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PubMed1981

Apical K+ channels in frog skin (Rana temporaria): cation adsorption and voltage influence gating kinetics.

Open-close kinetics of fluctuating K+ channels in the apical frog skin membrane were studied with noise analysis of the K+ current (IK). The mucosa to serosa directed IK was obtained with serosal NaCl- and mucosal KCl-Ringer under voltage clamp conditions. Mucosal protons (pH greater than 4), several polyvalent metal ions, and choline shifted the plateaus (SO) of the Lorentzian component in the IK noise spectrum to higher, but the corner frequency (fc) to lower values. SO was lowered at pH less than 4, due to a K+-channel block by H+. Ca2+, Sr2+, H+ (pH greater than 4) and choline did not affect IK. A slight reduction of IK was seen with Mg2+, Mn2+, Co2+, Ni2+, Zn2+, Cu2+ and La3+. At pH greater than 4, the H+-induced shifts in SO an fc were almost abolished in solutions of high mucosal Ca2+ concentrations. Clamping the transepithelial potential difference to more positive values (with respect to the serosa) shifted the Lorentzian parameters SO and fc in the same way as the cations did. As with protons, mucosal Ca2+ interferred with the effect of voltage. The interference of cationic (probably fixed charge screening) and voltage effects suggests a common, more general mechanism of action, namely alterations in K+-channel fluctuation kinetics by changes in local electrical fields. On this basis, the rates for the open-close reaction of K+ channels and their mean lifetime were calculated. We found that e.g. increasing [Ca2+]O from 1-10 mM caused no change of the mean open time, but increased the mean time "closed" of the K+ channel by a factor of about 1.5. Other mucosal cations, as well as depolarizing clamp potentials are thought to have the same effect.

Animals↗
PubMed1993

Centrally administered neuropeptide Y (NPY) inhibits gastric emptying and intestinal transit in the rat.

Neuropeptide Y is distributed abundantly not only in the brain, but also in the gastrointestinal tract and suppresses intestinal muscle contraction in isolated muscle preparations. The purpose of the present study was to determine whether centrally administered neuropeptide Y modulated gastric emptying and intestinal transit in conscious rats. Graded doses of neuropeptide Y were administered intracisternally 1 min before ingestion of test meals through an oral tube. Four hours after ingestion of 60 Amberlite pellets, the rats were sacrificed and residual pellets in the stomach and the small intestine segments were counted to calculate the solid meal transit rate. The liquid meal transit rate was calculated 1 hr after 0.07% phenol red ingestion by determining the residual phenol red in the stomach and the small intestine segments. Neuropeptide Y elicited potent suppression of gastric emptying and intestinal transit of both solid and liquid meals. Pretreatment with propranolol antagonized, whereas phentolamine did not affect, the suppressive effect of central neuropeptide Y. Although carbachol blocked the effects of neuropeptide Y, neither atropine nor hexamethonium altered the actions of neuropeptide Y. In conclusion, centrally administered neuropeptide Y strongly inhibited gastrointestinal transit by stimulating a beta-adrenergic pathway.

Animals↗
PubMed1983

Relationship between small bowel transit time and absorption of a solid meal. Influence of metoclopramide, magnesium sulfate, and lactulose.

The times taken for a radiolabeled solid meal to empty from the stomach and terminal ileum and the absorption of the components of that meal were measured in 14 patients with terminal ileostomies under control conditions and after administration of either lactulose (40 g) or metoclopramide (20 mg tds), or magnesium sulfate (0.1 g/kg body weight). Absorption of each of the components of the meal was determined by chemical analysis of the ileostomy effluent. The radioisotope proved an excellent marker for the delivery of fat, protein, and carbohydrate residues. All three agents significantly reduced the time taken for the meal to empty from the ileum. This was associated with significant reductions in the absorption of fat, carbohydrate, protein, water, and electrolytes in the case of lactulose and magnesium sulfate. Although metoclopramide reduced transit time to the same degree as the other agents, its effect on absorption of fat, fluid, and electrolytes was much less, and absorption of protein and carbohydrate was unaffected. We therefore conclude that, although agents that accelerate postprandial transit of a meal may diminish absorption of the component of that meal in the small bowel, the extent to which this occurs cannot be predicted by a knowledge of transit kinetics alone and depends on the means by which transit is altered. The action of lactulose on the small intestine causes fluid and fat losses, sufficient to result in diarrhea and steatorrhea in a normal subject.

