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Biomedical subjects

F Squadrito

Publications and source records attributed to F Squadrito.

At least 91 records · Page 5Linked to original sources
PubMed1993

The effect of cloricromene, a coumarine derivative, on leukocyte accumulation, myocardial necrosis and TNF-alpha production in myocardial ischaemia-reperfusion injury.

The effects of cloricromene, a coumarine derivative, were studied in an anaesthetized rat model of coronary artery ligation (60 min) followed by reperfusion (60 min; MI/R). Sham operated rats were used as controls (Sham MI/R). Myocardial ischaemia-reperfusion injury produced a marked myocardial injury (necrotic area/area-at-risk = 68 +/- 4%; necrotic area/total area = 48 +/- 3%) high serum creatinphosphokinase activity (Sham MI/R = 29 +/- 8 U/ml; MI/R = 205 +/- 11 U/ml) and elevated myocardial myeloperoxidase activity (investigated as an index of leukocyte adhesion and accumulation), in the area-at-risk (6.3 +/- 0.2 U x 10(-3)/g tissue) and in necrotic area (6.5 +/- 0.5 U x 10(-3)/g tissue). Furthermore, serum TNF-alpha was undetectable during the occlusion period, but upon the release of the coronary artery significantly increased. At the end of reperfusion, macrophage TNF-alpha was also enhanced. The administration of cloricromene (2 mg/kg, 5 minutes after the onset of reperfusion) significantly reduced myocardial injury (necrotic area/area-at-risk 30 +/- 1.3%; necrotic area/total area = 25 +/- 1.5) blunted the increase in serum creatinphosphokinase activity (92 +/- 5 U/ml) and lowered myeloperoxidase activity in area-at-risk (2.5 +/- 0.2 U x 10(-3)/g tissue) and in necrotic area (2.2 +/- 0.3 U x 10(-3)/g tissue) and decreased the serum and macrophage levels of TNF-alpha. These data indicate that cloricromene exerts beneficial effects on myocardial ischaemia/reperfusion injury. Finally, since we measured increased serum levels of TNF-alpha that were blunted by the cloricromene treatment, our data are consistent with an involvement of TNF-alpha in the reperfusion injury induced by myocardial ischaemia.

Analysis of Variance↗
PubMed1993

G619, a dual thromboxane synthase inhibitor and thromboxane A2 receptor antagonist, reduces myocardial damage and polymorphonuclear leukocyte accumulation following coronary artery occlusion and reperfusion in rats.

We investigated the effect of G 619, a dual thromboxane synthase inhibitor and thromboxane A2 (TxA2) receptor antagonist, in pentobarbital-anaesthetized rats subjected to left main coronary artery ligation (1 h) followed by reperfusion (1 h; MI/R). Sham-operated rats were used as controls (sham MI/R). Survival rate, myocardial necrosis, myocardial myeloperoxidase (MPO) activity (investigated as an index of leukocyte adhesion and accumulation) and serum creatine phosphokinase (CPK) activity were studied. MI/R injury significantly reduced survival rate (45%), caused a marked myocardial necrosis, increased serum CPK activity (sham MI/R = 35 +/- 12 U/ml; MI/R = 205 +/- 13 U/ml) and produced an increase in myocardial MPO activity in the area at risk and in the necrotic area (6.3 +/- 0.5 and 6.6 +/- 0.9 U x 10(-3)/g tissue, respectively). The administration of G 619 significantly increased survival rate, lowered the area of necrosis, blunted the increase in serum CPK activity and reduced the increase in MPO activity in both the area at risk and the necrotic area. These data are consistent with an involvement of TxA2 in MI/R injury and suggest that G 619 may represent a novel therapeutic approach to the treatment of acute myocardial infarction.

Animals↗
PubMed1993

Effects of intravenous administration of recombinant human erythropoietin in rats subject to hemorrhagic shock.

