Showing papers by "Achille P. Caputi published in 1996"

Thrombolytic therapy with urokinase reduces increased circulating endothelial adhesion molecules in acute myocardial infarction.

Abstract: The aim was to investigate circulating E-selectin and Intercellular Adhesion Molecule-1 (ICAM-1) in acute myocardial infarction. Our study was carried out in 80 patients, 40 hospitalized for acute myocardial infarction (AMI), 20 suffering from chronic stable angina and 20 healthy control subjects. Samples of venous blood were taken from all patients at the moment of hospitalization and after 2, 4, 6, 8, 10, 12 and 24 hours from the thrombolytic treatment (AMI+urokinase) or conventional therapy (AMI+nitroglycerin), for the dosage of creatinine kinase (CK) and adhesion molecules. The CK was determined by means of a Hitachi 901 automatic analyser using an enzymatic method (reagents Boheringer-Biochemia, Germany). Soluble E-selectin (sE-selectin) and soluble ICAM-1 (sICAM-1) were measured in the serum using a specific immunoassay (British Biotechnology Products). The serum levels of Tumor Necrosis Factor (TNF-α) were evaluated using an immunoenzymatic assay to quantitate the serum levels of the cytokine British Biotechnology Products). Patients with acute myocardial infarction (AMI) had increased serum levels of soluble E-selectin (sE-selectin; AMI+urokinase= 312±20 ng/ml; AMI+nitroglycerin=334±15 ng/ml) and soluble ICAM-1 (sICAM-1; AMI+urokinase= 629±30ng/ml; AMI+nitroglycerin=655±25 ng/ml) compared to both patients with chronic angina (sE-selectin =67±10 ng/ml; sICAM-1=230±20 ng/ml) and healthy control subjects (sE-selectin=53±15 ng/ml; sICAM-1 200±16 ng/ml). Furthermore patients with acute myocardial infarction also had increased serum levels of Tumor Necrosis Factor (TNF-α=309±10 pg/ml; control subjects=13±5 pg/ml). Thrombolytic therapy with urokinase (1,000,000 IU as an intravenous bolus for 5 minutes, followed by an infusion of an additional 1,000,000 IU for the following two hours) succeeded in producing reperfusion and reduced the serum levels of sE-selectin (52±13 ng/ml) and sICAM-1 (202±31 ng/ml). In contrast patients not eligible for thrombolytic therapy and therefore treated with conventional therapy (a continuous i.v. infusion of nitroglycerin at the dose of 50 mg/die) did not show any significant reduction in both sE-selectin and sICAM-1 throughout the study. Our results confirm previous experimental data and indicate that adhesion mechanisms supporting leukocyte-endothelium interaction may also be operative in human acute myocardial infarction.

Inhibition of nitric oxide formation reduces voluntary ethanol consumption in the rat.

Abstract: Brain nitric oxide is involved in the mechanisms that regulate ingestive behaviour. To test whether this compound plays a role in alcohol preference, we studied the effects of different doses ofNG-nitro-L-arginine (L-NO arg), an inhibitor of nitric oxide synthase (NOS), on voluntary consumption of ethanol and on blood alcohol levels produced by a single intraperitoneal dose of alcohol in the rat. L-NO arg produced a significant and dose-dependent reduction of ethanol intake (P<0.001) without influencing total fluid consumption or feeding behaviour. L-NO arg did not influence the kinetics of alcohol. Our data show that inhibition of nitric oxide formation accompanies reduction of ethanol intake and suggest a possible role for nitric oxide in ethanol self-administration.

Phenobarbital induces the 2-hydroxylation of desipramine.