Adult↗
PubMed1976

The effects of L-histidine and of specific histamine receptor agonists, on the expression of morphine tolerance and physical dependence in mice.

The effects of L-histidine, and of the specific histamine receptor agonists 2-methylhistamine and 4-methylhistamine, on the expression of morphine tolerance and physical dependence have been studied in mice. These agents were administered during the "withdrawal" phase of development. All of them significantly increased tolerance but reduced the degree of physical dependence. The effects of 2-methylhistamine, which has predominantly H1-receptor activity, were completely abolished by the prior administration of the H1-antagonist mepyramine. The H2-antagonist metiamide, on the other hand, did not alter the action of 2-methylhistamine on physical dependence, though tolerance was restored to its original level. The effects of 4-methylhistamine, which is a specific H2-receptor agonist, were inhibited by metiamide, but mepyramine was unable to reverse the actions of this agonist. The effects of L-histidine, the major precursor of brain histamine, were unaltered by mepyramine, but partially inhibited by metiamide. These experimental findings are discussed in detail, and are considered to give further support to the view that histamine is implicated in some way in the mechanisms of the "withdrawal" phase of morphine tolerance and physical dependence in mice, with H2-receptors probably playing the more important role.

Animals↗
PubMed1996

Novel estrogen feedback sites associated with stress-induced suppression of luteinizing hormone secretion in female rats.

1. The fasting-induced suppression of LH secretion is totally dependent on steroidal milieu because the suppression is observed only in intact or ovariectomized estrogen-primed rats but not in ovariectomized animals. The following neural pathway mediating fasting-induced suppression of LH secretion has been suggested by a series of experiment: A neural signal emanating from the stomach during fasting reaches the medulla oblongata via afferent vagal nerve so as to activate the noradrenergic system projecting to the PVN: this results in an increased CRH release, and in turn the suppression of the LHRH release and then LH release. Estrogen seems to activate the neural pathway by acting on somewhere in the pathway. 2. We found that the paraventricular nucleus of the hypothalamus (PVN) and A2 region of the medulla oblongata is the estrogen feedback sites associated the dependence of the fasting-induced suppression of LH secretion on estrogen. The estrogen feedback action on the PVN does not involve an increase in norepinephrine release in the PVN. In addition, we also found that estrogen receptors are increased in the PVN and A2 region by acute fasting. Therefore, the following hypothesis is proposed: fasting first induces an transient increase in the activity of noradrenergic system at the beginning of the first dark phase after the food deprivation; this activation results in an increase in estrogen receptors in the PVN and A2 region; the increase in estrogen receptors leads to an increase in the sensitivity of noradrenergic systems to the neural inputs associated with fasting to these nuclei. 3. The response of the reproductive activity to various external stimuli including stress is modulated by ovarian steroids. The estrogen feedback action on the PVN and A2 is totally different from the so-called "negative feedback action" of estrogen that is for monitoring the ovarian condition. The novel estrogen feedback action may alter the response of neurons regulating gonadal axis to the signal associated with environmental cues such as stress.

Animals↗
PubMed1981

[Control of gastric acidity with cimetidine given as premedication before general anesthesia: efficacy and tolerance].

Cimetidine 400 mg was administered intramuscularly 60 minutes before the beginning of general anaesthesia. The double blind experiment was conducted on 84 patients divided in two groups: cimetidine and control. There was no difference in gastric fluid volume between the two groups during general anaesthesia, but acid secretion decreased significantly in the cimetidine group. Values of pH lower than 2.5 were observed in 33.3 per cent at induction and 34 per cent at recovery in the control group against 14.6 per cent and 0 per cent in the cimetidine group. Clinical tolerance to cimetidine was studied in 100 patients during operation. Cimetidine did not alter pharmacological action of usual anaesthetics. There were no significant changes in cardiovascular and electrocardiographic data.