The effects of recombinant human erythropoietin (rHuEPO) on survival and blood pressure in hypovolemic hemorrhagic shock in rats have been studied by intravenous administration. The hormone caused an increase in the time of survival compared to the group of rats without treatment (102 +/- 4.5 vs. 25 +/- 4.5 min, p < 0.01, vehicle; 102 +/- 4.5 vs. 25 +/- 2 min, p < 0.01, saline solution) and an increase in the percentage of the surviving animals (5/7 after 120 min vs. 0/7, p < 0.05). The animals treated showed an increase in mean arterial pressure that was not present in the control group. Through their data, the authors suggest the vasopressor effect of erythropoietin. Furthermore, from other studies done before, they hypothesize that the vasoactive ability of the hormone is endothelin mediated.

Animals↗
PubMed1993

A new antioxidant drug limits brain damage induced by transient cerebral ischaemia.

Restoration of blood flow after an ischaemic event generates the formation of oxygen radicals which could augment brain damage. The authors studied the effects of different doses (50, 100, 200 mg/kg/i.p.) of a new antioxidant, IRFI-016, [2(2,3-dihydro-5-acetoxy-4,6,7-trimethylbenzofuranyl) acetic acid] on brain damage in the Mongolian gerbil induced by 5 min of bilateral carotid occlusion (BCO) followed by reperfusion. Post-ischaemic brain malondialdehyde (MDA) levels and locomotor activity at different times and delayed neuronal death of hippocampal CA1 area on the fourth day after occlusion were evaluated. During reperfusion, after BCO, enhancement of brain MDA occurs (37.5%, 62.5% and 100% at 15, 30 and 60 min of reperfusion, respectively). Brain MDA postischaemic increases were reduced at 15 min of reperfusion to 15.4% and 44.4% by IRFI-016, 100 and 200 mg/kg, respectively. After 30 min of reperfusion brain MDA was reduced to 31.25% and 53.13% by IRFI-016 100 and 200 mg/kg, respectively. Hyperactivity and delayed neuronal death of CA1 were significantly reduced in postischaemic gerbils treated with the highest doses of IRFI-016. Results indicate that pretreatment with the antioxidant IRFI-016 improves in a dose-dependent manner brain damage induced by ischaemia and reperfusion in the gerbil.

Animals↗
PubMed1993

Platelet activating factor interaction with tumor necrosis factor in myocardial ischaemia-reperfusion injury.

The role played by platelet-activating factor (PAF) and tumor necrosis factor (TNF-alpha) in myocardial ischaemia-reperfusion injury was investigated. Pentobarbital anaesthetized rats were subjected to left main coronary artery ligation (1 h) followed by reperfusion (1 h; MI/R). Sham-operated rats were used as controls (Sham MI/R). Myocardial ischaemia-reperfusion injury produced a marked myocardial injury (necrotic area/area-at-risk = 60 +/- 5%; necrotic area/total area = 50 +/- 6%), high serum creatine phosphokinase activity (Sham MI/R = 25 +/- 10 U/ml; MI/R = 190 +/- 12 U/ml), a severe leukopenia (Sham MI/R = 10367 +/- 630 WBC x mm3; MI/R = 4123 +/- 120 WBC x mm3) and elevated myocardial myeloperoxidase activity (investigated as an index of leukocytes adhesion and accumulation) in the area-at-risk (6.2 +/- 0.5 U x 10(-3)/g tissue) and in necrotic area (6.6 +/- 0.7 U x 10(-3)/g tissue. Plasma PAF and serum TNF-alpha were significantly increased only during reperfusion. The peak of PAF plasma levels (6.5 +/- 1.2 pmol/ml) occurred earlier (15 min of reperfusion) than the peak of serum TNF-alpha (150 U/ml at 30 min of reperfusion). At the end of reperfusion, macrophage TNF-alpha was also enhanced (Sham MI/R = undetectable; MI/R = 148 +/- 12 U/ml). The administration of CV 6209, a specific PAF receptor antagonist (5 mg/kg, 5 min after occlusion), significantly reduced myocardial injury (necrotic area/area-at-risk = 27 +/- 3%, P < 0.001; necrotic area/total area = 10 +/- 2%, P < 0.001), blunted the increase in serum creatine phosphokinase (70 +/- 12 U/ml), partially restored leukopenia (8234 +/- 143 WBC x mm3) and lowered myeloperoxidase activity in area-at-risk (2.3 +/- 0.3 U x 10(-3)/g tissue; P < 0.001) and in necrotic area (2.8 +/- 0.5 U x 10(-3)/g tissue). In addition, administration of CV 6209 reduced the serum and macrophage levels of TNF-alpha. The results of this study, therefore, suggest that PAF and TNF-alpha are key mediators of myocardial ischaemia-reperfusion injury and that PAF plays a permissive role in inducing the release of other factor(s) relevant to reperfusion injury.

