摘要:

The hemodynamic actions of a new inotropic agent, MCI-154, were compared to dopamine, ouabain and milrinone in conscious, chronically instrumented dogs. MCI-154 and milrinone produced similar hemodynamic changes: increases in heart rate, diastolic coronary blood flow velocity and peak positive dP/dt. Neither agent had significant effects on arterial pressure while both drugs reduced left ventricular end-diastolic pressure in a dose-related fashion and myocardial segment length, indicating a decrease in diastolic left-ventricular size. MCI-154 was found to be approximately twice as potent as milrinone. In contrast, dopamine and ouabain produced little change in left ventricular end-diastolic pressure or myocardial segment length during diastole, while both drugs produced increases in arterial and left ventricular systolic pressures. An increase in left ventricular afterload was not observed with either MCI-154 or milrinone, highlighting an important advantage of the latter compounds.

ISSN:0031-7012    

DOI:10.1159/000138388

出版商:S. Karger AG    

年代:1988

数据来源: Karger

摘要:

Conflicting reports exist about the effects of diabetes on vascular function. In the present study we investigated (1) the influences of diverse stages of diabetes on mechanical activity and pharmacological reactivity of portal vein and tail ventral artery isolated from male rats 7, 21 or 30 days after alloxan injection (150–180 mg/kg) and (2) the effects of in vitro or in vivo insulin treatment. Various parameters were used to assess the diabetic state (serum glucose levels, body weight, percentage of glycosylated hemoglobin and glucosuria). Isometric developed tension of portal vein from control rats was 10.86 ± 0.41 mN (n = 54), and was enhanced significantly in diabetics (+ 56% at 21 days and +45 % at 30 days; p < 0.001 vs. controls). When challenged with noradrenaline, portal veins from diabetics exhibited a greater contractility and lower reactivity (as reflected by EC50 values). The magnitude of responses to KCl remained similar to those obtained in controls, but nonetheless the reactivity seems to be higher. Tail ventral artery from diabetics also exhibits a greater contractility in response to noradrenaline with no significant changes in EC50 values. The results demonstrate that diabetes affects mechanical performance of the vascular smooth muscle in a differential manner depending on the stage of the endocrinopathy and on the types of vessel studied. These modifications were not avoided by insulin treatme

ISSN:0031-7012    

DOI:10.1159/000138389

出版商:S. Karger AG    

年代:1988

数据来源: Karger

摘要:

Oxfenicine (S-4-OH-phenyl-glycine) was proposed as a compound which would stimulate carbohydrate utilization in the heart and thus reduce oxygen requirement, especially in ischemic heart disease. Oral administration to rats for several weeks gave rise to an increase in heart, liver and kidney weights. The drug damaged mitochondrial metabolism, reducing oxygen consumption and uncoupling oxidative phosphorylation in all three organs. In heart mitochondria creatine phosphate kinase was inhibited and the creatine content of the mitochondria increased. Myocyte membrane functions (Ca uptake as well as Na/K-, Mg-and Ca-ATPases) were inhibited. In all three organs lipids (phospholipids and triglycerides) as well as free fatty acids showed a transient accumulation.

ISSN:0031-7012    

DOI:10.1159/000138390

出版商:S. Karger AG    

年代:1988

数据来源: Karger

摘要:

In rat cerebral cortex slices we investigated the Ca2+ dependency of noradrenaline release and the influence of inorganic and organic Ca2+ antagonists. Slices were prein-cubated with 3H-noradrenaline and then superfused with noradrenaline-free medium. Release of 3H-noradrenaline was elicited by electrical pulses. The stimulation-evoked release was dependent on the external Ca2+ concentration and was inhibited by Co2+, Co2+ and Mg2+ in a concentration-related manner. These results indicate that electrically stimulated noradrenaline release depends on the Ca2+ influx after opening of voltage-sensitive Ca2+ channels. Organic Ca2+ antagonists were used in concentrations which had no major influence on the basal release rate. Of the drugs tested (bepridil, diltiazem, flunarizine, nimodipine, isradipine, prenylamine, verapamil) only flunarizine and nimodipine showed a minor inhibition of the stimulation-evoked release, which was less than 20% at 1 μmol/l. With nimodipine 10 μmol/l, there was a 6 % facilitation of release. All other drugs except flunarizine and verapamil caused a slight facilitation of the stimulation-evoked release. The results provide evidence that the organic Ca2+ channel antagonists investigated do not or only minimally interfere with the noradrenergic nerve terminal Ca2+ channels in a tissue slice preparation. The release-facilitating effects of most organic Ca2+ antagonists cannot be interpreted by the present result

ISSN:0031-7012    

DOI:10.1159/000138391

出版商:S. Karger AG    

年代:1988

数据来源: Karger

摘要:

The effects of 2-pyrrolidone, a cyclic lactam of GABA, were studied on blood and organ levels of 2-pyrrolidone, GABA, glutamic acid, glutamate decarboxylase (GAD) and GABA-transaminase (GABA-T). When administered i.p., the only significant effects observed were increases of brain and liver 2-pyrrolidone. In contrast, regular oral administration for 7 months produced significant increases of GABA and glutamic acid in brain and of glutamic acid alone in liver while GAD decreased in brain and increased in liver; GABA-T was unchanged. A new method for the synthesis of radioactive 2-pyrrolidone was set up and the enzymatic conversion of 2-pyrrolidone to GABA was measured by an original procedure. The results obtained in vitro by this method on the conversion of 2-pyrrolidone to GABA catalyzed by tissue slices, together with the observed inhibition of the GABA-dependent oxygen consumption by 2-pyrrolidone, partially explain the effects of the oral administration.

