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"Peripheral" benzodiazepine binding sites (PBS) were studied in both the CNS and peripheral tissues of Maudsley reactive (MR) and Maudsley non-reactive (MNR) rats using the PBS specific ligand [3H]Ro 5-4864. A statistically significant reduction in the density of PBS was found in heart and kidney of the MR compared to the MNR. Similar reductions in the density of PBS were not observed in a number of areas of the central nervous system (including cortex, hippocampus, and hypothalamus) or other peripheral tissues, such as lung and adrenal. This selective decrease in PBS in a strain selectively bred for a high degree of "fearfulness" may be related to previous findings of a reduction in the density of PBS in the same tissues in rats subjected to uncontrollable shock. These observations suggest that PBS in heart and kidney may be altered in response to fear or anxiety.
In peripheral tissues from organs such as the kidney, liver and spleen, specific binding of 3H-baclofen was most highly detected in the kidney, and that in the liver and spleen was approximately one-tenth that in the kidney. The amount of specific binding did not differ at a room temperature of 20-25 degrees C or 0-4 degrees C, and equilibration occurred within 10 min. Divalent cations (Ca2+, Mg2+, Mn2+ and Ni2+) and monovalent cations (Na+ and K+) did not increase the specific binding, yet in higher concentrations, they decreased both specific and non-specific binding. Specific binding showed a single component, Kd and Bmax of which were 6.35 microM and 79 pmol/mg protein, respectively. The binding was stereospecific; (-)baclofen was 150 times as potent as (+)baclofen. Some of the structural analogues of baclofen inhibited 3H-baclofen binding whereas GABA and its related compounds showed little or no inhibition. Bmax of the binding in the kidney of spontaneously hypertensive rats (SHR) was higher by 28% than that of normotensive Wistar-Kyoto rats (WKY), whereas the Kd values did not differ. These results indicate that specific 3H-baclofen binding in the rat peripheral tissues is entirely different from the binding in the central nervous system (GABAB sites).
The peripheral production of high density lipoprotein (HDL) cholesterol and of the subclasses HDL2 and HDL3 was assessed by measurement of the arteriovenous fluxes across the human forearm, at rest and after 20 min isometric exercise in the forearm. Eight subjects were studied twice--fasting and after a high-fat meal--and one other subject was studied only after fat loading. In the fasted state the net fluxes of HDL2 and HDL3 cholesterol were slightly negative in the resting forearm, but they became positive during exercise, indicating greater production during short-term muscular activity. The effect of exercise, particularly that on HDL3 cholesterol, was greatly increased by a high-fat meal; the difference in HDL3 cholesterol arteriovenous flux between rest and exercise was significant (-0.06 [SEM 0.05] vs 0.51 [0.17] mumol/100 ml forearm/min). By contrast, there was no peripheral production of HDL2 or HDL3 cholesterol during exercise in two patients with lipoprotein lipase deficiency. These findings suggest that formation of HDL3 during lipolysis by lipoprotein lipase in the muscle capillary bed is influenced by the supply of chylomicrons and other lipoprotein substrates for this enzyme. Muscle blood flow may therefore be an important determinant of HDL production by this mechanism. The effect of exercise in raising HDL cholesterol, and the inverse relation between exercise and coronary heart disease, may be partly the result of this process.
