摘要:

Abstract:This study examined interactions between effects of the undecapeptide substance P and norepinephrine and the α‐adrenoceptor agonist clonidine in the mouse spinal cord. All compounds were injected into the lumbar subarachnoid space, and effects on the tail‐flick reflex and the behavioural response to intrathecal substance P were evaluated. The tail‐flick response latencies were markedly increased 5–20 min. after intrathecal application of norepinephrine (0.0125–0.1 μg) or clonidine (0.0125–0.1 μg). The actions of both intrathecal norepinephrine (0.025 μg) and intrathecal clonidine (0.025 μg) were significantly attenuated when substance P (5 μg) was given intrathecally 55 and 45 min. before the agonists. There was a significant relationship between the tail‐flick response latencies and the tail skin temperature. However, the tail‐flick results were not due to changes in the skin temperature. Intrathecally applied substance P (10 ng) produced a response consisting of biting of the caudal part of the body and a few hindlimb scratches. The number of bites was significantly reduced 5 min. after injection of norepinephrine (0.1 μg) or clonidine (0.05–0.1 μg), but the number of scratches was unchanged. The data show that increased stimulation of spinal α‐adrenoceptors inhibits a spinal nociceptive reflex as well as the action of substance P in the spinal cord. Substance P modulates the action of α‐adrenoceptor agonists on the tail‐flick reflex, which may tentatively be explained by downregulation

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00496.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:We studied the effects of phosphamidon (an organophosphate compound), obidoxime (a cholinesterase reactivator), and their combination, phosphamidon/obidoxime (PD/OB) on cardiac cycle length (RR), QT interval, and on QT‐RR relationship of isolated rat heart. Cardiac cycle length did not change significantly following perfusion with phosphamidon or obidoxime alone; however, following perfusion with PD/OB, RR significantly increased at high concentrations (10–3M) of both drugs. The QT interval lengthened by 5% following perfusion with phosphamidon, did not change following perfusion with obidoxime, and increased by 10% following perfusion with PD/OB. The QT‐RR relationship without drugs was positive and linear. Following perfusion with phosphamidon alone, the slope of the relationship decreased significantly, while perfusion with obidoxime alone did not change the QT‐RR relationship. Perfusion with PD/OB at low concentrations decreased the slope of the relationship; however, at the highest concentration (10–3M) the QT‐RR relationship was inverted and became negative. Ventricular arrhythmias as premature ventricular beats, or bigeminies, were noted with increasing frequency following perfusion with increasing doses of phosphamidon. Perfusion with obidoxime did not cause arrhythmias, whereas perfusion with PD/OB caused premature ventricular beats, bigeminies, and ventricular tachycardias at high doses. We suggest that obidoxime modulates the direct effects of phosphamidon on the cardiac repolarization process. PD/OB at high concentrations invert the normal depolarization‐repolarization coupling and may therefore potentiat

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00497.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:The ability of stobadine, a novel pyridoindole antioxidant, to inhibit lipid peroxidation induced by cumene hydroperoxide was investigated in rat liver microsomes. In the micromolar range stobadine effectively inhibited lipid peroxidation as measured by the formation of thiobarbituric acid reactive products. The peroxidation‐related degradation of microsomal cytochrome P‐450 was prevented by stobadine in the same pattern. Another line of evidence in support of the antioxidant action of stobadine was given by its inhibition of cumene hydroperoxide‐induced oxygen consumption in microsomal incubations. Inhibition of lipid peroxidation was not a function of decreased bioactivation of cumene hydroperoxide, as stobadine did not affect the rate of cytochrome P‐450 dependent cleavage of cumene hydroperoxide. Neither had stobadine any effect on cytochrome P‐450 peroxidase function characterized by the rate of cumene hydroperox‐ide‐dependent oxidation of TMPD, and no direct spectral interaction with microsomal cytochrome P‐450 was observed in the micromolar region. We suggest that it is the ability of stobadine to scavenge alkoxyl and peroxyl radicals that is predominantly responsible for the observed ant

