摘要:

Serotonin 1 μmol/l induces a contractile response in the isolated rat aorta in both the presence or absence of extracellular Ca. The present study analyzes the influence of temperature and caffeine on subsequent serotonin-induced contractions. In Ca-free medium, the contraction elicited by serotonin was higher at 25 °C than at 37 °C. In addition, the existence of two independent intracellular Ca pools releasable by serotonin, one of them also sensitive to caffeine, is postulated. The results also showed that addition of serotonin decreases the contractile response to this agonist in Ca-free medi

ISSN:0031-7012    

DOI:10.1159/000139091

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

The effect of the activator, phorbol 12,13-dibutyrate (PDB), and the inhibitor, H-7, of protein kinase C (PKC) has been assayed in rat uterus. PDB increases the amplitude of spontaneous contractions of rat uterus and this effect does not occur in the presence of H-7 or nifedipine. PDB did not modify the KCl-induced tonic contraction but H-7 relaxed it, in a concentration-dependent way. PDB inhibited the contraction induced by oxytocin in rat uterus incubated in Ca-free solution and relaxed the tonic contraction induced by oxytocin in this medium. The relaxing effect of PDB on oxytocin-induced contraction was not modified by H-7. Thus H-7 relaxed, in a concentration-dependent way, the tonic contractions induced by oxytocin and vanadate in the rat uterus incubated in Ca-free medium. Our results suggest a dual effect of PDB related to calcium, and a direct and PKC-independent inhibitory effect ofH-7.

ISSN:0031-7012    

DOI:10.1159/000139092

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

The effects of bupivacaine on myocardial contraction and membrane potential were examined in isolated canine right ventricular papillary muscles. Bupivacaine (10–6 to 10–4 mol/l) produced a dose-dependent and reversible decrease in the electrically induced contractile response of canine right ventricular papillary muscles. The inhibitory effects of bupivacaine on contraction were more pronounced at high stimulation frequencies (2 and 3 Hz) than at low frequency (<1 Hz). The resting membrane potential was not affected by bupivacaine. The maximal upstroke velocity of the action potential was reduced by 10–6 mol/l bupivacaine (74 ± 28% of control), and these effects were also dose dependent. At 10–4 mol/l, bupivacaine blocked fast action potentials in normal Tyrode’s solution. Furthermore, bupivacaine (10–4 and 10-3 mol/l) decreased both slow action potential duration and associated contractions in high-K+ (26 mmol/l) Tyrode’s solution in the presence of isoproterenol. Our results suggest that low concentrations of bupivacaine depress contraction mainly due to an Na+ channel block, whereas at higher concentration, this local anesthetic may block Ca2+<

ISSN:0031-7012    

DOI:10.1159/000139093

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

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 myelo-peroxidase (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 × 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 infa

ISSN:0031-7012    

DOI:10.1159/000139094

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

ABBOTT-81282, 4-{N-butyl-N-[(2’-[1H-tetrazol-5yl]biphenyl-4-yl)meth-yl] amino}pyrimidine-5-carboxylic acid is a novel nonpeptide angiotensin II (All) antagonist. In vivo studies were performed to evaluate ABBOTT-81282 for its antihypertensive effect, pharmacological mechanism(s) of action, and cardiovascular safety. In the conscious renal artery-ligated (RAL) hypertensive rat, a model of high renin hypertension, ABBOTT-81282 (1-10 mg/kg p.o. and 0.1–1.0 mg/kg i.v.) lowered mean arterial pressure (MAP) in a dose-dependent manner with the ED3o values of 2.2 mg/kg for p.o. administration and 0.08 mg/kg for i.v. administration. At 10 mg/kg p.o., ABBOTT-81282 lowered blood pressure in the RAL rat (ΔMAP 66 ± 9 mm Hg from control MAP 167 ± 7 mm Hg, n = 6) to a normotensive level (MAP, 115 + 5 mm Hg) for greater than 24 h and did not change heart rate. The i.v. administration of 1 mg/kg of ABBOTT-81282 also produced a sustained, long-lasting decrease (ΔMAP 27∼52 mm Hg) in blood pressure that was significantly different from the vehicle group at 8 h postdosing (143 ± 3 mm Hg, n = 4 for ABBOTT-81282 vs. 181 + 3 mm Hg, n = 6 for vehicle group, p < 0.01). When blood pressure in the renal hypertensive rat was maximally lowered (ΔMAP 72 ± 9 mm Hg, n = 4) following the 1 mg/kg i.v. dose (cumulative) of ABBOTT-81282, additional administration of captopril (3 mg/kg i.v.) produced no further decline in blood pressure. In the conscious normotensive rat, 10 mg/kg p.o. of ABBOTT-81282 had no effect on basal MAP (119 ± 3 vs. 115 ± 4 mm Hg, pre- vs. 3.5 h postdosing, n = 4) and heart rate (364 ± 18 vs. 363 ± 14 beats/min, pre- vs. 3.5 h postdosing, n = 4) but inhibited the All (0.1 μg/kg i.v.)-induced increase in MAP by 64-70%, while the MAP responses to norepinephrine (0.3 μg/kg i.v.), vasopressin (0.03 IU/kg i.v.) and bradykinin (3 μg/kg i.v.) remained intact. ABBOTT-81282 was also administered to conscious normotensive rats (n = 4) instrumented with ECG telemetry transmitters. At an i.v. dose of 10 mg/kg, which is 125 times greater than the i.v. ED30, ABBOTT-81282 caused a minimal decrease (<14%) in MAP and had no effect on ECG waveforms. These data demonstrate that ABBOTT-81282 is a safe and efficacious antihypertensive agent with selective All antagonism. ABBOTT-81282 may have potential for clinical use in the treatm