Quantitative receptor autoradiography using several radiolabeled tachykinins was used to localize and characterize tachykinin peptide receptor binding sites in rat CNS and peripheral tissues. Autoradiographic localization and displacement experiments using several radiolabeled tachykinins indicate that in the rat there are at least 3 distinct tachykinin receptor binding sites. One of these is present in both the CNS and peripheral tissues, one is present only in the CNS, and one is present only in peripheral tissues. The first tachykinin receptor binding site, which is detectable in both the CNS and peripheral tissues, appears to prefer substance P (SP) as an endogenous ligand. Areas expressing high concentrations of this binding site include the medial septum, superior colliculus, inferior olive, inner plexiform layer of the retina, external muscle of the bladder, and the muscularis externa of the esophagus. The second type of tachykinin receptor binding site, which is detectable only in the CNS appears to prefer either neuromedin K (NK) and/or substance K (SK) as the endogenous ligand. This receptor binding site is labeled by Bolton-Hunter conjugates of NK, SK, eledoisin, or kassinin and is found in high concentrations in laminae 4 and 5 of the cerebral cortex, the ventral tegmental area, laminae 1 and 2 of the spinal cord, and the inner plexiform layer of the retina. The third type of tachykinin receptor binding site is detectable only in peripheral tissues and appears to prefer SK as the endogenous ligand. This receptor binding site is labeled by SK, eledoisin, or kassinin radioligands and tissues that express high concentrations include the muscularis mucosae of the esophagus, the circular muscle of the colon, and the external muscle of the bladder. These data suggest that SP receptors are expressed in the brain and peripheral tissues, NK receptors are expressed in the CNS, and SK receptors are expressed in peripheral tissue. These data fit well with radioimmunoassay data that suggest that, whereas in the CNS SP, SK and NK are present in high concentrations, in peripheral tissues only SP and SK are present in detectable concentrations. The present classification of tachykinin receptors places a lower limit on the number of mammalian tachykinin receptor types and provides a functional/morphological framework for exploring the diverse actions of tachykinin peptides in both the CNS and peripheral tissues.
The effects of TRIAC on peripheral thyroid hormones, TSH incretion and peripheral tissue parameters were investigated in 13 mildly obese patients (group I) and 10 volunteers of normal body weight (group II). TRIAC was administered 3 x 1 mg daily over a period of 8 days to both groups. In group I (on a 400 kcal low caloric diet) bTSH and fT4 decreased significantly whereas TT4 decreased only insignificantly. TT3 and fT3 rose significantly due to the cross-reactivity of the employed antibody. The peripheral tissue parameters cholesterol, ankle jerk and systolic time interval did not reveal any changes suggesting an increase in metabolic rate. The increase in heart frequency was not significant either. The significant rise in sex-hormone binding globulin was most probably associated with the weight reduction of 3.1 +/- 1.2 kg per week. In group II (on normal diet) bTSH and fT4 decreased significantly whereas TT4 decreased only insignificantly. As in group I, TT3 and fT3 rose significantly. Also in group II TRIAC did not cause alterations in the peripheral tissue parameters. In contrast to the obese group the volunteers in group II showed no significant rise in sex-hormone binding globulin and no reduction of body weight. Side effects such as nervousness, tremor or palpitations were not observed. Thus, TRIAC does not induce an increase in peripheral metabolic rate, not even under a TSH-suppressive dose as high as 3 x 1 mg per day.
The conversion of 3 beta-hydroxy-5-ene steroids by the enzyme complex 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) is an essential step in the biosynthesis of all classes of hormonal steroids. We report the characterization of two types of cDNA clones encoding rat 3 beta-HSD isolated from a rat ovary lambda gt11 cDNA library with a human 3 beta-HSD cDNA probe. Both type I and type II cDNAs encode proteins of 372 amino acids having 94% homology. Transient expression of the type I and the type II 3 beta-HSD cDNAs in HeLa human cervical carcinoma cells reveals that both proteins possess 3 beta-hydroxysteroid dehydrogenase as well as delta 5-delta 4 isomerase activities for both delta 5-pregnene and delta 5-androstene precursors, although the type I 3 beta-HSD protein is more active than the type II. RNA blot analysis using type I 3 beta-HSD cDNA identifies major mRNA transcripts of 