Anesthesia, General↗
PubMed2001

Substituting dietary saturated for monounsaturated fat impairs insulin sensitivity in healthy men and women: The KANWU Study.

AIMS/HYPOTHESIS: The amount and quality of fat in the diet could be of importance for development of insulin resistance and related metabolic disorders. Our aim was to determine whether a change in dietary fat quality alone could alter insulin action in humans. METHODS: The KANWU study included 162 healthy subjects chosen at random to receive a controlled, isoenergetic diet for 3 months containing either a high proportion of saturated (SAFA diet) or monounsaturated (MUFA diet) fatty acids. Within each group there was a second assignment at random to supplements with fish oil (3.6 g n-3 fatty acids/d) or placebo. RESULTS: Insulin sensitivity was significantly impaired on the saturated fatty acid diet (-10%, p = 0.03) but did not change on the monounsaturated fatty acid diet (+2%, NS) (p = 0.05 for difference between diets). Insulin secretion was not affected. The addition of n-3 fatty acids influenced neither insulin sensitivity nor insulin secretion. The favourable effects of substituting a monounsaturated fatty acid diet for a saturated fatty acid diet on insulin sensitivity were only seen at a total fat intake below median (37E%). Here, insulin sensitivity was 12.5% lower and 8.8% higher on the saturated fatty acid diet and monounsaturated fatty acid diet respectively (p = 0.03). Low density lipoprotein cholesterol (LDL) increased on the saturated fatty acid diet (+4.1%, p < 0.01) but decreased on the monounsaturated fatty acid diet (MUFA) (-5.2, p < 0.001), whereas lipoprotein (a) [Lp(a)] increased on a monounsaturated fatty acid diet by 12% (p < 0.001). CONCLUSIONS/INTERPRETATION: A change of the proportions of dietary fatty acids, decreasing saturated fatty acid and increasing monounsaturated fatty acid, improves insulin sensitivity but has no effect on insulin secretion. A beneficial impact of the fat quality on insulin sensitivity is not seen in individuals with a high fat intake (> 37E%).

Adult↗
PubMed2001

Morphometric documentation of abnormal intramyocellular fat storage and reduced glycogen in obese patients with Type II diabetes.

AIMS/HYPOTHESIS: Insulin resistance of skeletal muscle has been associated with increased lipid availability. This study aimed to estimate volume fractions of intramyocellular triglyceride droplets and glycogen granules in skeletal muscle using electron microscopy and furthermore, relate these findings to insulin sensitivity and the level of circulating lipids. METHODS: We compared 11 obese patients with Type II (non-insulin-dependent) diabetes mellitus and 11 obese normoglycaemic subjects matched for age and sex. Glucose metabolism was determined using the euglycaemic hyperinsulinaemic clamp technique (40 mU.m(-2).min(-1)) coupled with indirect calorimetry and tritiated glucose. On the second day, using an automatic procedure, a fasting muscle biopsy was carried out and processed for electron microscopy. Volume fractions of intramyocellular structures were estimated by pointcounting on photographic pictures in a blinded manner. RESULTS: Insulin-stimulated total glucose disposal rate was lower in the Type II diabetic subjects compared with the obese normoglycaemic subjects (4.96 +/- 049 vs 10.35 +/- 0.89 mg.min(-1).kg ffm(-1), p < 0.001) as was glucose storage (2.03 +/- 0.50 vs 6.59 +/- 0.83, p < 0.001). The electron microscopy study revealed that the diabetic subjects had higher intramyocellular amounts of triglyceride (1.43 +/- 0.21 vs 0.39 +/- 0.07%, p < 0.001) and lower amounts of glycogen (3.53 +/- 0.33 vs 6.94 +/- 0.54%, p < 0.001). Mitochondrial volume was identical indicating equal aerobic capacity. The fractional intramyocellular lipid volume was found to be positively associated with fasting NEFA (r = 0.63, p = < 0.05 and r = 0.79, p = < 0.05) and triglyceride (r = 0.74, p = 0.01 and r = 0.62, p < 0.05) in the obese diabetic and normoglycaemic cohorts respectively. Intramyocellular lipid content was negatively correlated to insulin sensitivity (r = -0.71, p < 0.02) in the obese diabetic group whereas no significant association was found in the obese normoglycaemic group. CONCLUSION/INTERPRETATION: This study shows that fat accumulates intramyocellulary while glycogen stores are simultaneously reduced in obese subjects with Type II (non-insulin-dependent) diabetes mellitus. Quantitatively, a major component of the excessive lipid accumulation could be secondary in origin, related to the diabetic state in itself, although a contribution from the altered insulin action cascade of obesity and diabetes cannot be excluded. In both groups significant positive relations were found between circulating and intramyocellular lipid.

