摘要:

The pharmacological effects of acetaldehyde on the cardiovascular system, the liver, monoamine neurotransmitter metabolism, brain function and behaviour, and voluntary ethanol drinking are reviewed. The pharmacological effects of acetaldehyde, produced during the interaction of ethanol with the aldehyde dehydrogenase inhibitors disulfiram, calcium carbimide (calcium cyanamide), and 1-aminocyclopropanol (the pharmacologically active hydrolytic product of coprine) are discussed. The proposed involvement of acetaldehyde in the pharmacological effects of ethanol is critically assessed. The literature up to the end of 1981 has been reviewed.

ISSN:0008-4212    

DOI:10.1139/y83-001

出版商:NRC Research Press    

年代:1983

数据来源: NRC

摘要:

Spironolactone is a diuretic steroid which is capable of blocking the binding of aldosterone to its cytosol receptor at the distal convoluted tubule. In addition, it has been shown that spironolactone is a strong inhibitor of steroidogenesis. More recently, new aldosterone antagonists have been discovered. Some of these compounds are more active than spironolactone in competing with aldosterone and have higher specificity for mineralocorticoid receptors. In this study we compare the direct activity of new antimineralocorticoids (SC 23133, SC 19886, SC 26304, and SC 27169) on aldosterone biosynthesis. Marked differences were found in the activity of these compounds upon steroidogenesis. SC 23133 gave rise to a strong inhibiting activity (90%). This activity was reversible (recovery of spontaneous production occurs 150 min after the end of the administration of SC 23133). SC 19886 totally inhibited aldosterone biosynthesis (95%) in a lasting mean. Conversely, SC 27169 and SC 26304 presented no or weak inhibiting effect. Further experiments showed that SC 27169 was unable to block the stimulation of aldosterone biosynthesis induced by corticotropic peptides, whereas the administration of SC 23133 and SC 19886 totally suppressed the stimulatory effect of ACTH and angiotensin II. Owing to the important stimulation of the renin–angiotensin system induced by antimineralocorticoid treatment, these results suggest that SC 23133 and SC 19886 will exert a higher antinatriuretic activity than SC 27169.

ISSN:0008-4212    

DOI:10.1139/y83-002

出版商:NRC Research Press    

年代:1983

数据来源: NRC

摘要:

Increasing concentrations of neurotensin produced a biphasic contractile response, inhibition followed by excitation, when added to full-thickness circular strips of canine gastric corpus muscle cut in a circular orientation and incubated at 37 °Cin vitro. The inhibitory response (mean effective concentration (EC50) 7 × 10−9 M) was not altered by addition of concentrations of tetrodotoxin or scorpion venom sufficient to block field-stimulated neural responses nor by any other antagonist tested. Therefore, it would appear that inhibition is due to an excitation of the smooth muscle receptor. The excitatory response (EC504 × 10−7 M) was only present in full-thickness strips, i.e., was absent in strips of circular muscle, and was reduced by mepyramine or histamine tachyphylaxis. Pretreatment with disodium cromoglycate or repeated doses of 48/80 to extinction of the response completely eliminated the excitatory response as did repeated doses of substance P to tachyphylaxis. Since 48/80 and substance P have been shown to degranulate mast cells and disodium cromoglycate to stabilize mast cell membranes, neurotensin would appear to produce excitation by releasing histamine and other material from mast cells. In contrast toin vivostudies, where two classes of receptors producing inhibition were found, i.e., a high-affinity receptor on adrenergic nerves and a lower affinity receptor on smooth muscles,in vitrothere appears to be only one class of receptor producing inhibition on the smooth muscle itself as no neural receptors were found. The neurotensin receptor responsible for excitation appeared to be on mast cells. The action of neurotensin thus depends upon the locus and the affinity of the receptor and the presence of the receptor on the method of study, i.e.,in vivovs.in vitro.

ISSN:0008-4212    

DOI:10.1139/y83-003

出版商:NRC Research Press    

年代:1983

数据来源: NRC

摘要:

The renal medulla can play an important role in acid excretion by modulating both hydrogen ion secretion in the medullary collecting duct and the medullary. The purpose of these experiments was to characterize the intrarenal events associated with ammonium excretion in acute acidosis. Cortical events were monitored in two ways: first, the rates of glutamine extraction and ammoniagenesis were assessed by measuring arteriovenous differences and the rate of renal blood flow; second, the biochemical response of the ammoniagenesis pathway was examined by measuring glutamate and 2-oxoglutarate, key renal cortical metabolites in this pathway. There were no significant differences noted in any of these cortical parameters between acute respiratory and metabolic acidosis. Despite a comparable twofold rise in ammonium excretion in both cases, the urine pH,, and the urine minus blooddifference (U-B) were lower during acute hypercapnia. In these experiments, the urinewas 34 mmHg (1 mmHg = 133.322 Pa) lower than that of the blood during acute respiratory acidosis while the U-Bwas 5 ± 3 mmHg in acute metabolic acidosis. Thus there were significant differences in medullary events during these two conditions. Although the urine pH is critical in determining ammonium excretion in certain circumstances, these results suggest that regional variations in the medullarycan modify this relationship.