1.7 kilobase in rat ovary, testis, and adrenal poly(A)+ RNA. RNase protection assay using type I- and type II-specific cRNA probes revealed the existence of the two corresponding mRNAs in male and female rat adrenals and gonads as well as in female adipose tissue while only type I mRNA is present in male and female kidney. Moreover, in situ hybridization performed using type-specific labeled 24-mer oligonucleotides confirms that type I is the major mRNA species in the ovary and further indicates that both mRNA species have a similar cellular distribution in the ovarian tissue with the highest level of expression found in corpora lutea. Immunoblot analysis using polyclonal antibodies raised against purified human placental 3 beta-HSD identified a single 42-kDa band in rat ovary, testis, and adrenal, which agrees with the calculated molecular masses of 41,911 and 42,150 daltons for the type I and II proteins, respectively. Determination of 3 beta-HSD enzymatic activity using [14C]pregnenolone and [14C]dehydroepiandrosterone as substrates shows that 3 beta-HSD activity is present not only in the gonads and adrenals of animals of both sexes, but also in many peripheral tissues including adipose tissue, mammary gland, kidney, liver, prostate, seminal vesicle, uterus, skin, brain, heart, thymus, pancreas, lung, and spleen. The present data indicate the existence of two mRNAs encoding rat 3 beta-HSD and their differential tissular distribution in both steroidogenic and peripheral tissues.(ABSTRACT TRUNCATED AT 400 WORDS)
Peripheral neuroepithelioma of soft tissue belongs to the group of peripheral neuroectodermal tumors (PNETs), but because of its clinical, biological, and morphological characteristics, it differs from other small, round-cell sarcomas that appear in children (neuroblastoma) or in the thoracopulmonary region (Askin's tumor) and bone (peripheral neuroectodermal sarcoma of bone). We report ten new cases of such PNET variety, based on their histologic, immunohistochemical, and electron microscopic findings. In all of these cases, the clinicopathologic correlations demonstrated high malignancy, with an ominous outcome in nine cases. The mean age of the patients was 32.6 years and there was a clear male predominance (eight men, two women). Histologically, the presence of Homer-Wright rosettes is mandatory for diagnosis, being complemented with positive immunohistochemistry for several neural immunomarkers using paraffin-embedded material. Neuron-specific enolase, E-36, HNK-1, and chromogranin neural markers proved to be positive in a high number of cases, but other markers (S-100 protein, synapto-physin, GFA protein, and neurofilaments [70 kilodalton]) were absent. Electron microscopy confirmed the presence of neural structures, both by scanning and transmission electron microscopy.
To clarify the histamine (HA) dynamics in peripheral tissues, effects of drugs on the tissue HA and tele-methylhistamine (t-MH) levels were studied in mice. alpha-Fluoromethylhistidine (50 mg/kg, i.p.) significantly decreased the HA level in the stomach, but not in the liver, heart, ileum, submandibular gland and skin of mice. This compound had no significant effect on the t-MH level in any tissue examined. In non-fasted and 24-hr fasted animals, the t-MH level in the liver, heart and ileum was significantly increased by treatment with aminoguanidine (10 mg/kg, i.p.) plus pargyline (65 mg/kg, i.p.). However, in mice fasted for 48 hr, this treatment was ineffective in increasing the t-MH level in the heart and ileum, suggesting that the t-MH level in some peripheral tissues is under the influence of the food intake. Even if HA is synthetized and then metabolized in the peripheral tissues, the size of the HA pool with a rapid turnover in each tissue except for the gastric tissue seems to be very small.
The single pass mean residence time in peripheral tissues, tp1, is a characteristic constant of linear pharmacokinetic systems and nonlinear systems with linear distribution kinetics. It is descriptive of distribution kinetics in such systems and is not dependent on elimination kinetics as are other related parameters, e.g., mean residence time in peripheral tissues, tp. Equations are derived which permit estimation of tp1 from experimental data for systems in which no peripheral elimination occurs. The type of data required are systemic drug levels resulting from iv administration. The probability density function for single pass residence time in peripheral tissues is derived. It is shown that tp1 is related to the amount of drug in the peripheral tissues at steady state according to (Ap)ss = CLdCsstp1, where CLd is the distribution clearance, and Css is the steady-state systemic drug level. Values of tp1 are presented for several drugs.