Adipocytes↗
PubMed2006

Abeta peptides as one of the crucial volume transmission signals in the trophic units and their interactions with homocysteine. Physiological implications and relevance for Alzheimer's disease.

Amyloid peptides (Abeta) can operate as volume transmission (VT) signals since they are continuously released from cells of the central nervous system and diffuse in the extra-cellular space of the brain. They have both regulatory and trophic functions on cellular networks. In agreement with Abeta regulatory actions on glial-neuronal networks, the present paper reports new findings demonstrating that intrastriatal injections of Abeta peptides reduce striatal tyrosine hydroxylase, increase striatal GFAP immunoreactivities and lower pain threshold in experimental rats. Furthermore, it has been demonstrated that exogenous homocysteine (Hcy) binds Abeta(1-40) favouring its beta-sheet conformation both in vitro and in vivo and hence the formation of beta-fibrils and development of neurotoxicity. Thus, the hypothesis is discussed that Abeta peptides represent crucial VT-signals in the brain and their action is altered by dysmetabolic signals such as high Hcy extra-cellular levels, known to be an important risk factor for Alzheimer's disease.

Alzheimer Disease↗
PubMed1984

Influence of beta-adrenergic blockade on the hemodynamic effects of physical training in patients with ischemic heart disease.

Beta-blocking agents are widely used in the treatment of patients with coronary artery disease. Their negative chronotropic and inotropic actions may alter the effects of physical training in cardiac rehabilitation programs. Therefore, resting and exercise cardiac output, stroke volume, heart rate, and arteriovenous oxygen content difference were measured before and after training in 15 male patients with coronary artery disease, who were treated with beta blockers, and in a control group of 14 patients not treated with beta-blocking agents. At the end of a 3-month training period, oxygen uptake at peak exercise increased similarly in the two groups, 37% and 34%, respectively; this was related to increases in stroke volume and heart rate, and therefore cardiac output, and to increases in arteriovenous oxygen content difference. The effects were similar whether or not the patients were treated with beta blockers. Also, at rest and submaximal exercise, beta blockade did not affect the training-induced changes of cardiac output, heart rate, and arteriovenous oxygen content difference. In both groups heart rate decreased with training while stroke volume and cardiac output increased significantly. In conclusion, beta blockade did not significantly alter the hemodynamic effects of training.

Adrenergic beta-Antagonists↗
PubMed1986

Diabetes in the elderly: diagnosis, pathogenesis, and therapy.

The prevalence of diabetes mellitus increases with age; it occurs in approximately 10 percent of Americans 60 years of age and in 16 to 20 percent of those 80 years old. Type II diabetes mellitus is primarily found in the elderly, and it is estimated that an additional 20 percent of the elderly population has age-associated hyperglycemia, which may be part of a spectrum between normality and type II diabetes. The diabetic group is at risk for both microvascular and macrovascular complications of diabetes, whereas the group with the hyperglycemia of aging may be at risk for macrovascular-type complications. Thus, 40 percent of our senior population has abnormal carbohydrate tolerance and is at risk for diabetic-type chronic complications. The basis for both the diabetic state as well as for the hyperglycemia of aging is probably multifactorial--involving both altered insulin secretion and altered insulin action. Unique problems arise in treating older diabetic patients. Physiologic changes occurring during normal aging, age-associated pathologic processes, the increased prevalence of other chronic diseases, and polypharmacy must all be considered in selecting appropriate therapy for these patients. A rational approach for the maintenance of glucose homeostasis is presented for older patients with diabetes.

