摘要:

The effect of the new histamine H2-receptor antagonist zolantidine was studied in different cardiac and gastric H2-receptor assays in comparison with ranitidine. Zolantidine (0.1-10 µmol/l) competitively antagonized the positive effects of histamine in the spontaneously beating guinea pig atria and in the electrically stimulated guinea pig papillary muscle (pA2 values were 6.98 and 6.78, respectively). At the highest concentrations zolantidine also reduced basal heart rate and cardiac contractility. In the isolated rat gastric fundus zolantidine up to 100 µmol/l did not modify histamine-induced acid secretion; it was similarly ineffective against dimaprit-induced acid secretion in the gastric fistula of conscious cats (up to 3 µmol/ kg i.v.) and against histamine in the anesthetized rat with lumen-perfused stomach (up to 30 µmol/kg i.v.). In all these gastric secretory models ranitidine, as expected, antagonized histamine H2-receptor-mediated responses, showing a potency comparable to that found in cardiac preparations (pA2 values were 6.84, 6.38 and 6.78 in the atria, papillary muscle and gastric fundus, respectively). These data clearly showed that zolantidine is a very peculiar histamine H2-receptor antagonist, capable of distinguishing between cardiac and gastric H2-receptors; however, it still has to be elucidated whether this depends on a true heterogeneity in the histamine H2-receptor population or on the physicochemical properties of the d

ISSN:0031-7012    

DOI:10.1159/000139164

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

Muscarinic receptors (mAChRs) in the pontine reticular formation comprise a critical part of the REM sleep-generating system. Although the role of specific mAChR subtypes remains unclear, data from in vivo microinjection studies suggest that in the pons the M2 subtype is important for REM sleep generation. The present study tested the hypothesis that M2 antagonists would show a greater binding potency in feline pons than M1 or M3 antagonists. Competition binding assays showed 4-DAMP to be more potent than pirenzepine or AF-DX 116 in its ability to displace tritiated quinuclidinyl benzilate, and linear regression analyses indicated that 4-DAMP and pirenzepine each interacted with more than one binding site. These data demonstrate the presence of a mixture of mAChR subtypes in the feline pons, and are consistent with the view that REM sleep is mediated by more than one mAChR subtype.

ISSN:0031-7012    

DOI:10.1159/000139165

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

Spironolactone (SL) is a mineralocorticoid antagonist used clinically to treat hypertension and congestive heart failure. Its mechanism of action involves competitive binding to aldosterone receptors in the kidneys, resulting in diuresis. It is known that the actions of SL are mediated by metabolites of the drug, but the active metabolites have not been definitively identified. Accordingly, studies were done to determine which metabolites bind to renal mineralocorticoid receptors after SL administration to guinea pigs. The major metabolite found in the steroid receptor fraction of kidney cytosol was 7α-thiomethyl-SL (TM). Incubation of kidney cytosol with varying concentrations (0–100 pmol/l) of aldosterone resulted in the concentration-dependent displacement of TM from the steroid receptor fraction. The steroid receptor fraction from renal nuclei of SL-treated animals contained approximately equal concentrations of TM, 7α-thio-SL (TH), and canrenone (CAN). Incubation of kidney nuclei with aldosterone caused a concentration-dependent displacement of all three metabolites. The results indicate that TM is the major SL metabolite that interacts with cytosolic mineralocorticoid receptors in kidneys, but that TH and CAN may contribute to nuclear receptor bind

ISSN:0031-7012    

DOI:10.1159/000139166

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

It was previously shown in man that metoclopramide (MCP), a dopamine (DA)-2 receptor blocker, attenuates the natriuresis of water immersion. In the present study, we therefore investigated the effects of MCP on renal function and atrial natriuretic peptide (ANP) release in conscious rats. Under basal conditions MCP did not affect glomerular filtration rate (GFR)(7.4 ± 1.7 ml/min/kg without and 7.8 ± 0.6 ml/min/kg with MCP), urinary fractional excretion of Na (FENa) (0.3 ± 0.1% without and 0.3 ± 0.1% with MCP) and K (FEK) (20.6 ± 1.4% without and 28.0 ± 6.2% with MCP) or plasma ANP (37 ± 5 pmol/l without and 31 ± 6 pmol/l with MCP). During acute saline loading equal to a 10% rise in body weight, which significantly (p < 0.05) increased GFR, MCP again had no effects on GFR (8.8 ± 1.8 ml/min/kg with vs. 9.7 ± 2.5 ml/ min/kg without MCP), FENa (24.5 ± 6.9% with vs. 20.4 ± 5.1% without MCP), FEK (52.5 ± 6.9% with vs. 52.5 ± 9.5% without MCP) and plasma ANP (89 ± 8 pmol/l with vs. 91 ± 9 pmol/l without MCP). These results indicate that DA does not modulate renal function or ANP release via DA-2 receptors under basal conditions nor in response to acute saline loading in