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00498.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:Purified populations of rat peritoneal mast cells were used to study the effect of ouabain on compound 48/80‐induced histamine secretion and on86Rb+uptake.86Rb+was used as a tracer for extracellular K+. The calculated value of the ouabain‐sensitive uptake of K+and86Rb+was considered a measure of the Na+–K+pump activity of the cells. Ouabain caused an immediate inhibition of the pump activity and a time‐dependent increase in histamine secretion in the absence of extracellular calcium. No effect on the secretion was observed in the presence of calcium. The effect of ouabain on the secretion occurs in the presence of sodium but not when sodium was replaced by lithium. Preservation by ouabain of a high intracellular sodium content in sodium‐loaded cells was associated with preservation of the secretory response in a calcium‐free medium. In the presence of lanthanum in a calcium‐free medium, the pump activity was inhibited and the enhancement by ouabain of the secretion of histamine was blocked. A less marked inhibition of the pump was found in a calcium‐free medium containing magnesium. The inhibition exerted by magnesium was concentration‐dependent (0–5 mM) as was the counteraction of magnesium of the enhancement of ouabain of the secretion of histamine. These observations indicate that the enhancement by ouabain of the secretory response of mast cells preincubated in a calcium‐free medium is associated with accumulation of sodium inside the cell. In addition to a decreased rate of sodium‐calcium exchange caused by a decreased inward directed sodium gradient, the mechanism by which ouabain enhances the secretory response is likely to involve an increased binding of calcium to

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00499.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:The present work examines the effect of treatment of rats with graded doses of the aminoglycoside antibiotic gentamicin on the concentration of reduced glutathione (GSH) and diamine oxidase (DAO) activity in the kidney, and DAO activity, creatinine and magnesium (Mg) in the plasma. The animals were given the antibiotic intramuscularly in doses of 20, 40, and 80 mg/kg/day for 6 days, and were killed 24 hr after the last injection. In another experiment rats were injected intramuscularly with gentamicin at a dose of 80 mg/kg/day for 6 days and were killed 1, 7 or 14 days after the last injection, and the above parameters were measured. Gentamicin reduced the body weights of rats in a dose‐dependent manner. The weight reductions were most marked on days 4, 5 and 6 of the treatment. The body weights gradually recovered on withdrawing of the drug, and by day 14, they were not significantly different from those of the controls. Gentamicin produced significant and dose‐dependent decreases in the renal concentration of GSH. Seven and 14 days after withdrawing the drug, the GSH concentrations were still significantly below that of the controls. Plasma Mg concentrations were significantly decreased, and plasma creatinine concentrations significantly increased by gentamicin. These effects persisted 7 and 14 days after cessation of treatment. Plasma DAO activity was not detectable in the control or gentamicin‐treated rats. In the renal cortex, the activity of the enzyme, measured 1, 7 and 14 days after the treatment, was not significantly different from that of the control. Histopathologically, the drug produced dose‐dependent proximal renal tubular necrosis. Seven days after withdrawal of gentamicin, the degree of necrosis was less marked, and 14 days after drug withdrawal, renal histology was apparently

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00500.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:The pharmacokinetics of 3‐chloro‐4‐(dichloromethyl)‐5‐hydroxy‐2(5H)‐furanone (MX) was evaluated after a single oral or intravenous administration in the rats using14C‐labelled compound. Twenty to 35% of the dose was absorbed into circulation from the gastrointestinal tract as assessed from the excretion in urine. The mean elimination half‐life of the radioactivity in blood (T1/2k10) was 3.8 hr. Traces of radioactivity remained in the blood for several days. The tissues lining the gastrointestinal and urinary tract, kidneys, stomach, small intestines and urinary bladder contained the highest radioactivity. The activity declined slowest in the kidneys. Urine was the main excretion route. Seventy‐seven % of the total amount excreted appeared in urine in 12 hr and 90% in 24 hr. No radioactivity was exhaled in air suggesting that elimination through respiration did not occur. After an intravenous administration of14C‐MX, the T1/2k10, was much longer, 22.9 hr, and the total elimination half‐life (T1/2β), 42.1 hr. The results indicate that MX is absorbed from the gastrointestinal tract to a considerable degree and it is excreted in urine very rapidly. A fraction of MX or its metabolites is retained in blood for a longer period of time. The pharmacokinetics of MX does not suggest extensive cumulation of MX in tissues a