Adolescent↗
PubMed1986

Pharmacological analysis of the neurotransmitter mechanisms regulating phenylethanolamine N-methyltransferase in the adrenal gland.

The i.p. administration of reserpine daily for 4 days to rats brought about an increase of adrenal phenylethanolamine N-methyltransferase (PNMT) activity. However, the combination of the systemic administration of p-chlorophenylalanine (PCPA) and reserpine for 3 days produced an earlier increase in this adrenal enzyme. The effect was reduced significantly in the denervated gland. Prior administration of 5,7-dihydroxytryptamine (DHT) i.c.v. to rats greatly potentiated the inducing effect of reserpine. On the other hand, the depletion of catecholamines by giving rats alpha-methyl-p-tyrosine (AMPT) i.p. or 6-hydroxydopamine (6-OHDA) i.c.v. did not alter the action of reserpine on adrenal PNMT. PCPA, DHT, AMPT and 6-OHDA did not have any effect by themselves on adrenal PNMT, but the combination of PCPA and AMPT, each given i.p., caused increased adrenal PNMT activity. The administration of dopamine agonists, a treatment that increases adrenal TH, did not modify adrenal PNMT. We conclude that the induction of PNMT by reserpine involves depletion of catecholamines and serotonin, the depletion of serotonin having the more powerful effect. A monoaminergic (serotonergic) inhibitory pathway is involved in the central regulation of adrenal PNMT activity.

Adrenal Glands↗
PubMed1982

Inhibition of sympathetic preganglionic discharges by epinephrine and and alpha-methylepinephrine.

The present study was undertaken to determine the effect of iontophoretic applications of epinephrine (E) and its derivative alpha-methylepinephrine (mE) on the discharges of sympathetic preganglionic neurons (SPNs). Spontaneously active SPNs located in thoracic segment T2 were antidromically identified in White Carneaux pigeons anesthetized with urethane and immobilized with purified alpha-cobratoxin. All SPNs tested were inhibited by E, mE, several other catecholamines, clonidine, GABA, glycine and morphine. The inhibitory effects of E and mE but not those of GABA were antagonized by iontophoretic applications of the preferential alpha 2-antagonists piperoxane and yohimbine, but not by the alpha 1-antagonist prazosin or the beta-antagonist sotalol when similarly applied. The inhibitory effects of GABA, glycine and morphine were respectively antagonized by bicuculline methiodide, strychnine and naloxone, but these antagonists failed to alter the action of E. It is concluded that (1) epinephrine and its alpha-methyl derivative inhibit the discharges of SPNs via the activation of alpha 2-receptors and (2) the epinephrine-induced inhibition does not result from the secondary release of GABA, glycine or opioid peptides from afferent terminals or interneurons.

Animals↗
PubMed1989

Localization of prolactin binding sites in ring dove brain by quantitative autoradiography.

Specific binding sites for prolactin have been previously detected and characterized in ring dove brain membranes. In order to map the distribution of these sites, specific binding of 125I-ovine prolactin was examined in slide-mounted sections of 6 male and 6 female ring dove brains by in vitro film autoradiography and densitometry. Analysis of 34 brain regions revealed a sex-specific pattern in specific binding activity. Although no significant sex differences were observed in any individual brain region, a trend in this direction was observed in the preoptic area. Specific binding levels in which the lower limit of the 99% confidence interval was greater than zero were detected in choroid plexus, medial habenula, lateral mesencephalic nucleus, hippocampus, parahippocampal area, preoptic area and 4 hypothalamic sites: paraventricular nucleus, ventromedial nucleus, suprachiasmatic nucleus, and tuberal region. Autoradiographic analysis of specific binding in cerebellum, ventromedial hypothalamus, and hippocampus/parahippocampus yielded relative differences that closely approximated those obtained in binding studies on tissue homogenates from these regions. These results suggest possible sites of prolactin action in altering behavioral state and neuroendocrine function in this species.

