摘要:

The exact mechanism by which streptozotocin (STZ) destroys pancreatic β-cells has not been determined. Recently, nitric oxide was identified as a potent islet toxic compound. However, nitric oxide production by STZ has not been proved yet. In the present studies, we determined whether STZ spontaneously produces nitrite, measured by a spectrophotometric technique based on the Griess reaction. STZ, dissolved in the pH 4.0 citrate buffer, produced significantly more nitrite than that dissolved in pH 7.4. After incubation at 37°C for 120 min, nitrite concentrations were significantly decreased only in STZ dissolved in the pH 7.4 citrate buffer. Following 120 min incubation at 37°C, STZ dissolved at pH 7.4 failed to cause significant islet damage in rats previously deprived of food for 18 h. The present studies demonstrated that STZ may spontaneously produce nitrite in vitro. Nitric oxide production may, at least in part, be responsible for the STZ-induced damage of pancreatic β-cells of the rode

ISSN:0031-7012    

DOI:10.1159/000139268

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

The effects of sodium nitroprusside (SNP) on dopamine synthesis in a porcine renal epithelial cell line (LLC-PK1) were evaluated. Subsequent studies examined the actions of the degradation products of SNP (cyanide, ferrous ion and nitric oxide) on aromatic amino acid decarboxylase (AAAD) activity in tissue supernatants from LLC-PK1 cells and rat renal cortex. SNP (10–500 µmol/l) significantly inhibited dopamine production in LLC-PK1 cells in a dose-related manner. The activation of guanylate cyclase by nitric oxide was not found to be the mechanism whereby SNP inhibited dopamine synthesis in LLC-PK1 nor did the antioxidant glutathione attenuate the actions of SNP. Ferrous sulfate (0.5 mmol/l) and SNP (0.5 mmol/l) were found to inhibit dopamine synthesis in LLC-PK1 cells and to directly inhibit cytosolic AAAD activity from LLC-PK1 cells. A series of studies were conducted using AAAD from rat renal cortex and confirmed that SNP could directly inhibit the conversion of L-dopa to dopamine by AAAD. Furthermore, potassium ferricyanide (1 mmol/l) and potassium cyanide (1 mmol/l) could produce greater than 80% reductions in AAAD activity. Iron (0.5-1 mmol/l) was found to increase rat kidney AAAD activity. Kinetic analysis revealed that potassium cyanide was a potent (Ki = 40-50 µmol/l) noncompetitive/mixed noncompetitive inhibitor of AAAD. SNP was also found to be a noncompetitive inhibitor of AAAD with a Ki of approximately 300-500 µmol/l. In contrast, ferrous sulfate (0.5 mmol/l) was a competitive inhibitor (Ki = ∼650 µmol/l) that actually increased the Vmax of AAAD. The results of these studies support that cyanide released from SNP can potently inhibit AAAD, although SNP has somewhat more complex interactions with AAAD due to the presence of ferr

ISSN:0031-7012    

DOI:10.1159/000139269

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

The purpose of this study was to investigate the possible changes of cyclic nucleotide contents in portal hypertensive rats. Portal hypertension was induced by partial portal vein ligation (PVL) in Sprague-Dawley rats. Sham-operated rats served as controls. Hemodynamic and cyclic nucleotide measurements were performed at 14 days after surgery. The portal venous pressure was significantly higher, while systemic arterial pressure and heart rate were lower in PVL rats than those in controls. Basal cAMP (PVL, 10.91 ± 0.98, vs. sham, 8.08 ± 0.81 pmol/mg protein) and cGMP (PVL, 0.91 ± 0.12, vs. sham, 0.59 ± 0.05 pmol/mg protein) contents in the tail artery were significantly higher in PVL rats. Isobutyryl methylxanthine (10–5M), a nonspecific phosphodiesterase inhibitor, exerted similarly stimulating effects on the tissue cAMP (PVL, 158 ± 10, vs. sham, 178 ± 20%) and cGMP(295 ± 28 vs. 316 ± 71%) levels in both PVL and control rats; so did forskolin (10–6M) on the cAMP (184 ± 20 vs. 197 ± 66%) content in both groups. Our results showed that the arterial cAMP and cGMP contents were higher in PVL rats, which may contribute to the reduction of peripheral resistance in portal