A sensitive DNA-excess solution hybridization assay was used to quantitate apo-E mRNA in the liver and peripheral tissues of two nonhuman primates, Macaca fascicularis and Cercopithecus aethiops. When expressed on the basis of total RNA, apo-E mRNA values for M. fascicularis adrenal, brain, testis, and spleen ranged from 17-52% of the liver value. Apo-E mRNA values for mesenteric lymph node, kidney, thymus, and skeletal muscle were 1-5% of the liver value. When expressed on a cellular basis, apo-E mRNA was most abundant in the liver at approximately 1200 molecules/cell. Peripheral tissues showed a continuous range of apo-E mRNA from 1.5 molecules/cell in the thymus up to 350 molecules/cell in the brain. Similar results were obtained with peripheral tissues from C. aethiops in which case apo-E mRNA also was found in skin, lung, skeletal muscle, small intestine, and vascular tissues such as heart, aorta, and brachial artery. Calculation of the total apo-E mRNA/organ showed that most of the apo-E mRNA was present in the liver. However, summation of apo-E mRNA in peripheral tissues indicated that 20-40% of total body apo-E mRNA was extrahepatic. This results indicates that apo-E made in peripheral tissues may play a quantitatively important role in cholesterol metabolism since peripheral tissues have the potential to contribute a significant fraction of plasma apo-E.
Visceral and peripheral tissue perfusion and oxygenation were studied in ten patients in the early phase after coronary artery bypass grafting. Visceral perfusion was assessed indirectly, by determining gastric intramucosal pH. As parameters of peripheral tissue perfusion and oxygenation, subcutaneous tissue PO2 (PscO2), transcutaneous PO2 (PtcO2). PtcO2 index (PtcO2/PaO2), laser-Doppler skin red-cell flux (RCF) and fingertip temperature (Tft) were recorded in the upper extremity. Central haemodynamics, rectal temperature and blood gases were also measured. The inspired oxygen concentration was maintained at 30 v/v%. Gastric intramucosal pH declined progressively during the first 3 hours in the intensive care unit, reached its minimum at 5 hours and thereafter slowly increased. The peripheral vascular bed was shut down on admission to the ICU, as indicated by low values of PscO2, PtcO2, PtCO2 index, RCF and Tft. These parameters began to rise after the next 2-4 hours and peaked by the end of the 8-hour study period, indicating complete opening of the peripheral vascular bed.
The effects of cold exposure, exercise training, and diet (high fat versus high carbohydrate) on glucose tolerance and glucose metabolism in rat peripheral tissues will be briefly reviewed. Stimulation of energy expenditure by cold exposure (4 degrees C) or exercise training generally leads to decreased plasma insulin levels and to an improvement in glucose tolerance, suggesting that insulin action on peripheral tissues is increased when energy expenditure is stimulated. On the contrary, feeding high-fat diets to sedentary rats living in the warm (25 degrees C) induces hyperinsulinemia and insulin resistance resulting in a marked deterioration of glucose tolerance. Nevertheless, cold exposure reverses the diabetogenic effects of high-fat feeding, demonstrating that nutrition-induced insulin resistance is amplified in sedentary animals living at temperatures close to thermoneutrality. Radioactive tracer studies of 2-deoxyglucose uptake in peripheral tissues revealed that cold exposure synergistically potentiates the effects of insulin on glucose uptake in skeletal muscles as well as in white and brown adipose tissues. However, more recent data showed that cold exposure improves glucose tolerance and stimulates glucose uptake in starved animals (ie., in the virtual absence of circulating insulin) nearly by the same order of magnitude as in fed animals. It is therefore concluded that cold exposure, and possibly also exercise, improve glucose tolerance and stimulate glucose uptake in peripheral tissues primarily by enhancing glucose oxidation via insulin-independent pathways, and secondarily by increasing the responsiveness of peripheral tissues to insulin.