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00501.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:Effects of androgen treatment of young female rats on glucagon‐ and catecholamine‐sensitive adenylate cyclase activity and adrenergic receptors of hepatic membranes have been studied. Injections of testosterone propionate for 7 days showed a significant decrease in the adenylate cyclase activity responding to isoproterenol and glucagon. The decrease in hormonal stimulation of the enzyme was accompanied with the fall in activation by non‐hormonal stimuli, such as forskolin, sodium fluoride, Gpp(NH)p and Mn, without any changes in the number and the affinity of p‐adrenergic receptors of the membrane. These results suggest that androgens exert post‐receptor effects by inhibiting the activity of the catalytic unit of adenylate cyclase system in rat hepatic

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00502.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:Adenosine administered to humans has been reported to induce pain after intravenous administration. On the other hand adenosine analogues have been shown to possess antinociceptive effects after peripheral and intrathecal administration in animals. The aim of the present study was to investigate the effect of peripheral administration of adenosine agonists with different affinities for the A1 and A2 adenosine receptors on a persistent pain stimulus using the formalin test. The drugs chosen were, R‐phenylisopropyl‐adenosine (R‐PIA) with high affinity for the A1 receptor, N‐ethylcarboxamide‐adenosine (NECA) with almost equal affinity for the A1 and A2 receptor and 2‐(2‐aminoethylamino)‐carbonylethylphenylethylamino‐adenosine (APEC) with high affinity for the A2 receptor. The drugs were mixed with formalin and administered subcutaneously into the dorsal hind paw in mice to study the local effects. They were also injected separately from the formalin solution in different paws to evaluate the systemic effect. The total time of licking the injected paw during the first 5 min. was recorded. In high doses all compounds reduced the licking activity, but a low dose of APEC (1 μM) injected together with the formalin solution had an algesic effect. All effects were antagonized by theophylline. These results suggests that A1 adenosine receptors mediate a local peripheral antinociceptive effect and the involvement of local peripheral A2 receptors in the enhancement of th

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00503.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:The dietary administration of the calcium channel blocker oxodipine to Fischer (F344) rats for 12 and 30 months resulted in increased incidence of altered hepatocytic foci (AHF). As the Environmental Protection Agency (EPA) regards AHF as potentially precancerous it is important to accumulate experimental evidence which may negate this theory. In the case of oxodipine we proved that with dosages close to maximum tolerated dose (MTD) for prolonged periods no hepatic neoplasms were produced. The possible nature of such AHF is discussed.

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00504.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:We studied the haemodynamic and metabolic effects of the novel class III antiarrhythmic agent almokalant (H 234/09) in acute ischaemic heart failure at a dose prolonging ventricular repolarization. In pentobarbital anaesthetized dogs, heart failure was induced by microembolization of the area supplied by the main left coronary artery until a stable left ventricular end‐diastolic pressure (LVEDP) of 32 ± 2 mmHg was achieved. Embolization depressed LV dP/dtmax, LV dP/dtmin, left ventricular systolic pressure (LVSP) and cardiac output. After intravenous infusion of almokalant (0.35 μg/kg) LV dP/dtmaxand LV dP/dtminwere not significantly changed at paced cycle length of 300 msec, whereas LVSP and aortic pressure decreased both at spontaneous and paced cycle length of 300 msec. LVEDP remained unchanged. Heart rate decreased from 185 ± 7 to 167 ± 5 beats/min., and corrected QT‐time (QTc) increased from 9.5 ± 0.3 to 10.4 ± 0.5 msec. Arterial concentration and net myocardial uptake of glucose, lactate and free fatty acids were not significantly influenced by almokalant. In conclusion, almokalant at a dose prolonging ventricular repolarization had no negative inotropic effect in acute ischaemic hear

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00505.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY