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2.
Arch Toxicol ; 66(2): 126-30, 1992.
Article in English | MEDLINE | ID: mdl-1605727

ABSTRACT

A single oral dose of alpha-naphthylisothiocyanate (ANIT) induces intrahepatic cholestasis and endotoxemia in the rat. To assess if a pathogenic relationship between endotoxin and ANIT-induced liver injury could be postulated, rats were pretreated by either induction of endotoxin tolerance, or with the anti-endotoxin agent polymyxin B. A single oral dose (10 or 20 mg/100 g body wt) of ANIT was then given to ascertain whether these methods of modifying endotoxicity would protect the animals against ANIT damage. Both pretreatments significantly reduced the incidence of endotoxemia after ANIT administration, as detected by either lead acetate enhancement method or the Limulus gelation test (LGT). The lethality of a single 20 mg/100 g body wt dose of ANIT was reduced from 55% to 15% by polymyxin B administration, and to 10% by an endotoxin-tolerant state. Moreover, when 10 mg/100 g body wt ANIT was given none of the animals died in 10 days, and the serum levels of bilirubin, alkaline phosphatase (AlPh), gamma-glutamyl transferase (gamma-GT), and transaminases (evaluated 1, 2, and 5 days after treatments) were significantly lower in the endotoxin-tolerant or polymyxin B administered rats; this biochemical protection was mirrored in the lack of histological alteration. The results demonstrate that the modification of endotoxicity offers significant protection against acute liver damage induced by ANIT. Thus the development of endotoxemia may play a pathogenic role in ANIT-induced liver injury. This conclusion is supportive of the hypothesis that endotoxins are necessary for the hepatotoxic agent to exert its full effects.


Subject(s)
1-Naphthylisothiocyanate/toxicity , Chemical and Drug Induced Liver Injury/prevention & control , Cholestasis/prevention & control , Endotoxins/pharmacology , Polymyxin B/pharmacology , Salmonella typhimurium , Alkaline Phosphatase/blood , Animals , Bilirubin/blood , Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury/pathology , Cholestasis/chemically induced , Cholestasis/metabolism , Lead Poisoning/metabolism , Lead Poisoning/physiopathology , Liver/pathology , Male , Rats , Rats, Inbred Strains
4.
J Lab Clin Med ; 115(6): 756-60, 1990 Jun.
Article in English | MEDLINE | ID: mdl-2114471

ABSTRACT

The prostaglandin system is impaired in cholestasis; bile salts, which are a specific biochemical feature of this condition, have been shown to affect functional properties of cells and tissues, and, in some cases, their action is mediated through an alteration of prostaglandin pathway. Endothelium is a privileged site for the production and the action of arachidonate metabolites-prostacyclin in particular. To determine the effects of bile salts on the properties of vascular endothelium, cultured human endothelial cells were studied. Cholic acid sodium salt was seen to induce a direct injury on endothelial cells, as was demonstrated by a massive dismission of the intracellular radiolabel chromium 51. In the absence of detectable toxic effect, sodium taurocholate caused a significant depression of prostacyclin constitutive production from human endothelial cells. The action of sodium taurocholate was related to its concentration and to the time of exposure, and the alteration of prostacyclin production was found to be reversible. Conversely, the generation of thromboxane A2 was not influenced by this bile salt, which may suggest a specific action of sodium taurocholate on arachidonic acid metabolism. These findings indicate that bile salts may directly alter some functional properties of cultured human endothelial cells and may provide a basis for explaining some generalized manifestations that are observed in pathologic conditions characterized by cholemia.


Subject(s)
Endothelium, Vascular/drug effects , Epoprostenol/biosynthesis , Taurocholic Acid/pharmacology , 6-Ketoprostaglandin F1 alpha/biosynthesis , Cell Survival/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Endothelium, Vascular/metabolism , Endothelium, Vascular/pathology , Humans , Thromboxane A2/biosynthesis , Thromboxane B2/biosynthesis , Time Factors
5.
Ann Ital Med Int ; 5(1): 5-12, 1990.
Article in Italian | MEDLINE | ID: mdl-2119672

ABSTRACT

A normally functioning vascular endothelium is required for vascular tone modulation and blood fluidity. Systemic and local circulatory and coagulation alterations, even to the point of renal failure, may be observed in obstructive jaundice; bile salts are included among the potential pathogenetic factors. To assess the effects of taurocholic acid, glycocholic acid, and cholic acid on the integrity and properties of the endothelium, cultured human endothelial cells (HUVEC) were studied. Taurocholic and glycocholic acids (up to 2000 mumoles/L) did not exhibit any significant effect on 51Cr release from HUVEC after 6 h incubation. Following HUVEC exposure to 2000 mumoles/L of the unconjugated compound, cholic acid, a significant discharge of the radiolabel and LDH leakage in the supernatant were observed, to some extent prevented by the presence of human plasma or albumin (physiologic carrier). Prostacyclin spontaneous release from HUVEC was significantly depressed by both taurocholic and glycocholic acid; the action was related to bile salt concentration (200-1000 mumoles/L) and to the time of exposure (1 to 24 h); the reduced production of PGI2 was demonstrated to be reversible. Conversely, spontaneous TxA2 generation and fVIII release were not affected by the presence of bile salts in culture medium. Previous investigations showed that experimental obstructive jaundice could impair prostacyclin release from rat aortic tissue. The same effect was also demonstrated after in vitro exposure of the vessel wall to jaundiced serum and bile salts alone; furthermore, bile salts exert toxic effects on the integrity of several cells and impair the prostaglandin system of different tissues.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Bile Acids and Salts/pharmacology , Endothelium/metabolism , Epoprostenol/metabolism , Factor VIII/metabolism , Thromboxane A2/metabolism , Cells, Cultured , Culture Media , Humans , Time Factors
6.
Arch Int Pharmacodyn Ther ; 296: 144-54, 1988.
Article in English | MEDLINE | ID: mdl-2853612

ABSTRACT

In this study the in vitro influence of phentolamine on platelet aggregating responses, thromboxane B2 (TxB2) production and intraplatelet cyclic AMP (cAMP) content has been investigated. The drug exerts a dose-dependent inhibitory effect on aggregating response to ADP, PAF, collagen, thrombin, sodium arachidonate and ionophore A 23187. Inhibiting phentolamine concentrations prevent also platelet release reaction and TxB2 synthesis. No significant influence on intraplatelet cAMP levels has been observed. The pre-incubation with low concentrations of ionophore A 23187 overcomes phentolamine inhibition of collagen-induced platelet aggregation. Our results provide evidence that phentolamine modulates the human platelet function and that its effects could also be related to a decrease of Ca++ availability.


Subject(s)
Phentolamine/pharmacology , Platelet Aggregation/drug effects , Thromboxane B2/biosynthesis , Adenosine Diphosphate/pharmacology , Adult , Arachidonic Acid , Arachidonic Acids/pharmacology , Calcimycin/pharmacology , Collagen/pharmacology , Cyclic AMP/blood , Humans , In Vitro Techniques , Platelet Activating Factor/pharmacology , Thrombin/pharmacology , Thromboxane B2/metabolism
8.
Pharmacol Res Commun ; 20(10): 883-99, 1988 Oct.
Article in English | MEDLINE | ID: mdl-2976942

ABSTRACT

The effects of hypotensive drug urapidil on human platelet functions were investigated. Urapidil failed to evidence direct aggregating properties or potentiating effects. Furthermore, drug high concentrations inhibited the platelet response to ADP, PAF, collagen, adrenaline and bovine thrombin, and influenced the platelet release reaction induced by ADP and PAF. Data indicate that urapidil possesses negligible agonistic effects on human platelet alpha 2-adrenoceptors and interferes at high concentrations with the platelet activation, as evidenced for other anti-aggregating compounds.