The effect of ketanserin and tetrabenazine treatment on monoamine and metabolite levels in central and peripheral tissues was investigated in young and senescent male Wistar and spontaneously hypertensive Okamota rats. Control animals showed significantly higher brain monoamine levels and 3 and 5.5 times higher dopamine levels in the vas deferens of the senescent and hypertensive rats, as compared with young normotensive rats. Ketanserin (20 mg/kg) produced an average of 20% reduction of brain monoamines without changing metabolite levels. In the vas deferens, dopamine was reduced by 85% and norepinephrine by 30%. In cardiovascular tissues, norepinephrine was 40% to 50% decreased and in the spleen norepinephrine was 60% and 5-hydroxytryptamine 30% reduced. Ketanserin (5 mg/kg) had only a marked effect on dopamine in the vas deferens and on norepinephrine in the portal vein. Tetrabenazine at 20 mg/kg produced complete depletion of the monoamine and 3-methoxytyramine levels in the brain with a concomitant rise in acid metabolites. In peripheral tissues, amine levels were reduced by 55% to 80%; dopamine in the vas deferens was 93% decreased. Tetrabenazine (5 mg/kg) still had marked effects in all tissues. The drug effects were the same in the three types of rats and the effects did not markedly change with chronic treatment up to 20 days. It is hypothesized that at least two different mechanisms are involved in monoamine depletion, 1) the classically proposed inhibition of uptake of monoamines in the storage vesicles, a property of tetrabenazine not shared by ketanserin in vivo and 2) triggering of the release of monoamines from a ketanserin-sensitive pool, which is relatively more important in peripheral tissues than in the brain. The latter process is probably mediated by previously identified ketanserin-binding release sites on nerve terminals and platelets. The ketanserin-sensitive monoamine pools in peripheral tissues may have a role in cardiovascular pathologies.
The effects of diabetes on the uptake and incorporation of 3H-progesterone (P) in various brain areas and peripheral tissues were analyzed in C57BL/KsJ mice. Littermate control (+/?) and diabetic (db/db) mice were pulse-treated (60) min with 10 mu Ci of 3H-P at either 8 or 16 weeks of age. Subsequently, the peripheral tissues and brains were dissected, weighed, digested and the amount of incorporated 3H-P assessed. The pituitary, amygdala, septum and hypothalamus were found to concentrate the highest levels of 3H-P of all the brain areas examined. The brain areas of 16-week-old (+/?) mice accumulated higher concentrations of 3H-P than the comparable 8-week-old brain tissues. In addition, all the brain areas of 8-week-old (db/db) mice accumulated equal or more 3H-P than the comparable (+/?) brains. By 16 weeks of age, however, the 3H-P accumulation rate was significantly higher in all brain areas of (+/?), as compared to (db/db), mice. Of the peripheral tissues examined, the ovary, uterus, pancreas, kidney and mesometrial fat pad consistently exhibited the highest rates of 3H-P accumulation in both (+/?) and (db/db) mice. By 16 weeks of age, all peripheral tissues of (+/?) mice exhibited greater accumulation rates of 3H-P than the comparable (db/db) tissues. Following 4 days of estradiol treatment (10 micrograms/day s.c.), the 3H-P accumulation rates in 16-week-old (+/?) and (db/db) brain were essentially equal. Only the hypothalamus, septum and amygdala of the (db/db) mice failed to normalize to (+/?) levels following estradiol treatment. In a similar manner, the pancreas, uterus, ovary and fat of (db/db) mice exhibited 3H-P accumulation rates similar to those of (+/?) mice following estradiol treatment. These data indicate that estradiol therapy effectively normalizes the normal age- and diabetes-related declines in brain and peripheral tissue sensitivity and/or responsitivity to progesterone in C57BL/KsJ mice.
Prior studies of developmentally protein malnourished rats have reported substantial changes in brain and peripheral utilization of 14C-leucine, 14C-phenylalanine, and 14C-tryptophan. In the present study rats born to dams fed a low protein diet (8% casein) compared to the offspring of control rats fed a normal diet (25% casein) showed few significant differences in the uptake and incorporation of 14C-tyrosine into brain and peripheral tissues from birth to age 21 days. At birth, the 8% casein pups exhibited significant decreases in brain and peripheral tissue incorporation of tracer only at short post-injection times (10 and 20 min), but not at longer intervals (90 and 180 min). During ontogenetic development (Days 5-21), the 8% casein rats showed significant increases in uptake of 14C-tyrosine into the brain and peripheral tissues on Day 11 and a significantly higher percent incorporation of tracer into brain protein on Day 21 as compared to the 25% casein rats. For the most part, there were no significant changes in incorporation of radioactivity in peripheral tissues for the 2 diet groups on these post-birth days. Overall, the data indicates that developmental protein malnutrition causes relatively fewer changes in brain and peripheral utilization of the semi-essential amino acid tyrosine than those observed in previous studies with essential amino acids.