ISSN:0008-4212    

DOI:10.1139/y83-004

出版商:NRC Research Press    

年代:1983

数据来源: NRC

摘要:

Previous studies have suggested that the release of dopamine (DA) in the rat brain may be sensitive to modulation by opioid agents, including the endogenous opioid peptides (enkephalins and endorphins). The present study examined the effects of morphine and the enkephalin analogueD-Ala2-Met5-enkephalinamide (DALA) on the release of radiolabeled DA from superfused slices of rat brain regions. The release of preloaded [3H]DA was evoked from slices of the caudate–putamen (CP) by application of potassium (K+), nicotine (NIC), orL-glutamic acid (L-GLU). The release of [3H]DA from slices of the nucleus accumbens (NA), olfactory tubercle (OT), and substantia nigra (SN) was evoked byL-GLU. Both K+and NIC evoked a concentration-related release of [3H]DA from CP slices. K+-induced release was only partially dependent on calcium (Ca2+), while NIC-evoked release was completely Ca2+independent. Neither morphine nor DALA influenced the release of [3H]DA evoked by K+or NIC.L-GLU produced a concentration-dependent release of [3H]DA from slices of CP, NA, OT, and SN. In all four brain regions, this release was (a) Ca2+-dependent, (b) strongly inhibited by low concentrations of magnesium (Mg2+), (c) greater than the release evoked byD-GLU, (d) attenuated by the putativeL-GLU receptor antagonist glutamic acid diethylester (GDEE), and (e) insensitive to tetrodotoxin (TTX) except in the SN. Morphine produced a significant inhibition ofL-GLU-evoked [3H]DA release from all four regions. Naloxone, which by itself had no significant effect on theL-GLU-evoked release of [3H]DA, blocked the inhibitory effect of morphine on this release in the CP but not in the other regions. Levorphanol and dextrorphan were equipotent in reducing the glutamate-stimulated release of [3H]DA from CP slices. DALA had no effect onL-GLU-induced release in any of the brain regions examined. The results indicate thatL-GLU provokes regional release of DA by acting at a Mg2+-sensitive glutamate receptor. This release is selectively modified by morphine through a mechanism which is insensitive to naloxone.

ISSN:0008-4212    

DOI:10.1139/y83-005

出版商:NRC Research Press    

年代:1983

数据来源: NRC

摘要:

The affinities of a number of α and β-adrenergic binding sites and muscarinic cholinergic binding sites in rabbit urethra and bladder have been determined, using specific radioligand receptor binding assays. There was a greater density of β-binding sites than α-binding sites in the bladder, while, in the urethra, there was a greater density of α-binding sites than β-binding sites. The number of α-binding sites was fourfold greater in the urethra, whereas there were fewer β-binding sites in the urethra. There were fewer muscarinic binding sites in the urethra than in the bladder. The dissociation constant for [3H]dihydroalprenolol at the β-binding site was 6.4 nM, for [3H]dihydroergocryptine at the α-binding site was 2.11 nM, and for3H-labelledl-quinuclidinyl benzilate at the muscarinic binding site was 0.22 nM.

ISSN:0008-4212    

DOI:10.1139/y83-006

出版商:NRC Research Press    

年代:1983

数据来源: NRC

摘要:

Amobarbital metabolism in human liver and in rat liver, lung, kidney, and small intestine was measuredin vitrousing thin-layer chromatography (TLC) for separation of metabolites generated from incubation with [2-14C]amobarbital. Formation of 3′-hydroxyamobarbital (C-OH) occurred primarily in the liver. The kinetics of C-OH formation by rat liver microsomes or isolated hepatocytes could be described by a Michaelis–Menten model incorporating two metabolic sites, one characterized by high-affinity and low-velocity constants (Km = 0.054 ± 0.012 mM,Vmax = 16.89 ± 4.27 nmol C-OH∙g liver−1∙min−1), the other by low-affinity and high-velocity (Km = 0.679 ± 0.097 mM,Vmax = 66.0 ± 5.41 nmol C-OH∙g liver−1∙min−1). The kinetic parameters of the high-affinity site differed significantly between whole cells and homogenates. Pretreatment with phenobarbital for 3 days induced only the high-affinity site. Quantitation of C-OH formation in four human liver samples from several sources showed that metabolism may conform to the two-site model observed in ra