ISSN:0031-7012    

DOI:10.1159/000139270

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

The dose-related cardioprotective efficacy of the thromboxane A2/prostaglandin endoperoxide (TP) receptor antagonist, ifetroban (BMS-180291), was investigated in an anesthetized ferret model of myocardial ischemia (90 min) followed by reperfusion (5 h). Treatment was begun at either the 75th minute of ischemia or 5 min after initiating reperfusion. The magnitude of TP receptor blockade was evaluated by ex vivo platelet function. Additional experiments in ferrets tested the antithrombotic potency of ifetroban as an inhibitor of thrombotic cyclic flow reduction (CFR) in the stenosed abdominal aorta (Folts model). Continuous ifetroban infusions of 0.03, 0.1 and 0.3 mg/kg/h reduced myocardial infarct size from 22% of the left ventricle in vehicle-control ferrets to 20, 12 and 9%, respectively. These represented reductions in infarct size of 8, 43 and 56%. Delaying initiation of treatment with high-dose ifetroban until 5 min into reperfusion also significantly reduced infarct size by 45%. High-dose ifetroban treatment did not prevent neutrophil (PMNL) accumulation measured as tissue myeloperoxidase activity in infarcted tissue. At the end of the 5-hour reperfusion period, the low, medium and high doses produced 90, 98 and 98% blockade of platelet TP receptors, respectively, measured as inhibition of ex vivo platelet shape change responses to U-46,619. Ifetroban inhibited thrombotic CFR at a threshold dose of 0.03 ± 0.004 mg/kg, which antagonized 92% of ferret platelet TP receptors. Thus, ifetroban exhibited cardioprotective and antithrombotic activities and was effective at doses producing > 90% TP receptor blockade. Cardioprotective activity was not associated with any reductions of PMNL accumulation in infarcted tissue and was demonstrable even when treatment was delayed until 5 min after initiation of reperfusion

ISSN:0031-7012    

DOI:10.1159/000139271

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

The present study describes the action of H2O2 on active transporting epithelium, and the partial blockade of this action by antioxidants. The addition of increasing concentrations of H2O2 (0.80; 8.0 and 24.0 mmol/l) to the mucosal surface of isolated toad skin causes an irreversible and dose-dependent inhibition of the short circuit current (SCC) and potential difference (PD). Quantitative determination of the parameters of the electrical equivalent circuit of the skin, by means of Isaacson’s amiloride test, shows that the most affected parameters were the SCC, PD and shunt conductance. When the skins were preincubated with mannitol and vitamin E, the inhibition elicited by H2O2 was partially blocked; on the other hand, when the skins were preincubated with superoxide dismutase or allopurinol, this inhibition remains unchanged. The thiobarbituric acid method was used as an indirect quantification of lipid peroxidation. The inhibitory action of H2O2 in terms of the equivalent electrical circuit and the parallel production of lipid peroxidation points to free-radical formation. Furthermore, the significant blockade of this action by some enzymatic antioxidants is in agreement with this hypothesi

ISSN:0031-7012    

DOI:10.1159/000139272

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

Bladder strips from sensitized guinea pigs respond to ovalbumin challenge with a contraction accompanied by release of histamine, prostaglandin, and leukotriene. Histamine and prostaglandin release occurs preferentially from the bladder mucosa, while leukotrienes are released by the smooth muscle. This study investigated the effects of removal of the bladder mucosa on contractile responses of strips from control and sensitized guinea pigs to electrical stimulation and to contractile agonists. Removal of the mucosa potentiated the contractile response to electrical stimulation at low voltages and pulse durations. The presence of ovalbumin had no effects on the response to electrical stimulation. Removal of the mucosa had no effect on the contractile responses of bladder strips to bethanechol, histamine, KC1, or ovalbumin, although after correction for the decreased strip mass after mucosa removal there was a tendency for the responses to increase. We conclude that the responsiveness of bladder strips from sensitized guinea pigs to ovalbumin challenge results primarily from effects which occur within the smooth muscle.

ISSN:0031-7012    

DOI:10.1159/000139273

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

Nicotine is oxidized to its major metabolite, cotinine, which has a long biological half-life (19–24 h). The plasma concentration of cotinine has been used as an index of tobacco smoke exposure. Cotinine possibly increases the turnover rate of platelet-activating factor (PAF) because it is a potent activator of PAF hydrolase, and it may play a significant role in tobacco-induced arterial thrombosis. Therefore, we studied the distribution and retention of nicotine as it was metabolized to cotinine in the rat. Nicotine (1 mg/kg, 5 µCi/kg) was administered into the femoral vein of male Sprague-Dawley rats under nembutal anesthesia. At different times (5–60 min) after nicotine administration, nicotine and its metabolite, cotinine, were determined by HPLC in plasma, liver, kidney, heart and brain. Within 5–10 min after administration, nicotine concentrations reached peak values in plasma (2,160 pmol/ml) and the organs analyzed. The plasma level of nicotine decreased by 50% within 20 min (half-time) after its intravenous administration. The half-time of nicotine in the brain was about 50 min. The half-times of nicotine for the other organs were about 20–25 min. The major metabolite, cotinine, accumulated in plasma, and by about 30 min the concentrations of nicotine and cotinine in plasma were about equal (890–1,000 pmol/ml). While cotinine accumulated in plasma, nicotine was eliminated by the kidney. While the nicotine concentrations decreased with time in all organs, cotinine concentrations remained constant. These observations indicate that nicotine is renally eliminated or metabolized to cotinine while cotinine exhibits a long retention time and accumulates in plasma. This plasma accumulation may contribute to activation of PAF turnover rate and to

ISSN:0031-7012    

DOI:10.1159/000139274

出版商:S. Karger AG    

年代:1995

数据来源: Karger