摘要:

Alcohol or drug tolerance has been viewed traditionally as a homeostatic response to a direct chemical action of the agent on the neuron. This concept has undergone major modification as a result of recent observations that behavioral and environmental factors can alter markedly the tolerance developed to the same drug regimen. Obligatory task performance under the influence of the drug, classical conditional stimuli in an environment habitually associated with drug administration, previous exposure to a tolerance-producing regimen, and environmental modification of the expression of the drug's effect can all influence dramatically the degree of tolerance produced by a given dosage. Attempts to identify possible cellular mechanisms of tolerance development are illustrated by a review of studies on the relations between ethanol tolerance and changes in the neuronal membrane Na+–K+ATPase and its interaction with ethanol and norepinephrine, hippocampal serotoninergic systems and their interaction with a vasopressin derivative, a membrane-bound calcium- and calmodulin- dependent kinase, and hypothalamic–hypophyseal endorphin-producing systems. None of these studies or other similar ones, whether correlational or interventional in nature, has yet provided full and credible explanations of the effects of behavioral and environmental factors on tolerance development. Finding such explanations is the major current challenge in the neurobiology of tolerance.

ISSN:0008-4212    

DOI:10.1139/y85-245

出版商:NRC Research Press    

年代:1985

数据来源: NRC

摘要:

We have looked at the plasma concentrations of motilin, pancreatic polypeptide (PP), and somatostatin (STS) during the various phases of the interdigestive motor complex (IDMC) in dogs. As expected, motilin cyclical increase was always associated with the phase III of the IDMC. Statistical analysis of PP variations revealed a significant rise 10 min before duodenal phase III; however, in individual animals, this relationship was inconsistent. Although a dose-related increase in PP blood levels was induced by administration of synthetic canine motilin (0–200 ng kg−1 iv), fasting plasma levels of PP were not correlated with the concentrations of circulating endogenous motilin. After truncal vagotomy, while motilin release and the intestinal motility pattern remained unaltered, the phase III associated cyclical increases of PP disappeared. Infusion of physiological amounts of PP (1 μg kg−1 h−1for 3 h) mimicking the postprandial release failed to reproduce a fed pattern type of intestinal motility and of motilin secretion. No statistical correlation could be established between STS plasma levels and the motor activity of the intestine. STS plasma levels were not correlated with circulating concentrations of motilin and the exogenous administration of physiological doses of synthetic canine motilin failed to modify STS plasma levels. Morphine (200 μg kg−1 iv) stimulated only the release of motilin. These data suggest that the role played by circulating concentrations of PP and STS in the control of the IDMC in dog is at most minimal.

ISSN:0008-4212    

DOI:10.1139/y85-246

出版商:NRC Research Press    

年代:1985

数据来源: NRC

摘要:

Neurons containing arginine vasopressin (AVP) have been shown to project from the paraventricular nucleus of the hypothalamus to the nucleus tractus solitarius (NTS) in the medulla. We investigated whether AVP acts in brain stem regions to influence sympathoadrenal outflow. Cannulae were implanted into the fourth ventricle of rats 7 days prior to the experiment. The effects of intracerebroventricular (icv) injections of AVP, the vehicle, and AVP antagonist,d(CH2)5Tyr(Me)AVP, on mean arterial pressure (MAP) and plasma noradrenaline (NA) and adrenaline (A) levels were determined in conscious unrestrained rats. Injections of AVP (icv, 23 and 73 ng/kg) but not the vehicle increased MAP and plasma NA and A levels. In contrast, iv injection of AVP increased MAP but decreased plasma concentrations of A and NA. The pressor response to icv injection of AVP was abolished by prior icv injection of AVP antagonist. Injection of AVP antagonist (icv, 0.5 and 1.5 μg/kg) had no effect on MAP or plasma NA or A levels. These results show that centrally injected AVP activates sympathoadrenal outflow, possibly via an inhibition of baroreceptor reflexes. Since centrally administered AVP antagonist did not influence MAP or plasma NA or A levels, it appears that endogenously released AVP does not have a tonic influence on central cardiovascular reflex system in conscious, unrestrained rats.