ISSN:0008-4212    

DOI:10.1139/y83-007

出版商:NRC Research Press    

年代:1983

数据来源: NRC

摘要:

The pattern of urinary urea excretion and labelling with15N was examined in eight meal-fed 6 to 9 year old children, over a 3-day period using a simulated constant infusion of the label. The children had cystic fibrosis but were healthy and in a good nutritional status at the time of the study. Reciprocal diurnal patterns of urea excretion and [15N]urea enrichment were noted and found to be suitable for mathematical description. Urea excretion was maximal in the evening at approximately 2000 and minimal at 0800, whereas the [15N]urea enrichment was maximal at about 0800 and minimal at 2000. In addition to the diurnal variation the [15N]urea enrichment increased exponentially to a plateau or isotopic steady state. The diurnal variation in [15N]urea enrichment resulted in large diurnal changes in the calculated rates of whole body amino nitrogen flux, synthesis, and breakdown. Flux rates were approximately 44% higher in the evening than in the morning. Synthesis rates were 19% higher in the evening, whereas breakdown rates were 27% greater in the morning. Mean amino nitrogen flux rates were 1.28 (SD 0.13) g N∙kg−1∙day−1. Isotope recycling was estimated from the slope of the [15N]urea enrichment curve between 30 and 54 h from the start of the study. There was a wide range in recycling, 2.9–19.4% (mean 11.4, SD 5.4). Some of the biological and pharmacological importance of the diurnal variation in the protein metabolism is discus

ISSN:0008-4212    

DOI:10.1139/y83-008

出版商:NRC Research Press    

年代:1983

数据来源: NRC

摘要:

Cats underwent treatment with chlordiazepoxide hydrochloride (0.4, 10.0, and 20.0 mg/kg per os), for 7 consecutive days, and were killed 18 h after the last administration. The endogenous levels of serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), noradrenaline (NA), and dopamine (DA) were assayed in 12 brain areas. Few effects on 5-HT, 5-HIAA, and NA content and on the 5-HT:5-HIAA ratio were observed with a 0.4 mg/kg treatment. These changes were localized in the piriform lobe (amygdala), hippocampus, mesencephalon, and mesencephalon raphe nuclei. Moreover, the DA concentration was not affected. The changes produced by 10.0 and 20.0 mg/kg chlordiazepoxide treatments were extended to many more structures, including the limbic system, brainstem, diencephalon, and neostriatum with respect to 5-HT, 5-HIAA, and NA content and also to DA levels. The changes observed after the three doses generally included an increased 5-HT content, a decreased 5-HIAA level, a high 5-HT:5-HIAA ratio, and increased NA and DA concentrations. However, in some structures, a decreased NA content and an increased 5-HIAA level were found. The present results suggest that administration of chlordiazepoxide for 7 consecutive days in cats produces regional changes in the content of endogenous biogenic amines in the central nervous system (CNS) at low doses; much more extended effects are produced at high doses. These findings are in agreement with a reducing effect of benzodiazepines on the turnover and release of biogenic amines in the CNS, but also suggest that certain discrete areas are more involved in these changes, thus dissociating them from the rest of the brain.

ISSN:0008-4212    

DOI:10.1139/y83-009

出版商:NRC Research Press    

年代:1983

数据来源: NRC

摘要:

The composition and activity of the rat hepatic mixed-function oxidase system were investigated, in male rats 17 to 127 weeks old, with respect to content of its various components and their response to induction by phenobarbital and β-naphthoflavone. There were decreases in many of the components of this enzyme system in older rats which could not be fully compensated by phenobarbital induction. However, there appeared to be no age-related loss of response to induction by β-naphthoflavone. Decreases in mixed-function oxidase enzymes with age did not occur at the same rate or to the same extent. Metabolic studies with ethylmorphine and aniline demonstrated some age-associated changes which did not necessarily parallel reductions in the enzyme system. For example, there was a reduction in apparentKmas a function of age for the hydroxylation of aniline in rats treated with β-naphthoflavone, even though they showed no apparent change in the amount of cytochrome P-450. There was also a trend to alteredKmfor the demethylation of ethylmorphine in saline or corn oil treated rats in older animals. We feel that these changes are a reflection of differential reductions in the various isozymes of cytochromes P-450. Further studies are planned to confirm this hypothesis.

ISSN:0008-4212    

DOI:10.1139/y83-010

出版商:NRC Research Press    

年代:1983

数据来源: NRC