seen in proliferative glomerulonephritides.

Animals↗
PubMed1990

Secretion of insulin-like growth factor-I and binding proteins by rat liver fat-storing cells: regulatory role of platelet-derived growth factor.

Insulin-like growth factor (IGF-I) is synthesized in multiple organs, including the liver, and may play a role in tissue growth and repair. We report that liver fat-storing cells (FSC) secrete IGF-I immunoreactivity in the culture medium. Secretion of IGF-I immunoreactivity was blocked in the presence of cycloheximide, suggesting de novo synthesis. Culture medium conditioned by FSC was concentrated and applied to a Sephadex G100 column equilibrated in a denaturing buffer. Two major species with apparent mol wts of 7.5 and greater than 25 k were identified by IGF-I RIA. Reverse phase HPLC of the 7.5 kilodalton species (the size of IGF-I) showed that it eluted in a single peak. To determine whether the higher mol wt species possessed IGF-I binding activity, appropriate fractions were desalted, incubated with [125I]IGF-I for 2 h at 30 C and applied to a Sephadex G100 column equilibrated in a nondissociating buffer. The major peak of radioactivity was confined to a high mol wt region. Western blot ligand analysis revealed the presence of two insulin-like growth factor binding proteins of approximately 28 and 31 kilodaltons. Platelet-derived growth factor, a potent mitogen for FSC, resulted in a 230% increase in release of IGF-I immunoreactivity that could be accounted for by an increase in IGF-I binding activity. In addition IGF-I increased DNA synthesis in FSC and this effect was additive to that of platelet-derived growth factor. IGF-I treatment also resulted in an increase in cell number. IGF-I and insulin-like growth factor binding proteins secreted by FSC may play a role in the hepatic tissue response to injury via autocrine and/or paracrine mechanisms.

Animals↗
PubMed1989

Renal hemodynamic and natriuretic effects of human atrial natriuretic factor infusion in cirrhosis with ascites.

We investigated the effect of a continuous infusion (50 micrograms as an initial bolus followed by a maintenance infusion at a rate of 0.1 micrograms/min.kg body wt for 45 min) of synthetic human atrial natriuretic factor (hANF) on renal hemodynamics and the renin-angiotensin-aldosterone system in 15 cirrhotic patients with ascites. Basal hANF levels were higher in cirrhotic patients when compared with normal values. Human atrial natriuretic factor infusion induced a significant decrease in mean blood pressure (from 77.8 +/- 1.1 to 68.6 +/- 1.5 mmHg, p less than 0.001) and a significant increase in heart rate (from 76.4 +/- 2.7 to 89.8 +/- 2.4 beats/min, p less than 0.001) in the patients studied. A remarkable increase in natriuresis (i.e., greater than or equal to 200 muEq/min) was observed in 5 patients (responders), whereas the infusion did not modify sodium excretion (i.e., less than or equal to 20 muEq/min) in 6 patients (nonresponders) and induced an intermediate response in 4 patients. Human atrial natriuretic factor-induced natriuresis was related to changes in renal hemodynamics that occurred during hANF infusion. In responders, the extent of the natriuretic response paralleled the increase of effective renal plasma flow and glomerular filtration rate; in non-responders the absent natriuretic response was associated with an evident reduction of these parameters. The reduction of blood pressure was similar in responders and nonresponders, but in the latter group it was followed by a marked increase of plasma renin activity and heart rate. It is likely that in nonresponders the natriuretic effect of hANF was blunted by the hemodynamic and hormonal changes triggered by the concomitant hANF-induced hypotension. This probably occurs in the presence of a greater reduction of effective arterial blood volume, as suggested by the higher baseline levels of plasma renin activity and the inability to increase free water excretion after a water load observed in nonresponders.

Adult↗
PubMed1989

Effects of repeated atrial natriuretic peptide bolus injections in cirrhotic patients with refractory ascites.

The renal and hormonal effects of repeated atrial natriuretic peptide (ANP) boli (1 microgram/kg of body weight) were studied in eight cirrhotic patients with refractory ascites. Under basal conditions the patients showed a striking activation of the renin-angiotensin-aldosterone system (plasma renin activity 19.3 +/- 3.0 ng/ml.h, plasma aldosterone concentration 3.87 +/- 0.58 ng/ml) and a tenfold elevation in plasma ANP levels compared to healthy subjects (131.7, range 47.0-288.6, vs. 9.8, range 5.0-15.0, fmol/ml, p less than 0.001). The first ANP injection was followed by a remarkable increase in plasma ANP levels and by a slight increase in urinary cyclic guanosine-monophosphate excretion (from 1050.8 +/- 454.8 to 1446.6 +/- 822.2 pmol/min). A significant reduction of mean blood pressure (MBP) occurred 5 min after the first injection (from 86.7 +/- 7.2 to 79.9 +/- 5.8 mmHg, p less than 0.05), but values gradually returned to the baseline after 30 min. Heart rate (HR) increased 10 min after the first bolus injection (from 83.75 +/- 4.7 to 88.1 +/- 4.6 beats/min) and reached baseline values after 30 min. Similar behaviour of MBP and HR was observed after the second, third and fourth bolus injections. Urinary sodium excretion, urinary flow, glomerular filtration rate, plasma renin activity, and plasma aldosterone concentration did not show any significant modification during ANP administration, nor did these parameters change in the following 12-h recovery period.(ABSTRACT TRUNCATED AT 250 WORDS)