ISSN:0008-4212    

DOI:10.1139/y85-247

出版商:NRC Research Press    

年代:1985

数据来源: NRC

摘要:

In both isolated canine ventricular trabecular muscle and Purkinje strand preparations,dl-sotalol and its two optical isomersd- andl-sotalol produced a concentration-dependent increase in action potential duration while other transmembrane electrical characteristics were not significantly affected. The magnitude of the increase in action potential durations was greater in Purkinje strand preparations. In Purkinje strand preparations, the effect was rate dependent (i.e., the increase in duration was proportionately greater when stimulation frequency was slowed). From the concentration of each compound calculated to produce a 50% maximal increase in Purkinje fiber action potential durations,d-sotalol appeared to be one to three times more potent than eitherl-sotalol or the racemate. Each compound appeared to increase force development in ventricular trabecular muscle preparations stimulated at a frequency of 2 Hz. Increased force development was only observed in Purkinje strand preparations stimulated at slower rates (0.5–0.33 Hz). These results are unlike those produced by other beta-adrenergic blockers and suggest that the antiarrhythmic effects of sotalol are related primarily to its effect of action potential duration. The estimated potency ratios established for the effect ofdl-sotalol and its optical isomers on both trabeculae and Purkinkje fiber action potential durations (d > dl − l) may indicate that these effects are unrelated to the beta-adrenergic blocking properties of these compounds. The differential effect of sotalol on isolated trabeculae and Purkinje strand preparations may help to explain the clinically reported phenomenon of sotalol-induced torsade de pointes.

ISSN:0008-4212    

DOI:10.1139/y85-248

出版商:NRC Research Press    

年代:1985

数据来源: NRC

摘要:

Cardiac hyperactivity and its consequent metabolically induced coronary vasodilatation (MCD) were studied in isolated, perfused, electrically paced rat hearts. The α-adrenoceptor agonists, phenylephrine and methoxamine, produced a concentration-dependent inhibition of the inotropic responses to noradrenaline, dobutamine, isoprenaline, tyramine, and glucagon, while relatively potentiating their MCD reactions. This inhibition was unrelated to the α-agonists' known inotropic action and was not affected by catecholamine depletion of the heart. Withdrawal of the α-agonists or administration of the α-adrenoceptor antagonists phentolamine, phenoxybenzamine, or prazosin returned the inotropic and MCD reactions to normal. Neither the MCD response to electrically induced tachycardia nor the inotropic reactions produced by calcium chloride were affected by α-adrenoceptor agonists or antagonists. Alone, α-adrenoceptor antagonists were shown to potentiate the inotropic responses to noradrenaline and isoprenaline while the MCD was relatively diminished. The responses to glucagon were unaltered by α-antagonists. We postulate that myocardial reactivity to sympathetic stimulation can be modulated through α-adrenoceptors by the inhibition of processes that mediate cardiostimulation at post-β-adrenoceptor sites, together with facilitation of those leading up to MCD. Accordingly, this modulation would act to prevent ischaemic damage to the heart by acting to limit the inotropic responses to increasing sympathetic stimulation while maximizing the blood supply to the myocardium.

ISSN:0008-4212    

DOI:10.1139/y85-249

出版商:NRC Research Press    

年代:1985

数据来源: NRC

摘要:

The effect of aldosterone on the density and affinity of binding sites for125I-labelled angiotensin II was investigated in a particulate fraction prepared from the rat mesenteric arteriolar arcades. The infusion of aldosterone 6.6 μg/h intraperitoneally via Alzet osmotic minipumps for 6 d produced an increase in the density of binding sites for125I-labelled angiotensin II without change in affinity. After sodium depletion, mesenteric artery angiotensin II receptors were down-regulated as expected. An increase in the number of binding sites could be found when aldosterone was infused into sodium-depleted rats with no change in the elevated plasma renin activity. The intraperitoneal infusion of angiotensin II (200 ng ∙ kg−1 ∙ min−1for 6 d) simultaneously with aldosterone resulted in down-regulation of vascular angiotensin II receptors, whereas after intravenous angiotensin II infusion (at 60 ng ∙ kg−1 ∙ min−1) the density of angiotensin II binding sites rose with aldosterone infusion. Plasma renin activity (PRA) was reduced and plasma angiotensin II increased in a dose-dependent fashion after angiotensin II infusion. An aldosterone concentration of 3 ng/mL for 18 h produced an increase in the number of angiotensin II binding sites in rat mesenteric artery smooth muscle cells in culture. We conclude that increased plasma aldosterone may result in up-regulation of vascular angiotensin II receptors independently of changes in plasma renin activity, and may in certain physiological states effectively antagonize the down-regulating action of angiote