Analysis of Variance↗
PubMed1993

[Evaluation of the anti-arrhythmic action of propafenone treatment and its influence on left ventricular function].

Twelve patients (9 males, 3 females, mean age 59.2 +/- 7.0 years) with hyperkinetic ventricular arrhythmias were treated for 30 days with 150 mg propafenone three times daily; the daily dosage was raised to 900 mg in non responders (< 85% reduction of ectopic ventricular beats/h). A 24-hour ECGD and mono- and bidimensional echocardiography were carried out at baseline, after 30 days on 450 mg, 30 days on 900 mg propafenone, and one week after drug withdrawal. Propafenone treatment was found to reduce significantly ectopic ventricular beats, especially with the higher dosage (44.9% reduction under 450 mg; 88.8% reduction under 900 mg). At the lower dosage, 25% of patients responded, under the higher dosage 88.9%; the latter dosage also induced a significant reduction of Lown class. Propafenone treatment was also accompanied by a reduction of maximum and mean heart rate, and by a lengthened PR interval which was almost always within the normal range, without changes of QTc. The two months of propafenone treatment did not induce significant changes of cardiac volume or left ventricular function; on the contrary, at the end of the treatment period an increase, albeit not a significant one, of the ejection fraction and a shortening of the circumference inversely proportional to the reduction in ectopic ventricular beats could be noted. In conclusion, propafenone was found to have a valid antiarrhythmic effect, especially at the 900 mg/day dosage without interfering with left ventricular function which was even found to improve under chronic treatment, probably as a result of improved compliance thanks to the reduction of ventricular ectopic beats.

Aged↗
PubMed1993

[Tumor necrosis factor in myocardial ischemia and reperfusion].

The role of tumor necrosis factor (TNF-alpha) was investigated in an anaesthetized rat model of coronary artery ligation (60 min) followed by reperfusion (60 min; MI/R). Sham operated rats were used as controls (Sham MI/R). Myocardial necrosis, myocardial myeloperoxidase activity (MPO; investigated as an index of leukocyte adhesion and accumulation), serum creatinphosphokinase (CPK) activity and serum and macrophage TNF-alpha were studied. Ischemia and reperfusion produced a marked myocardial injury, with enhancement of serum CPK levels and myocardial MPO activity in the area at risk and in the necrotic area. Furthermore, serum TNF-alpha was undetectable during the occlusion period, but increased significantly after release of the coronary artery. At the end of reperfusion, macrophage TNF-alpha was also enhanced. A passive immunization with a hyperimmune serum containing antibodies against murine TNF-alpha or administration of an inhibitor of TNF-alpha synthesis, such as cloricromene, significantly lowered myocardial necrosis, reduced the increase in serum CPK and decreased MPO activity in the area at risk and in the necrotic area. Finally, the administration of the specific anti-TNF-alpha antibodies neutralized the serum levels of TNF-alpha and the injection of cloricromene reduced both serum and macrophage TNF-alpha. These data are consistent with an involvement of TNF-alpha in myocardial ischemia-reperfusion injury and suggest that drugs capable of reducing TNF-alpha might represent a novel therapeutic approach to the treatment of myocardial reperfusion injury.