Subject(s)
Antihypertensive Agents/pharmacology , Epinephrine/pharmacology , Piperazines/pharmacology , Platelet Aggregation/drug effects , Adenosine Diphosphate/pharmacology , Adult , Collagen/pharmacology , Humans , Male , Platelet Factor 4/analysis , Thrombin/pharmacology , beta-Thromboglobulin/blood
9.
Clin Exp Pharmacol Physiol ; 15(6): 437-48, 1988 Jun.
Article in English | MEDLINE | ID: mdl-2856060

ABSTRACT

1. The effects of the alpha-beta-adrenergic antagonist labetalol on the activation of human platelets by adrenaline and other aggregating stimuli have been investigated. 2. Labetalol inhibited platelet aggregation and secretion induced by collagen and the second phase of aggregation caused by ADP, platelet activating factor, adrenaline and ionophore A23187. Adrenaline-induced platelet activation was inhibited by the lowest labetalol concentration. The response to Na arachidonate was minimally affected and the arachidonate-induced thromboxane B2 generation was only partially prevented. 3. The pre-incubation with low concentration of ionophore A23187 overcame labetalol's inhibition of collagen-induced platelet aggregation. 4. Labetalol did not influence intraplatelet cyclic AMP levels. 5. The present investigation provided evidences that the modulation of human platelet function by labetalol could be related also to a decreased Ca2+ availability.


Subject(s)
Blood Platelets/drug effects , Labetalol/pharmacology , Adult , Blood Platelets/metabolism , Catecholamines/pharmacology , Cyclic AMP/blood , Humans , In Vitro Techniques , Male , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors , Platelet Factor 4/metabolism , Platelet Function Tests , Thromboxane B2/blood , beta-Thromboglobulin/metabolism
10.
Enzyme ; 39(2): 119-22, 1988.
Article in English | MEDLINE | ID: mdl-3396519

ABSTRACT

Urinary enzyme excretion was investigated in healthy volunteers before and after infusion of single low doses of aminoglycoside (gentamicin, tobramycin and amikacin) in the same subjects. Significant increases were detected in urinary leucine aminopeptidase, lactate dehydrogenase and alkaline phosphatase following gentamicin infusion; after amikacin administration only urinary release of leucine aminopeptidase was found to be increased. No difference was detected compared to basal values in enzyme excretion after tobramycin infusion. Urinary enzyme release in our conditions suggests low tubular damage after single doses of gentamicin and amikacin.


Subject(s)
Aminoglycosides/pharmacology , Enzymes/urine , Adult , Alkaline Phosphatase/urine , Amikacin/pharmacology , Aminoglycosides/blood , Dose-Response Relationship, Drug , Female , Gentamicins/pharmacology , Humans , L-Lactate Dehydrogenase/urine , Leucyl Aminopeptidase/urine , Male , Tobramycin/pharmacology
11.
Gerontology ; 32(6): 308-16, 1986.
Article in English | MEDLINE | ID: mdl-3582991

ABSTRACT

Polymorphonuclear leukocytes (PMNs) represent an important defensive mechanism against infectious agents. Some of their functions are impaired in old people, with a decreased effectiveness of nonspecific immunity. In vitro PMN phagocytic activity was studied with different techniques on 74 healthy subjects (20-82.5 years; 40 males, 34 females). Serum-mediated ingestion resulted to be impaired with age with a lower ratio of active PMNs and a lower activity of phagocytosing cells. The behavior of these parameters was age-related, without significant difference between males and females; the decline was found to be a continuous phenomenon with no threshold age. Serum-independent ingestion had very low values and was not impaired with aging. The present data can represent a further explanation for the finding of a higher incidence and mortality of bacterial diseases in elderly population.


Subject(s)
Aging/immunology , Neutrophils/immunology , Phagocytosis , Adult , Aged , Aged, 80 and over , Azo Compounds , Female , Humans , In Vitro Techniques , Male , Middle Aged , Opsonin Proteins , Zymosan
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