Animals↗
PubMed1994

Transendothelial electrical potential across pial vessels in anaesthetised rats: a study of ion permeability and transport at the blood-brain barrier.

Brain pial microvessels have previously been demonstrated to have blood-brain barrier properties. The potential difference (PD) across exposed brain pial microvessels, 20-60 microns in diameter and superfused with artificial CSF, has been measured in anaesthetised rats using glass microelectrodes. The PD on insertion into venous vessels, V(in), was 3.2 mV lumen negative, and in arterial vessels it was higher at 4.5 mV. Superfusion with high K(+)-CSF, made by replacing Na+ with K+, caused a positive deflection in PD, VK+, whereas reducing the Na+ alone, by replacing Na+ by Tris-HCl, made the lumen more negative. These two effects were additive. Studies on venous vessels showed that ouabain had no effect on V(in) and only affected VK+ under conditions of low Na pre-exposure. Neither histamine nor cimetidine had any effect on V(in) or VK+ whereas tetraethylammonium, a K(+)-channel blocker, reduced VK+ by 20%. These experiments demonstrate that changes in PD caused by changing abluminal Na+ or K+ are due predominantly to movement of ions through channels in the endothelial cell membranes, and that actions that alter the activity of the Na+,K(+)-ATPase or reduce the resistance of the paracellular pathway in parallel with increased membrane permeability have less effect on the PD.

Anesthesia↗
PubMed1994

The involvement of sympathetic nerves in plasma extravasation induced by prostaglandin E2 and substance P.

The effects of intravenous injection of prostaglandin E2 (PGE2), substance P (SP) and a metabolically stable SP analogue, [pGlu5,Me-Phe8,Sar9]-SP (5-11) on plasma extravasation of albumin in the rat after blockade of prostaglandin synthesis with indomethacin or chemical sympathectomy with guanethidine were studied. Blood pressure was decreased by all agonists, but only the hypotensive effects of SP were enhanced by pretreatment with indomethacin and guanethidine. The increase in plasma extravasation induced by PGE2 in the tongue, skin and lungs was blocked by both guanethidine and indomethacin. Pretreatment of the rats with guanethidine or indomethacin increased extravasation induced by SP in the tongue-tip, dorsal skin and foot, but decreased the enhanced permeability in the pinna, and did not alter the actions of the peptide in other tissues. In contrast, both guanethidine and indomethacin pretreatment increased vascular permeability responses to [pGlu5,Me-Phe8,Sar9]-SP (5-11) administration in 9 and 14 of 16 tissues examined, respectively. Thus, intact sympathetic nerves and functional cycloxygenase activity exert inhibitory constraints on the vascular permeability effects of intravenously administered SP or its analogue. On the other hand the integrity of the sympathetic nerves and prostaglandin synthesis are required for PGE2-induced increases in vascular leak.

Amino Acid Sequence↗
PubMed1980

Modulation by histamine of peripheral vagal transmission in anesthetized mongrel dogs.

Intravenous infusion of histamine (6.0 microgram/kg/min) attenuated bradycardic responses to electrical stimulation of right vagus in anesthetized mongrel dogs. Similarily histamine also reduced reflexly mediated decreases in the heart rate to phenylephrine, while bradycardia induced by exogenous acetylcholine was not altered. This inhibitory action of histamine on responses to vagal stimulation could be antagonized by pretreatment with metiamide, an H2-receptor antagonist; but not by pyrilamine, and H1-receptor blocker. Metiamide significantly potentiated the negative chronotrophic effect of vagal stimulation. These results indicate that histamine could inhibit peripheral vagal transmission via a presynaptic action. The ability of histamine to alter vagal transmission may have physiological significance and play a role in histamine-induced tachycardia.

Acetylcholine↗