Ascites↗
PubMed1989

Effects of platelet-derived growth factor and other polypeptide mitogens on DNA synthesis and growth of cultured rat liver fat-storing cells.

In vitro and in vivo studies suggest that liver fat-storing cells (FSC) may play an important role in the development of liver fibrosis. We explored the effects of platelet-derived growth factor (PDGF), epidermal growth factor (EGF), transforming growth factor (TGF)-alpha and TGF-beta, and basic fibroblast growth factor (bFGF) on DNA synthesis and growth of rat liver FSC. PDGF, EGF, TGF-alpha, and bFGF induced a dose-dependent increase in DNA synthesis with a peak effect at 24 h. PDGF produced the most striking effect with a maximum 18-fold increase over control. EGF, TGF-alpha, and bFGF elicited a maximum three- to fourfold increase in DNA synthesis. Analysis of growth curves revealed a similar pattern of potency of the growth factors. TGF-beta did not affect DNA synthesis of FSC; however, TGF-beta markedly potentiated the stimulatory effects of both EGF and PDGF. FSC showed high specific binding of 125I-PDGF and Scatchard analysis revealed high affinity receptors with an apparent Kd of 2.3 x 10(-10) M. Our data suggest that PDGF is a key mitogen for FSC and that the coordinate release of other growth factors together with PDGF by inflammatory cells represents a potent potential stimulus for FSC proliferation in conditions of chronic self-perpetuating liver inflammation.

Animals↗
PubMed1988

Intrarenal thromboxane A2 generation reduces the furosemide-induced sodium and water diuresis in cirrhosis with ascites.

To assess the effects of intrarenal thromboxane A2 generation on furosemide-induced sodium and water excretion we administered furosemide (40 mg i.v.) to 8 nonazotemic cirrhotic patients with ascites and 8 healthy subjects before and after the administration of OKY 046 (200 mg twice orally), a powerful thromboxane-synthase inhibitor. Selective thromboxane-synthase inhibition significantly reduced basal and postfurosemide (1 h) urinary thromboxane B2 excretion in healthy subjects (65% before and 62% after furosemide) as well as in cirrhotic patients (52% before and 67% after furosemide) without affecting urinary prostaglandin E2 and 6-keto prostaglandin F1 alpha excretion. During the first hour after furosemide administration, OKY 046 administration significantly enhanced postfurosemide water excretion (milliliters per minute) in both healthy subjects (from 8.5 +/- 2.0 to 11.6 +/- 2.1, p less than 0.001) and cirrhotic patients (from 1.1 +/- 0.8 to 4.2 +/- 0.5, p less than 0.005), whereas furesemide-induced natriuresis (microequivalents per minute) was significantly increased only in the latter group (from 973 +/- 125 to 1405 +/- 121, p less than 0.05). Our data indicate that intrarenal thromboxane A2 generation, elicited by furosemide administration, may reduce the effects of the drug on water and sodium diuresis. Such a reduction seems to be more marked in the presence of an activated intrarenal prostaglandin system, suggesting that renal thromboxane A2 may represent an additional factor in conditioning the impaired responsiveness to furosemide, which is frequently observed in cirrhotic patients with ascites.

6-Ketoprostaglandin F1 alpha↗
PubMed1988

Effects of OKY 046, a thromboxane-synthase inhibitor, on renal function in nonazotemic cirrhotic patients with ascites.