Animals↗
PubMed1992

Platelet activating factor interaction with tumor necrosis factor and myocardial depressant factor in splanchnic artery occlusion shock.

Anaesthetized rats, subjected to total occlusion of the superior mesenteric artery and the celiac trunk for 45 min, developed a severe shock state (splanchnic artery occlusion shock) resulting in a fatal outcome within 75-90 min after release of the occlusion. Shocked rats, treated with an intravenous bolus of L-659,989, a specific platelet activating factor (PAF) receptor antagonist (12.5, 25 or 50 nmol/kg, 4 min after reperfusion followed, 8 min thereafter, by a continuous infusion of 125, 250 or 500 nmol/kg for 30 min), maintained post-release mean arterial blood pressure at significantly higher values than did rats receiving the vehicle. Treatment with L-659,989 significantly increased survival rate, blunted the rise in plasma myocardial depressant factor activity and lowered serum and macrophage levels of tumor necrosis factor (TNF-alpha). In addition, the drug completely restored macrophage phagocytosis, improved macrophage killing and significantly inhibited leukopenia. To investigate the interaction between PAF, TNF-alpha and myocardial depressant factor, the blood levels of these three mediators were evaluated: shocked rats exhibited increased PAF levels with a peak at 30 min. The plasma levels of PAF peaked earlier than did either serum TNF-alpha or plasma myocardial depressant factor. Both peaks occurred 75 min after the release of occlusion. The results of this study therefore suggest that PAF is a key mediator of splanchnic artery occlusion shock and plays a permissive role in inducing the release of other factors (i.e. TNF-alpha and myocardial depressant factor) that are relevant to shock.

Anesthesia↗
PubMed1992

Cloricromene, a coumarine derivative, protects against lethal endotoxin shock in rats.

Endotoxin shock was induced in male rats by an intravenous (i.v.) injection of Salmonella enteriditis lipopolysaccharide (LPS; 20 mg/kg i.v.). Survival rate, macrophage and serum tumor necrosis factor (TNF-alpha), mean arterial blood pressure (MAP) and white blood cell count were then evaluated. Furthermore the in vitro effect of cloricromene on peritoneal macrophage phagocytosis and TNF-alpha release by primed peritoneal macrophages was investigated. LPS administration caused animal death (0% survival 24 h after endotoxin challenge), hypotension, marked leukopenia and increased the levels of TNF-alpha in both serum and macrophage supernatants. Cloricromene administration (0.5, 1 and 2 mg/kg i.v. 15 min after endotoxin) protected against LPS-induced lethality (100% survival rate 24 h after endotoxin challenge), reverted LPS-induced hypotension and leukopenia, and decreased TNF-alpha in both serum and macrophage supernatants. Finally, cloricromene, added in vitro to peritoneal macrophages collected from endotoxin-treated rats increased macrophage phagocytosis and reduced TNF-alpha formation by activated mononuclear phagocytes. Our data suggest that cloricromene increases survival rate in endotoxin shock through an inhibition of TNF-alpha production.

Animals↗
PubMed1992

Cloricromene antagonizes antidipsogenic effects induced by endotoxin, but not by TNF alpha, in the rat.

Intravenous (640 micrograms/kg) or intracerebroventricular (0.5 and 1 microgram) injection of Escherichia coli endotoxin (LPS) causes inhibition of water intake induced by 24 hour period of water deprivation in the rat. Tumor necrosis factor alpha (TNF-alpha; 20 and 40 ng/rat) given into the lateral cerebral ventricle (i.c.v.) causes effects similar to those observed after LPS. Cloricromene, given either intravenously (1 and 2 mg/kg) or i.c.v. (250 and 500 ng), abolished the antidipsogenic effect induced by LPS (administered both i.v. and i.c.v.). Cloricromene (2 mg/kg, i.v. or 500 ng/rat, i.c.v.), on the contrary, did not modify the antidipsogenic effects induced by TNF-alpha. These data indicate that peripherally injected cloricromene (as well as that i.c.v. injected) antagonizes the effects of mediators of LPS on sites regulating thirst and suggest that cloricromene's action may be due to inhibition of brain TNF-alpha formation induced by LPS.