The effect of morphine tolerance dependence and protracted abstinence on the levels of dynorphin (1-13) in discrete brain regions, spinal cord, pituitary gland and peripheral tissues was determined in male Sprague-Dawley rats. Of all the tissues examined, the highest level of dynorphin (1-13) was found to be in the pituitary gland. Among the brain regions and spinal cord examined, the levels of dynorphin (1-13) in descending order were: hypothalamus, spinal cord, midbrain, pons and medulla, hippocampus, cortex, amygdala and striatum. The descending order for the levels of dynorphin (1-13) in peripheral tissues was: adrenals, heart and kidneys. In morphine tolerant rats, the levels of dynorphin (1-13) increased in amygdala but were decreased in pons and medulla. In morphine abstinent rats, the levels of dynorphin (1-13) were increased in amygdala, hypothalamus and hippocampus. The levels of dynorphin (1-13) were increased in pituitary but decreased in spinal cord and remained so even during protracted abstinence. The levels of dynorphin (1-13) in the peripheral tissues of morphine tolerant rats were unaffected. However, in the heart and kidneys of morphine abstinent rats, the levels of dynorphin (1-13) were increased significantly. It is concluded that both morphine tolerance and abstinence modify the levels of dynorphin (1-13) in pituitary, central and peripheral tissues. Morphine abstinence differed from non-abstinence process in that there were additional changes (increases) in the levels of dynorphin (1-13) in brain regions (hypothalamus and hippocampus) and peripheral tissues (heart and kidneys) and may contribute to the symptoms of the morphine abstinence syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)
With the use of [125I]acetyl human beta-endorphin (Ac-hBE), specific binding sites for beta-endorphin (BE) were identified in the liver, kidney, adrenal, spleen, and testis of adult male rats, whereas specific BE-binding sites were not present in the ventral prostate or pancreas. In those tissues containing specific BE-binding sites, microsomal membranes (15,000-100,000 X g pellet) exhibited higher BE-binding capacity than the crude homogenate (125-100,000 X g pellet). The binding of BE was saturable, and maximal, specific binding was achieved with a 60-min incubation at 22 C. Furthermore, optimal BE binding was dependent on the presence of magnesium chloride. Scatchard analysis of BE binding to hepatic membranes revealed the existence of two classes of binding sites. One class had an apparent Ka of 0.019 X 10(9) M-1 and a lower number of binding sites (9.1 pmol BE/mg protein), whereas the other class had a lower affinity (apparent Ka of 0.0006 X 10(9) M-1) and a higher number of binding sites (159 pmol/mg protein). Specific BE binding to hepatic membranes was inhibited (80-100%) by rat AcBE-(1-27) and -(1-31), nonacetylated rat BE-(1-31), and human beta-lipotropin. At substantially higher peptide concentrations (greater than 10(-5) M), gamma-endorphin, met-enkephalin, or leu-enkephalin inhibited BE binding by 20-40%. In addition, opiate receptor-binding drugs, such as morphine and naloxone, at 10(-5) M did not alter BE binding to hepatic membranes. Incubation of hepatic membranes with BE induced a dose-related increase in membrane adenylate cyclase activity, and 0.5 X 10(-10) M BE resulted in a maximal enhancement of adenylate cyclase activity to 148% above control values. Water-deprived or salt-loaded male rats with chronically lowered immunoreactive plasma BE exhibited substantially increased BE binding to adrenal and kidney tissue. Specific binding sites for BE occur in a variety of peripheral tissues, and alterations of circulating BE result in changes in the capacity of certain peripheral tissues to bind BE. Finally, occupancy of specific BE-binding sites in peripheral tissue stimulates the adenylate cyclase-cAMP system, which suggests that the peripheral actions of circulating BE may be mediated via this system.