ISSN:0031-7012    

DOI:10.1159/000138392

出版商:S. Karger AG    

年代:1988

数据来源: Karger

摘要:

Azelastine is a phthalazinone derivative with a wide spectrum of pharmacologically relevant activities. Since PAF-acether has been considered to be a potent mediator of asthma, azelastine was assayed for its ability to counteract PAF-acether-induced platelet aggregation, paw edema development and bronchoconstriction. Azelastine exerted a concentration-dependent inhibition of PAF-acether-induced platelet aggregation in human platelet rich plasma with an IC50 of 87 μmol/l and was as effective as ketotifen. PAF-acether-induced paw edema was reduced by intraperitoneal administration of azelastine resulting in an ID50 of 14.4 mg/kg after 2 h. By contrast, ketotifen was not able to inhibit edema development up to a dose of 32 mg/kg i.p. Azelastine and ketotifen, administered intravenously, dose-dependently inhibited PAF-acether-induced bronchoconstriction, starting from the dose of 0.01 mg/kg and resulting in ID50s of 0.03 and 0.02 mg/kg, respectively. These results show that azelastine is endowed with a peculiar anti-PAF-acether action, which may be advantageous in its therapeutic use, in the treatment of asthma

ISSN:0031-7012    

DOI:10.1159/000138393

出版商:S. Karger AG    

年代:1988

数据来源: Karger

摘要:

The pathogenesis of aplastic anemia from chloramphenicol (CAP) remains uncertain. Recent observations suggest that metabolites of CAP generated by intestinal bacteria may play an important role in mediating hematotoxicity from the drug. Thus, it is possible that once in circulation and after passage through the liver, some CAP metabolites may gain access to the marrow causing hematotoxicity. Based on this possibility, we have studied the stability of CAP and the three cytotoxic analogues dehydrochloramphenicol (DH-CAP), nitrophenylaminopropanedione (NPAP) and nitrosochloramphenicol (NO-CAP) in human blood and liver. Determination of these compounds was accomplished by using a high-performance liquid chromatography system uniquely suited for their separation and detection. Several methods for deproteinization were utilized in order to ensure a full quantitative extraction of the drugs. At zero time, a 100% recovery of CAP, DH-CAP and NPAP was reached with acetonitrile (1 vol/3 vol); whereas NO-CAP was slightly or not detectable with all methods. Incubation of CAP and analogues with blood or liver at 37 °C for up to 30 min showed the following: CAP was stable in both tissues with full recovery; DH-CAP was stable for 5 min, then gradually decreased reaching 50 or 70% of the initial amount after 30 min of incubation with blood and liver, respectively; NPAP decreased at a faster rate than DH-CAP, and NO-CAP completely disappeared. The data suggest that if and when formed in the body, DH-CAP and NPAP may stay in the circulation long enough to reach the marrow and interact with its cellular components

ISSN:0031-7012    

DOI:10.1159/000138394

出版商:S. Karger AG    

年代:1988

数据来源: Karger

摘要:

A decrease of the hepatic intrinsic clearance could contribute to the increase of the plasma concentrations of α1-acid glycoprotein-bound drugs such as propranolol in animals and humans with inflammation. Therefore, the influence of inflammation upon the metabolism of propranolol and another high clearance drug, lidocaine, and of the low clearance drug antipyrine, was studied in isolated rat hepatocytes. For comparative purposes, the influence of the enzyme inhibitor SKF 525A (100 mg/kg i.p.) was also evaluated. Turpentine pretreatment of the rats significantly decreased the metabolism of the three drugs by the hepatocytes; the decrease was least pronounced for propranolol. The inhibitory effect of turpentine-induced inflammation was somewhat lower than that of SKF 525A. These results are in agreement with the results found for the same drugs in the 9,000-g supernatant fraction of the rat liver and point to a marked decrease of intrinsic clearance in some types of inflammation

ISSN:0031-7012    

DOI:10.1159/000138395

出版商:S. Karger AG    

年代:1988

数据来源: Karger

摘要:

We synthesized the 4-hydroxy derivatives of nitrofurazone, furazolidone and nitrofurantoin. Then we dosed rats orally with these antibiotics and isolated the intensely yellow, polar metabolites from their urine. A comparison of the ultraviolet and nuclear magnetic resonance spectra of these metabolites with the corresponding synthetic derivatives confirmed that the metabolites are 4-hydroxynitrofurazone, 4-hydroxyfurazolidone and 4-hydroxynitrofurantoin.

ISSN:0031-7012    

DOI:10.1159/000138396

出版商:S. Karger AG    

年代:1988

数据来源: Karger