ISSN:0008-4212    

DOI:10.1139/y85-250

出版商:NRC Research Press    

年代:1985

数据来源: NRC

摘要:

Alterations in transport function have been described 6 weeks after surgical resection of 50% of the distal small intestine. Previous studies demonstrated a modest increase in the jejunal uptake of medium chain length fatty acids following resection, while the uptake of many other lipids (cholesterol, bile acids, fatty alcohols, short and long chain length fatty acids) appears to be unaffected. Marked changes in the kinetic constants for the carrier-mediated uptake of four sugars and leucine were observed following resection, but the changes in transport were not associated with changes in the mucosal surface area. This study was undertaken to examine the possible adaptive mechanisms that occur with ileal resection in the rabbit. A 29% increase in the wet weight of jejunal mucosal scrapings and a 53% increase in jejunal brush border membrane (BBM) protein was observed following resection. The jejunal BBM sucrase (S) was unchanged following ileal resection, but alkaline phosphatase (AP) total activities were increased in the resected rabbits. This resulted in a 45% increase in the ratio of AP/S with resection. The lipid composition (total free fatty acids, total bile acids, total cholesterol, total phospholipids, individual phospholipids, and the ratio of total phospholipids/total cholesterol) of BBM was similar in control and resected rabbits. This suggests that quantitative rather than qualitative changes in the membrane composition may be responsible for the transport changes observed in resected animals.

ISSN:0008-4212    

DOI:10.1139/y85-251

出版商:NRC Research Press    

年代:1985

数据来源: NRC

摘要:

Distension of the isolated mouse stomach stimulated gastric acid secretion. Atropine, cimetidine, or proglumide antagonized the actions of cholinomimetics, histamine, and gastrin, respectively. However, these antagonists and the nerve blocking agent, tetrodotoxin, were without effect on basal secretion or distension-stimulated secretion. It is concluded that in the isolated mouse stomach neither basal secretion nor secretion evoked by distension involve the release of any of the established "physiological" secretagogues or the activation of intramural nerves.

ISSN:0008-4212    

DOI:10.1139/y85-252

出版商:NRC Research Press    

年代:1985

数据来源: NRC

摘要:

The effects of several toxic halogenated aryl hydrocarbons including 2,3,7,8-tetrachlorodibenzo-p-dioxin, 2,3,7,8-tetrachlorodibenzofuran, 2,3,4,7,8-pentachlorodibenzofuran, 3,3′,4,4′-tetrabromobiphenyl, 3,3′,4,4′5-pentachlorobiphenyl, and 3,3′,4,4′-tetrachloroazobenzene on hepatic microsomal testosterone hydroxylases were determined in the immature male rat. All of these compounds induced hepatic testosterone 7α-hydroxylase and inhibited testosterone 6β-, 16α-, 16β-, and 2α-hydroxylases and androstenedione formation. It was observed that there was a good correlation between the increase in testosterone 7α-hydroxylase by the halogenated hydrocarbons and their ability to cause body weight loss in the exposed rats. Comparable linear correlations were observed between toxicity and the decreased activities of other testosterone hydroxylases. The role of altered testosterone metabolism in the toxicity of halogenated aryl hydrocarbons is unknown.

ISSN:0008-4212    

DOI:10.1139/y85-253

出版商:NRC Research Press    

年代:1985

数据来源: NRC

摘要:

The calcium ionophore, A23187, and the tumor-promoting phorbol ester, phorbol 12-myristate 13-acetate (PMA), interacted synergistically to elicit an accelerated superoxide production response in human neutrophils. The lag period preceding PMA-induced superoxide generation was decreased in a dose-dependent manner by A23187 at a concentration range from 1.0 × 10−8to 1.0 × 10−5 M. Superoxide production rate, however, was subject to biphasic effects. While the rate was potentiated in a dose-dependent manner at A23187 concentrations below 1.0 × 10−6 M, inhibitory influences became manifest at higher concentrations. Total superoxide production was subject to inhibitory effects, characterized by a mean inhibitory dose of 1.3 × 10−6 M. The synergistic interaction of A23187 with PMA is consistent with a role for protein kinase C in neutrophil activation. Inhibition at high A23187 concentrations appeared to result from the effects of elevated intracellular Ca2+levels on either NADPH oxidase itself, or some step in the transduction process linking protein kinase C to the oxidase complex.

ISSN:0008-4212    

DOI:10.1139/y85-254

出版商:NRC Research Press    

年代:1985

数据来源: NRC