The role of some central catecholamine systems in cholecystokinin-induced satiety

Cholecystokinin (CCK), bombesin and gastrin were stereotaxically injected into catecholamine (CA) innervated areas of the lateral hypothalamus (LH), the nucleus caudatus putamen (NP) and the olfactory tubercle (OT) in male Sprague Dawley rats. Bilateral injections of 100 ng of CCK in 2 μl of vehicle into the LH produced a slight but significant decrease in food intake during the first hour of a 4 hour eating test. The other peptides when injected into any of the brain areas did not significantly alter food intake. Water intake was affected by the injection of all three hormones although differentially in all 3 sites. The observed changes in drinking were not related to the prandial characteristics of drinking typically seen in rodents. Denervation of the CA innervation of the OT, LH or NP with 6-hydroxydopamine did not change the satiety response to peripherally administered CCK displayed by intact animals. These results suggest that the satiety which occurs after the central and peripheral administration of CCK may be mediated by different mechanisms and that central CA systems may not be necessary for CCK-induced satiety to occur during natural feeding.     

Peripheral factors in the mediation of cholecystokinin-induced satiety as assessed by comparative potencies of cholecystokinin antagonists.

Cholecystokinin COOH-terminal octapeptide (CCK-8) produces a satiating effect in the rat and other animals upon peripheral administration. Although it has been demonstrated that the receptors which mediate this action are located in the periphery and are of the CCK-A subtype, their anatomical location has not been firmly established. A dense population of CCK receptors in the pyloric sphincter has been suggested as a candidate. We here quantify the potency of several CCK antagonists to inhibit the contractile effect of CCK-8 on the rat pyloric sphincter in vitro. The potent and selective antagonist MK-329 has a Schild pK of 8.85; the less potent but selective antagonist lorglumide (CR-1409) a pK of 6.37; the related antagonist phenoxyacetylproglumide (phi oAc proglumide) a pK of 5.1; and the weak parent compound proglumide a pK of about 3.3. These data can be compared with the potencies of these compounds to inhibit the actions of CCK-8 to produce satiety in the rat; this comparison supports the contention that CCK receptors of the rat pyloric sphincter could in part mediate the satiety effect produced by exogenous CCK-8.     

Central and peripheral administration of amylin induces energy expenditure in anesthetized rats

Amylin is a peptide hormone that is co-released with insulin from pancreatic β-cells following a meal. Intracerebroventricular (icv) administration of amylin (1–100 pmol), or an amylin agonist, salmon calcitonin, elicited dose-dependent thermogenic, tachycardic, and hyperthermic responses in urethane-anesthetized rats. Intravenous (iv) administration of higher doses of amylin (100 pmol–20 nmol) also induced similar responses, although the amplitudes of these responses were significantly smaller than those elicited by icv administration, suggesting the primary action of amylin to be in the brain. However, the iv administration of amylin induced the responses slightly faster than the icv injection, the former responses occurring <4 min and the latter, at 8–10 min, after the administration. The iv but not the icv injection of amylin increased the respiratory exchange ratio transiently (<20 min), though the thermogenic response lasted for a longer period after both injections, indicating a shift from mixed fuel to predominantly carbohydrate utilization in the initial phase of thermogenesis induced by the iv injection of amylin. The differences in substrate utilization and latency of the responses suggest that the actions of amylin include partly different targets when administered centrally and peripherally. Moreover, pretreatment with a β-adrenergic blocker, propranolol (5 mg kg⁻¹, iv), blocked all responses elicited by either icv or iv administration of amylin, whereas ablation of the area postrema in the hindbrain did not influence the effects of icv-administered amylin. These results suggest the involvement of amylin in postprandial energy expenditure, mediated by peripheral β-adrenoceptors.     

Central and peripheral monitoring of the cellular redox state after reduced glutathione administration in the rat

In this study we measured reduced glutathione as DTNB reactive material in different brain areas as well as in liver and kidney of rat, before and after exogenous administration of GSH. Treatment with GSH produced an increase in DTNB positive material as well as a decrease of lipoperoxidation, in central and peripheral organs of rat, suggesting the possibility of an exogenous modulation of redox balance in mammalian cells.     

Cholecystokinin and satiety

Fourteen normal volunteers were given intravenous or subcutaneous injections of the synthetic C-terminal octapeptide of cholecystokinin (SQ-19, 844) 10 or 20 minutes prior to the ad libitum consumption of a liquid noontime meal. The drug was given in doses of 20 ng/kg, 40 ng/kg, or 80 ng/kg versus equal volumes of a normal saline control in a random double blind fashion. There was no significant difference between the volumes of lunch consumed after injecting SQ-19, 844 and saline control except one patient who consumed less (p<.05) after 20 ng/kg SQ-19, 844 intravenously. This is interpreted as a random event since higher doses of SQ-19, 844 did not give similar results. It is concluded that cholecystokinin does not reduce food intake and doubt is raised regarding its role as an endogenous satiety signal in man.     

Central and peripheral noradrenergic tone in primary hypertension

The contents of norepinephrine (NE), epinephrine (E), dopamine (DA), normetanephrine (NMN), and 4-hydroxy-3-methoxyphenylethylene glycol (MHPG) were measured in the plasma and cerebrospinal fluid (CSF) of 66 patients with primary hypertension and 24 patients with normal blood pressure and minor neurological disorders. Plasma and CSF NE and NMN concentrations were raised in the hypertensive patients. The plasma and CSF NE levels and arterial blood pressure of a small subset of hypertensive patients were normalized after clonidine therapy. In hypertensive patients the content of DA was lower and the ratio of NE/DA was greater; CSF and plasma NE contents were related to the level of arterial blood pressure; and the content of MHPG in CSF was linked strongly with NE content in plasma and CSF and to the level of arterial blood pressure. Thus both central sympathetic nerve tone and peripheral sympathetic nerve tone were enhanced in young patients with uncomplicated hypertension. The elevated levels of neurohormones and their metabolites in some patients with primary hypertension may be related to increased synthesis and release of neural NE and may be pathogenic in the blood pressure elevation.     