ISSN:0031-7012    

DOI:10.1159/000139095

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

The protective effects of phosphoramidon, a dual inhibitor of endothelin-converting enzyme and neutral endopeptidase (E.C. 24.11), on renal function in ischemic acute renal failure were investigated in anesthetized rats. Intravenous infusion of phosphoramidon (0.03 and 0.1 mg/kg per min) signiñcantly suppressed tubular sodium wasting (measured by fractional excretion of sodium) and proteinuria in the postischemic kidney without modifying functional parameters in the contralateral normal kidney. Phosphoramidon (0.1 mg/kg/min) was associated with increased glomerular filtration in the ischemic kidney. In comparison, SCH 42354, a highly selective inhibitor of neutral endopeptidase at 0.3 mg/kg/min, did not inhibit endothelin-converting enzyme or afford renal protection. The data suggest that the protective action of phosphoramidon against ischemic acute renal failure is most likely mediated by inhibition of endothelin formation

ISSN:0031-7012    

DOI:10.1159/000139096

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

Renal hypoperfusion which occurs in hemorrhagic shock creates an environment in which cellular injury and organ dysfunction can occur during the episode of shock as well as re-oxygenation and reperfusion. At the same time, mast cell degranulation which is observed during hemorrhage may have an additinal deleterious effect on the kidney. Twenty-two (Mus norvegicus albinos) rats (200–250 g) of either sex were used. The animals were divided into three groups. Group 1, the control group, was exposed to a 40% hemorrhage. Group 2 was exposed to 40% hemorrhage and then shed blood reperfused. Group 3 was exposed to 40% hemorrhage, and in addition to shed blood reperfusion 25 ng kg–1 vasoactive intestinal peptide (VIP) + 5 mg kg–1 naloxone (NLX) were given. At the end of the experiment the kidneys were evaluated either histologically or by measurement of the urinary N-acetyl-β-D-glucosaminidase (NAG) activity. Shed blood reperfusion caused continuation of ischemic tissue damage and elevation of urinay NAG activity. Addition of VIP and NLX to the blood reperfusion caused a decrease in urinary NAG excretion, and the histology of renal tissue was almost

ISSN:0031-7012    

DOI:10.1159/000139097

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

The process of high-affinity IgE receptor (FcεRI)-mediated signal transduction in human basophils and mast cells is accompanied by activation of protein kinase C (PKC). The present study investigated the effects of a novel protein kinase inhibitor with in vitro selectivity for PKC (CGP 41251) in comparison with the potent but non-selective PKC inhibitor staurosporine on the activation of human peripheral basophilic leukocytes and enzymatically isolated human skin mast cells. CGP 41251 exerted strong concentration-dependent inhibitory effects on FcεRI-mediated histamine release from both cell populations. In addition, the IgE-mediated generation of arachidonic acid metabolites (leukotriene C4/D4 and prostaglandin E2) from human basophils was also significantly inhibited by this compound. Its action was not significantly different from the action of staurosporine. Direct activation of cellular PKC by the phorbol ester 12-o-tetradecanoyl-phorbol-13-acetate and subsequent histamine release from basophils was also inhibited by both compounds. CGP 41251 did not suppress N-formyl-met-leu-phe- or A23187-induced activation of basophils, whereas A23187-induced mediator release from human skin mast cells was inhibited in a concentration-dependent fashion. We conclude that an increase of in vitro selectivity for PKC does not significantly enhance inhibitory effects on immunological activation of histamine-containing cells. Moreover, nonimmunological pathways of signal transduction in basophils and mast cells appear to be mediated by distinct biochemical event

ISSN:0031-7012    

DOI:10.1159/000139098

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

Previous studies have demonstrated that the hepatotoxin carbon tetrachloride rapidly promotes lipid peroxidation and inhibits microsomal calcium sequestration, microsomal glucose-6-phosphatase activity and cytochrome P-450. Due to its profound effects on lipid peroxidation, we have examined the oral administration of 2.5 ml/kg carbon tetrachloride on the urinary excretion of the lipid metabolites formaldehyde, malondialdehyde, acetaldehyde and acetone. Urine samples were collected up to 48 h after treatment. The urinary metabolites were identified and quantitated by gas chromatography-mass spectrometry and high-pressure liquid chromatography. Time-dependent increases in the urinary excretion of the four metabolites were observed after carbon tetrachloride administration. At 48 h after treatment, the increases in the excretion of malondialdehyde, formaldehyde, acetaldehyde and acetone were approximately 55, 78, 57 and 268%, respectively, relative to control values. The data were expressed in nanomoles per kilogram body weight per 4.5 h. The results clearly demonstrate that carbon tetrachloride increases the urinary excretion of four lipid metabolites which may serve as noninvasive bio-markers of xenobiotic-induced lipid peroxidation.

ISSN:0031-7012    

DOI:10.1159/000139099

出版商:S. Karger AG    

年代:1993

数据来源: Karger