ISSN:0031-7012    

DOI:10.1159/000139167

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

Subchronic (30 days) exposure of rats to Co(NO3)2 or NiSO4 (20 mg·kg–1) in drinking water caused suppression of the isolated vas deferens contractile responses to exogenous adeno-sine 5’-triphosphate (ATP), noradrenaline, and l-phenylephrine, shifting the concentration-response curves to the relevant agonist to the right. Both metals facilitated the α1-adrenoceptor antagonistic effects of prazosin, which resulted in increased pA2 values for the drug (9.68 ± 0.13 in controls vs. 10.15 ± 0.12 in Co2+-eated preparations and 12.60 ± 0.67 in Ni2+-treated preparations). The inhibitory effect of cloni-dine on the contractions in response to low-frequency electrical field stimulation (EFS) in metal-treated preparations was decreased with pD2 values: 10.52 ± 0.04 in controls, 9.56 ± 0.13 in Co2+-treated preparations and 9.92 ± 0.16 in Ni2+-treated preparations. The monophasic contractile responses to low-frequency EFS (0.1 Hz, 1 ms, 80 V) as well as the first phase of the biphasic contractions after high-frequency long-lasting EFS (300 pulses, 0.1 ms, 40 V, at 4, 8 or 20 Hz) were significantly increased in both groups of heavy metal-treated preparations. Therefore, subchronic exposure to Co2+ or Ni2+ leads to changes in pre- and postjunctional mechanisms underlying the sympathetically mediated contractile activity of isolated rat v

ISSN:0031-7012    

DOI:10.1159/000139168

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

We investigated the effect of WEB 2086, 3-[4-(2-chlorphenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo-[4,3-a][1,4]-diaze-pin-2-yl]-1-(4-morpholinyl)-1-propanon, an antagonist of platelet-activating factor, on the generation of active oxygen by human polymorphonuclear leukocytes. This agent inhibited the production of oxidative metabolites by these cells following stimulation by opsonized zymosan and formyl-methionyl-leucyl-phenylalanine in a time-dependent fashion. To determine whether it would directly inhibit the production of oxygen metabolites by these cells, they were preincubated with WEB 2086 and washed prior to stimulation. WEB 2086 was found to directly inhibit the generation of active oxygen metabolites by these cells. WEB 2086 may be a scavenger of active oxygen metabolites since it rapidly inhibited the production of active oxygen metabolites by these cells. It also directly affected the scavenging of active oxygen metabolites that were generated by the opsonized zymosan-stimulated human polymorphonuclear leukocytes. This action of WEB 2086 was also noted to be exerted against hydroxyl radicals and superoxide anions produced biochemically by an electron spin resonance spectrometer. It thus follows that WEB 2086 may inhibit the generation of active oxygen metabolites by human polymorphonuclear leukocytes and directly influence the scavenging of these metabolites.

ISSN:0031-7012    

DOI:10.1159/000139169

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

The metallothionem II genes, whose structures are highly conserved throughout the animal kingdom, are composed of three exons and two introns. By using synthetic oligonucleotides with sequences complementary to the mRNA coding for human metallothionem II, we have shown that (a) inhibition of metallothionem synthesis causes cells to die from metal toxicity, (b) metallothionem possesses an essential gene, and (c) modifications in oligonucleotide structures exhibit specificity in inhibiting metallothionem synthesis. Furthermore, we have prepared a synthetic antisense oligodeoxyribonucleotide to the mRNA specific for human c-myc and tested its potential to regulate metallothionein synthesis in Chang liver cells in culture. The results of this study revealed that the c-myc antisense oligodeoxyribonucleotide led to greater induction of zinc-promoted but not of cadmium- or dexamethasone-induced synthesis of metallothionein. These data are interpreted to suggest that c-myc acts as a repressor of at least one of the six human metallothionein isoforms and demonstrates a unique mode of regulation capable of discriminating between zinc- and dexamethasone-induced synthesis of metallothionein.

ISSN:0031-7012    

DOI:10.1159/000139170

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

Recent studies have implicated tumor necrosis factor α (TNF-α) in the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Since TNF-α sensitizes and activates phagocytic cells to agents that induce them to release reactive oxygen species, TNF-α may act as an amplifying loop in TCDD-induced oxidative stress (OS). Therefore, the effects of anti-TNF-α antibody (40 µg/mouse) and dexamethasone (2 mg/kg) treatment on TCDD-induced OS as measured by DNA single-strand breaks (SSB) in hepatic nuclei, lipid peroxidation in hepatic mitochondria and microsomes, and activation of peritoneal lavage cells (PLC) in C57BL/6J mice were studied. One day after treatment with 125 µg TCDD/kg, anti-TNF-α resulted in 70, 27, 33 and 21% decreases in DNA-SSB, mitochondrial and microsomal lipid peroxidation and PLC activation, respectively, relative to TCDD-treated mice. Dexamethasone produced 8, 32, 35 and 9% decreases in DNA-SSB, mitochondrial and microsomal lipid peroxidation and PLC activation, respectively, in TCDD-treated animals. The combination of anti-TNF-α and dexamethasone resulted in 67, 55, 61 and 25% decreases in the above parameters of OS, respectively. The results suggest that TNF-α release may play a role in sensitizing and activating phagocytic cells following treatment with TCDD, contributing to the overall OS of animals following exposur

ISSN:0031-7012    

DOI:10.1159/000139171

出版商:S. Karger AG    

年代:1994

数据来源: Karger