Peripheral administration of GLP-2 to humans has no effect on gastric emptying or satiety

Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are secreted in parallel to the circulation after a meal. Intravenous (IV) GLP-1 has an inhibitory effect on gastric emptying, hunger and food intake in man. In rodents, central administration of GLP-2 increases satiety similar to GLP-1. The aim of the present study was to assess the effect of IV administered GLP-2 on gastric emptying and feelings of hunger in human volunteers. In eight (five men) healthy subjects (age 31.1+/-2.9 years and BMI 24.1+/-1.0 kg m(-2)), scintigraphic solid gastric emptying, hunger ratings (VAS) and plasma concentrations of GLP-2 were studied during infusion of saline or GLP-2 (0.75 and 2.25 pmol kg(-1) min(-1)) for a total of 180 min. Concentrations of GLP-2 were elevated to a maximum of 50 and 110 pmol l(-1) for 0.75 and 2.25 pmol kg(-1) min(-1) infusion of GLP-2, respectively. There was no effect of GLP-2 on either the lag phase (29.5+/-4.4, 26.0+/-5.2 and 21.2+/-3.6 min for saline, GLP-2 0.75 or 2.25 pmol kg(-1) min(-1), respectively) or the half emptying time (84.5+/-6.1, 89.5+/-17.8 and 85.0+/-7.0 min for saline, GLP-2 0.75 or 2.25 pmol kg(-1) min(-1), respectively). The change in hunger rating after the meal to 180 min was also unaffected by infusion of GLP-2. GLP-2 does not seem to mediate the ileal brake mechanism.     

Central and peripheral hemodynamics during maximal leg extension exercise

The purpose of this study was to examine the central and peripheral hemodynamic adaptations to maximal leg extension exercise. Seventeen men (X = 25 years, 84 kg) performed leg extension exercise (Universal equipment) for 12 repetitions (90s) to fatigue. Each repetition consisted of a 3s lifting motion, 1s pause, and 3s lowering motion. Impedance cardiography was used to measure stroke volume (SV), cardiac output (Q), systolic time intervals, and impedance contractility indices on a beat-by-beat basis. There were significant increases in systolic, diastolic, mean arterial pressure, total peripheral resistance, and HR during exercise. The mean Q remained similar throughout the protocol. SV decreased even though indices of myocardial performance indicated an enhancement of contractility. The magnitude of Q and SV were dependent upon the phase of leg extension. SV and Q during the lifting portions of the exercise were smaller than the lowering portions. The differences in SV and Q during the concentric and eccentric phases of the exercise most likely reflect the large static forces in exercising muscle which impeded venous return and increased afterload.     

Central and peripheral alpha adrenergic activity of imidazoline derivatives

Intravenous injection of a number of imidazoline derivatives into rats induced an increase in blood pressure due to peripheral alpha adrenergic receptor stimulation. Some of these compounds, however, caused a secondary, long lasting decrease which was caused by central nervous system alpha adrenergic receptor stimulation. This central hypotensive action was only observed in the case of 2-amino-imidazolines such as clonidine, tramazoline and St 600, a clonidine analogue. Imidazolines lacking the nitrogen between the imidazoline and the benzene or naphtalene group such as oxymetazoline, xylometazoline and naphazoline were found to exert no central hypotensive action.Within the series of 2-amino-imidazolines lipid solubility turned out to be a major factor in the potency of a drug's central hypotensive action.Oxymetazoline — peripherally a very potent alpha adrenergic receptor stimulating agent — did not even cause hypotension when injected into the anterior hypothalamus, a brain structure where alpha adrenergic receptors mediating depressor effects have been localized. These data show that the hypothalamic alpha adrenergic receptors differ from peripheral alpha receptors and that only imidazolines with 2-amino substitution show affinity for these central hypotensive alpha adrenergic receptors.     

Central and peripheral mechanisms of difficult breathing in man

The review is dedicated of phenomenology of the difficult breathing and analysis of the peripheral and central mechanisms of it. Analysis based on model investigations with resistive loads in awake or sleeping healthy humans, including results of experiments in the anesthetized animals. The recent data having principle importance in estimation of the central mechanisms of the control breathing are included too in the review. It concerned to the contemporary visualization of central neuronal activity on the awake person during dyspnoea. It became possible due to application of the unique precision equipment--functional magnetic--resonance and positron--emission tomography.     

Cholecystokinin tetrapeptide,proglumide and open-field behavior in rats

The effect of cholecystokinin tetrapeptide (CCK-4) was studied in an open field situation. CCK-4 increased locomotion and rearing and the effect was enhanced by proglumide, a selective antagonist of CCK-8. This is in sharp contrast to our earlier findings that CCK-8 decreased the open-field behavior and that proglumide completely blocked the effect. Thus, the effects of CCK-4 and CCK-8 appear to be opposite to each other in that one is excitatory and the other inhibitory to open-field responses.     

Brain and serum levels of naloxone following peripheral administration

Striatal, hypothalamic and serum concentrations of naloxone were measured by a new high-performance liquid chromatographic procedure at various time up to 120 min following subcutaneous administration of 1, 5, and 10 mg naloxone hydrochloride/kg to rats. A dose-concentration relationship was evident throughout. Peak levels were observed at the first measurement time (15 min) and tissue values were consistently higher than concentrations in serum. The correlations between serum and brain naloxone levels suggests that in normal rats central concentrations of the drug can be extrapolated from serum concentrations.