To assess the possible role of increased renal thromboxane A2 (TXA2) synthesis in nonazotemic patients with cirrhosis and ascites and to establish the potential beneficial effect of inhibitors of renal TXA2 production in this clinical setting, we administered OKY 046, a selective TXA2 synthase inhibitor, 200 mg t.i.d. for 5 days, to 9 nonazotemic cirrhotic patients with ascites and avid sodium retention. OKY 046 inhibited platelet TXA2 production, as expressed by serum thromboxane B2 (TXB2) concentration, by approximately 85% (p less than 0.001 vs. baseline values) and reduced urinary TXB2 excretion by 72% (p less than 0.01). A significant increase of approximately 19% in inulin clearance was observed during the treatment (from 61.0 +/- 8.42 to 72.7 +/- 7.45 ml/min, p less than 0.05), whereas renal blood flow was unchanged (from 408.50 +/- 19.97 to 424.50 +/- 30.84 ml/min). Drug administration did not affect positive sodium balance [sodium excretion was 4.67 +/- 1.22 mEq/day before drug administration and 6.26 +/- 1.05 mEq/day during drug administration (on day 7)], plasma renin activity, plasma aldosterone concentration, or the urinary excretion of prostaglandin E2, 6-keto prostaglandin F1 alpha, or prostaglandin F2 alpha. These results suggest that renal TXA2 synthesis contributes to the regulation of renal hemodynamics in nonazotemic cirrhotic patients with ascites and avid sodium retention, but it does not seem to affect sodium balance.

Acrylates↗
PubMed1987

Altered furosemide pharmacokinetics in chronic alcoholic liver disease with ascites contributes to diuretic resistance.

Some patients with chronic alcoholic liver disease and ascites have an impaired natriuretic response to furosemide. To elucidate the mechanism of this diuretic resistance, we measured para-aminohippurate and inulin clearances and urinary excretion of electrolytes, prostaglandin E2, and furosemide after intravenous administration of 80 mg of furosemide in 26 patients. The natriuretic response was variable (3.3-172 mEq/h) and was unrelated to basal sodium excretion, renal clearances, or urinary prostaglandin E2. Natriuresis correlated negatively with plasma aldosterone (r = -0.54, p less than 0.01), and strongly with urinary furosemide (range 5.5-76 mg/h, r = 0.71, p less than 0.001). As urinary furosemide excretion reflects the amount of furosemide reaching the active site on the luminal side of the tubule, the data demonstrate markedly reduced amounts of furosemide at its primary site of action in patients with diuretic resistance. Plasma furosemide was higher in patients with reduced furosemide excretion and impaired natriuresis, suggesting that the defect was an impairment of furosemide transport into the tubule. Thus, a major factor in diuretic resistance is altered furosemide pharmacokinetics.

Dinoprostone↗
PubMed1987

Immediate effects of furosemide on renal hemodynamics in chronic liver disease with ascites.

Furosemide occasionally causes azotemia in patients with ascites, independently of induced volume depletion. To define this effect, we measured renal clearances in patients with chronic liver disease and ascites and in nonascitic controls. Furosemide (80 mg i.v.) transiently increased p-aminohippurate clearance in controls (from 693 +/- 67 to 928 +/- 93 ml/min) and in 11 patients with ascites (from 418 +/- 81 to 526 +/- 80 ml/min). In contrast, in 13 patients with ascites, p-aminohippurate clearance fell by 34% (from 545 +/- 51 to 360 +/- 24 ml/min) within 20 min and by 41% within 60 min, and inulin clearance fell by 19% at 20 min and by 30% at 60 min. The renal effects lasted approximately 4 h. The renal response could not be predicted by renin activity, urinary prostaglandin excretion, urinary sodium, or clinical characteristics. In all 14 patients who received oral furosemide, p-aminohippurate clearance fell within 90 min (by 24%) and remained suppressed for at least 4 h. These immediate effects of furosemide on renal perfusion may contribute to azotemia in some patients with ascites.

Ascites↗
PubMed1987

Effects of captopril on renal function in patients with cirrhosis and ascites.

Blockade of angiotensin-converting enzyme has been variously reported to increase or to decrease sodium excretion in patients with cirrhosis and ascites. We administered captopril (50-150 mg) to 11 patients with cirrhosis and ascites to determine the effects on blood pressure, renal blood flow and sodium excretion. Plasma renin activity increased and mean blood pressure fell (by 14 mm Hg). Para-aminohippurate clearances increased from 321 +/- 53 to 559 +/- 83 ml/min (P less than 0.005), but inulin clearances were minimally altered (73 +/- 8 to 76 +/- 7 ml/min), suggesting preferential dilation of glomerular efferent arterioles. Despite unchanged glomerular delivery of sodium, urinary sodium excretion fell in all subjects (from 2.70 +/- 1.00 to 0.48 +/- 0.21 mEq/h), urinary volume was reduced (377 +/- 55 to 182 +/- 42 ml/h, P less than 0.005), and the natriuretic effect of furosemide was blunted. The antinatriuretic effect of captopril may be mediated by reduced angiotensin II-mediated sodium excretion, by decreased prostaglandin production, and/or by indirect effects of reduced blood pressure. Captopril impairs rather than promotes sodium excretion.

Adult↗