Abstract: The kinetics of a single oral dose of desipramine (DMI; 100 mg) were studied in eight epileptic patients chronically treated with phenobarbital (PB) and in eight drug-free healthy controls. All subjects were extensive metabolizers with respect to the genetically determined CYP2D6-related metabolic polymorphism. Compared with controls, epileptic patients exhibited lower peak plasma DMI concentrations (74 +/- 24 vs. 107 +/- 32 nmol/L; means +/- SD, p < 0.05), smaller DMI area-under-the-curve values (1,943 +/- 461 vs. 3,234 +/- 1,145 nmol L-1 h; p < 0.01), and shorter DMI elimination half-lives (15.1 +/- 2.1 vs. 20.6 +/- 3.4 h; p < 0.01). The proportion of the dose excreted as 2-hydroxydesipramine (2-OH-DMI) was significantly higher in the patients (54 +/- 8 vs. 40 +/- 9%; p < 0.05). In one single poor metabolizer volunteer, a 3-week treatment with PB was associated with no major changes in DMI kinetics, but the urinary excretion of 2-OH-DMI tended to increase. These results suggest that PB is an inducer of the 2-hydroxylation of DMI, a reaction primarily catalyzed by CYP2D6, but do not provide further information on the specific P450 isoenzyme(s) being induced.

Protection of ischemic and reperfused rat myocardium by the nonglucocorticoid 21-aminosteroid U-74389G, a new inhibitor of lipid peroxidation.

Abstract: We studied the effects of the aminosteroid U-74389G (21-[4-(2, 6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazinyl]-pregna-1,4,9(11)- triene-3,20-dione(2)-2-butenenedionate), a putative inhibitor of lipid peroxidation, which protects the rat myocardium after ischemia and reperfusion. Pentobarbital-anesthetized (50 mg/kg) rats were subjected to 60 min of occlusion of the left main coronary artery followed by 60 min of reperfusion. Myocardial ischemia/reperfusion produced a large cardiac necrosis (81 +/- 8.6% of the area at risk and 65 +/- 14.8% of the total left ventricle), polymorphonuclear infiltration in the jeopardized tissue (myeloperoxidase activity = 4.2 +/- 2.1 U X 10(-3)/g tissue in the area at risk and 7.0 +/- 3.6 U X 10(-3)/g tissue in the necrotic area), hydroxyl radical (OH.) formation (0.55 +/- 0.16 nmol/ml), increased plasma malonylaldehyde (40.2 +/- 3.9 nmol/ml) and lactate dehydrogenase (431 +/- 30 mIU/ml) and caused a decrease in the survival rate. Treatment with U-74389G (15 and 30 mg/kg i.v.) at the onset of reperfusion caused a reduction of necrotic area expressed as a percentage of either the area at risk (76 +/-7.4% with 15 mg/kg and 69 +/- 13.5% with 30 mg/kg; P < .05) or the total left ventricle (53 +/- 13.6% with 15 mg/kg and 46 +/- 16.8% with 30 mg/kg; P < .05). Treatment U-74389G reduced the myeloperoxidase activity, evaluated as an index of neutrophil infiltration, both in the area at risk (2.7 +/- 1.1 and 2.2 +/- 1.7 U X 10(-3)/g tissue with the doses of 15 and 30 mg/kg, respectively; P < .05) and in the necrotic area (4.3 +/- 2.4 and 3.8 +/- 2.9 U X 10(-3)/g tissue with 15 and 30 mg/kg, respectively; P < .05); decreased OH. formation (measured indirectly by the administration of the trapping agent salicylic acid); and analyzing the hydroxylation product 2,5-dihydroxybenzoic acid during reperfusion (0.35 +/- 0.12 and 0.32 +/- 0.15 nmol/ml with the doses of 15 and 30 mg/kg, respectively; P < .005). Treatment inhibited lipid peroxidation by blunting plasma malonylaldehyde (26.7 +/- 3.1 and 20.8 +/- 3.3 with the doses of 15 and 30 mg/kg, respectively; P < .001), prevented cellular disruption by reducing the increase of plasma lactate dehydrogenase (288.6 +/- 28 and 201.3 +/- 16 mIU/ml with the doses of 15 and 30 mg/kg, respectively; P < .001). Finally, U-74389G enhanced the survival rate evaluated at the end of the experiment (from 40 to 87%). These outcomes suggest that the drug may have potential for cardioprotective use in acute myocardial infarction.

Effects of S-ethylisothiourea, a potent inhibitor of nitric oxide synthase, alone or in combination with a nitric oxide donor in splanchnic artery occlusion shock.