Animals↗
PubMed1992

Evidence that nitric oxide modulates drinking behaviour.

The involvement of the L-arginine-nitric oxide (NO) pathway in brain, in the regulation of drinking behaviour, has been evaluated by injecting L-arginine and N omega-nitro-L-arginine methyl ester (L-NAME) into the lateral cerebral ventricle (i.c.v.). L-Arginine (5 and 10 micrograms/rat), but not D-arginine, was antidipsogenic when administered to 24 hr water-deprived rats but did not change the intake of water in normally hydrated rats. However, L-NAME (5 and 10 micrograms/rat) did antagonize the effect of L-arginine in water-deprived animals but, by itself, did not increase thirst. L-Arginine (100 ng), when injected into the preoptic area significantly reduced water deprivation-induced drinking. The same dose was unaffective when given intraventricularly. Finally, L-arginine (5 and 10 micrograms/rat, i.c.v.) inhibited drinking induced by intraventricular injection of angiotensin II (250 ng/rat). The effect was dose-dependent. The results indicate that: (1) NO acts as an inhibitory mechanism when thirst is stimulated by water deprivation or by angiotensin II; (2) the preoptic area might be one of the central sites of antidipsogenic action of NO and (3) nitric oxide synthase might be inhibited during water deprivation.

Angiotensin II↗
PubMed1992

Protective effects of G 619, a dual thromboxane synthase inhibitor and thromboxane A2 receptor antagonist, in splanchnic artery occlusion shock.

Splanchnic artery occlusion (SAO) shock was induced in anesthetized rats by clamping the celiac trunk and the superior mesenteric artery for 45 min. The arteries were then released and survival rate, mean survival time, mean arterial blood pressure (MAP), plasma levels of thromboxane B2 (TxB2) and 6-keto-PGF1 alpha, and the phagocytotic activity of peritoneal macrophages were evaluated. Shocked animals died within 89 +/- 10 min, while all sham-shocked rats survived greater than 3 h. SAO shock produced relevant changes in MAP, significantly increased plasma levels of TxB2 and 6-keto-PFG1 alpha, and decreased peritoneal macrophage phagocytotic activity. The administration of G 619, a dual thromboxane synthase inhibitor/thromboxane A2 receptor antagonist (50 mg/kg, 15 min before SAO shock) significantly increased survival time (190 +/- 13 min) and survival rate, reduced plasma levels of TxB2, and partially restored the impairment in peritoneal macrophage phagocytosis. Finally, the administration of G 619 had beneficial effects on changes in MAP-induced bay SAO shock. These data further confirm the involvement of TxA2 in SAO shock and suggest that G 619 may have positive effects in low-flow states.

6-Ketoprostaglandin F1 alpha↗
PubMed1992

Evidence for a role of nitric oxide in hypovolemic hemorrhagic shock.

Hypovolemic hemorrhagic shock was induced in rats by intermittently withdrawing blood from an iliac catheter for 20 min until mean arterial blood pressure (MAP) decreased to 30 mm Hg. Survival rate, survival time, plasma myocardial depressant factor (MDF) activity, MAP, and microscopic gastric alterations were then evaluated. NG-nitro-L-arginine methyl-ester (L-NAME), a selective inhibitor of nitric oxide (NO) production from L-arginine, was injected intravenously (i.v.) after the bleeding was discontinued. Untreated hemorrhagic shocked rats died in 27 +/- 3.3 min, had enhanced plasma activity of MDF, and exhibited hemorrhagic infiltrates in gastric fundus mucosa. L-NAME (5 and 10 mg/kg) significantly increased survival rate and time, blunted the increase in plasma MDF activity, and protected against the gastric lesions induced by hemorrhagic hypovolemic shock. All these protective effects were reversed by a bolus of L-arginine (30 mg/kg/i.v.), given 2 min after administration of L-NAME. Our findings suggest that NO production plays an important role in the pathophysiology of hemorrhagic shock.

Animals↗
PubMed1992

Passive immunization with antibodies against tumor necrosis factor (TNF-alpha) protects from the lethality of splanchnic artery occlusion shock.

Splanchnic artery occlusion shock was induced in anesthetized rats by clamping splanchnic arteries for 45 min. Survival rate, serum and macrophage tumor necrosis factor (TNF-alpha), peritoneal macrophage phagocytosis, and killing activities were evaluated. Shocked rats died within 2 hr, whilst all sham-shocked rats survived more than 6 hr. Serum and macrophage TNF-alpha was undetectable in sham-shocked rats while shocked rats exhibited increased serum (110 +/- 5 U/ml 90 min after release of occlusion) and macrophage levels (122 +/- 4.5 U/ml 90 min after release of occlusion) of TNF-alpha. Furthermore, splanchnic artery occlusion shock produced cardiovascular changes, reduced macrophage phagocytosis (23 +/- 4.6%) and killing (6 +/- 1.1%) activities, and induced a massive necrosis of the ileum. A passive immunization with a hyperimmune serum containing antibodies against murine TNF-alpha significantly protected rats from the lethal effects of splanchnic artery occlusion shock, lowered serum TNF-alpha (6 +/- 2.1 U/ml), and completely reverted the impairment in peritoneal macrophage phagocytosis (48 +/- 4.8%) and killing (13 +/- 1.5%) activities. In addition passive immunization had beneficial effects on the cardiovascular changes occurring during splanchnic artery occlusion shock and prevented necrosis of the ileum induced by this model of shock. By contrast, pretreatment with polymyxin B, an "antiendotoxin" antibiotic, did not modify the lethal effects and the TNF-alpha production induced by splanchnic artery occlusion shock. Furthermore, endotoxin was undetectable in the blood of splanchnic artery occlusion shocked rats. These findings are consistent with the involvement of TNF-alpha in splanchnic artery occlusion shock and suggest that the cytokine represents an important mediator of non-septic shock.

Animals↗
PubMed1992

Effects of captopril on the development of rat doxorubicin nephropathy.

The effects of a daily administration of an anti-converting enzyme inhibitor. Captopril (CPT) (100 mg/kg/orally), on the development of functional and morphological alterations induced in rats by a single injection (7.5 mg/kg/iv) of Doxorubicin (DXR) (Adriamycin*), were investigated. Twenty-four-hour protein excretion, urine output, food intake, water intake, and body weight gain were measured weekly for 30 days. Transmission and scanning electron microscopy observations were performed on kidney samples after 30 days. Four groups were studied. Group 1 were control rats. Group 2 were rats injected with DXR. Group 3 were rats injected with DXR and treated with CPT for 30 days. Group 4 were rats injected with DXR and treated with CPT for 15 days (CPT treatment started 15 days after DXR injection). Group 1 did not show significant functional or morphological changes. Group 2 showed severe proteinuria, significant increase in urinary volume within 2 weeks, significant body weight reduction and diffuse morphological changes. These changes mainly consisted of podocyte swelling, severe foot process fusion, and presence of casts within tubular lumen. Group 3, with respect to group 2, showed a significant reduction of the 24 h protein excretion and urine output. This group displayed morphological changes similar to those observed in group 2, but with a focal distribution. Group 4 showed functional and morphological changes comparable with those of group 2. It is concluded that CPT partially inhibits the development of the functional and morphological damage induced by DXR in the rat kidney. However, CPT did not influence the natural development of nephropathy when treatment started 15 days after DXR injection.

Animals↗