Abstract: 1. The aim of this study was to compare the effects of an intravenous infusion of a potent and non selective nitric oxide synthase inhibitor S-ethylisothiourea (Ethyl-TU) with that of a nitric oxide (NO) donor on the pathological sequelae associated with splanchnic artery occlusion (SAO) shock. In addition the effects of the combination of these two treatments were also investigated. 2. SAO shock was induced in anaesthetized rats by clamping splanchnic arteries for 45 min. Sham operated animals were used as controls. Survival time, white blood cell (WBC) count, mean arterial blood pressure, myeloperoxidase activity (MPO; studied as a quantitative means to evaluate neutrophil accumulation) and the responsiveness of aortic rings to acetylcholine (ACh, 10 nM-10 microM) and to phenylephrine (PE, 1 nM-10 microM) were studied. 3. SAO shocked rats had a decreased survival rate (0% survival 2 h after the release of occlusion) and survival time (76 +/- 10 min), increased MPO activity in the ileum (3.39 +/- 0.8 u x 10(-3) g-1 tissue), a marked leukopenia and a profound hypotension. In addition aortic rings from shocked rats showed a marked hyporeactivity to PE and reduced responsiveness to ACh. Endothelium denuded aortic rings had also a marked hyporeactivity to PE. 4. In vivo administration of Ethyl-TU (0.1 mg kg-1 h-1, beginning 1 min after the onset of reperfusion) significantly increased survival time and rate, improved mean arterial blood pressure, restored the responsiveness to PE, but did not change MPO activity, leukopenia or the impairment in the responsiveness of aortic rings to ACh. Addition of Ethyl-TU (2 microM) to endothelium denuded aortic rings in vitro, restored the marked hyporeactivity to PE. Administration of the NO donor C87-3754 (0.75 mg kg-1 h-1, beginning 1 min after the onset of reperfusion) slightly increased survival time and reduced MPO activity and leukopenia, but did not change survival rate and mean arterial blood pressure. In addition C87-3754 restored the responsiveness of aortic rings to ACh to control values, but did not modify the hyporeactivity to PE. The combination of these two interventions produced a higher degree of protection than either Ethyl-TU or C87-3754 alone. In fact, co-administration of Ethyl-TU plus C87-3754 completely prevented mortality, reduced MPO activity, attenuated leukopenia and the profound hypotension and restored the impaired responsiveness of aortic rings to PE and ACh. 5. Our study suggests that treatment with a nitric oxide synthase inhibitor combined with an NO donor may be a new therapeutic approach to the treatment of splanchnic artery occlusion shock.

Monocytes and lymphocytes as active participants in the pathogenesis of experimental shock.

Abstract: We investigated the role played by monocytes and lymphocytes in the pathogenesis of experimental shock Splanchnic artery occlusion (SAO) shock was induced in anaesthetized rats by clamping splanchnic arteries for 45 min followed by reperfusion Sham operated animals were used as controls SAO shocked rats had a decreased survival time (80 +/- 11 min, while sham shocked rats survived more than 4 h), increased serum (248 +/- 21 U/ml) and macrophage (145 +/- 15 U/ml) levels of TNF-alpha, enhanced myeloperoxidase (MPO) activity in the ileum (338 +/- 02 U x 10(-3)/g tissue), decreased number of monocytes, lymphocytes and neutrophils and a profound hypotension In addition we found an increased expression of vascular cell adhesion molecule-1 (VCAM-1) on aortic endothelium and a reduced percentage of VLA-4 positive monocytes and lymphocytes Inhibition of TNF-alpha synthesis, reversed the increased endothelial expression of VCAM-1, increased the percentage of integrin VLA-4 positive leukocytes and improved monocyte, lymphocyte and neutrophil count Furthermore a passive immunization with specific antibodies raised against VCAM-1 (2 mg/kg, iv 3 h before SAO) increased survival, reduced MPO activity in the ileum (0034 +/- 004 U x 10(-3)/g tissue) and improved mean arterial blood pressure Our data suggest that monocytes and lymphocytes participate in the pathogenesis of splanchnic ischaemia-reperfusion injury and may amplify the adhesion of neutrophils to peripheral tissues

Effects of Cloricromene on the Levels of Endothelin and on the Microcirculatory Function in Peripheral Atherosclerotic Arteriopathies

Abstract: The effects of cloricromene on plasma endothelin-1 (ET-1) levels and on microcirculatory function in 9 patients with peripheral atherosclerotic arteriopathy (PAA) and in healthy control subjects were