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Sympathetic dysfunction is suggested to contribute to development of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) alike. Considering important role of microglia in development/resolution of neuroinflammation, contribution of noradrenaline, the key sympathetic end-point mediator, in modulation of microglial phenotypic and functional properties in rat EAE model was examined. The study showed that noradrenaline acting in neurocrine and autocrine/paracrine way might influence microglia during EAE. Propranolol treatment over the effector phase moderated EAE course. This was associated with the increased proportion of microglia expressing CX3CR1, the key molecule in their immunomodulatory/neuroprotective action, and up regulation of CX3CR1 downstream Nrf2 gene. This correlated with the increased heme oxygenase-1 (HO-1) expression and phagocytic capacity of microglia, and their phenotypic changes mirrored in increased proportion of CD163- and CD83-expressing cells. The enhanced HO-1 expression was linked with the decreased proportion of microglial cells expressing IL-1 beta and IL-23, and possibly IL-6, followed by increased proportion of IL-10 expressing microglia, and downregulated MCP-1/CCL2 expression. Consistently, spinal cord infiltration with blood-borne myeloid and CD4 + T cells, as well as CD4 + T-cell reactivation/proliferation and differentiation into highly pathogenic IL-17 + cells co-producing IFN-gamma and GM-CSF were decreased in propranolol-treated rats compared with saline-injected controls. The in vitro investigations of the effects of noradrenaline on microglia showed that noradrenaline through beta-adrenoceptor may influence Nrf2 expression also via CX3CR1-independent route. The study suggests beta-adrenoceptor-mediated neuroinflammation-promoting role of noradrenaline in EAE via modulation of microglial Nrf2 expression, and thereby forms the basis for further translational pharmacological research to improve multiple sclerosis therapy.

International audience; ObjectiveTo evaluate whether active immunization producing β1- or β3-antibodies (β1-ABs and β3-ABs) detected in sera of patients with dilated cardiomyopathies has deleterious effects on vascular reactivity in Lewis rat thoracic aorta (TA) and small mesenteric arteries (SMA).Design and methodLewis rats were immunized for 6months with peptidic sequences corresponding to the second extracellular loop of β1- and β3-adrenoceptors (ARs). During the immunization, systolic blood pressure (SBP) was monitored using the tail cuff method. The vascular reactivity of immunized rats was assessed by ex vivo studies on SMA and TA using various β-AR agonists, phenylephrine and KCl.ResultsThe immunizations producing functional β1-ABs and β3-ABs did not affect the SBP. However, in TA from β1-AR-immunized rats, the relaxations mediated by dobutamine and salbutamol were significantly impaired in comparison with adjuvant rats whereas nebivolol-induced relaxation was not modified. Moreover, phenylephrine and KCl-mediated contractions were enhanced in these rats. In contrast, immunization with β3-AR peptide led to the increase of relaxations induced by dobutamine in TA but did not change those induced by salbutamol and nebivolol. Surprisingly, in SMA from both rats immunized with β1- or β3-peptides, relaxations induced by the various β-agonists were not changed whereas phenylephrine and KCl-mediated contractions were impaired.ConclusionsOur study shows that β1- and β3-ABs can affect vascular reactivity. β1-ABs would have a pathogenic action whereas β3-ABs would have a beneficial effect on aorta reactivity.Array( [0] => public://js/js_NhB8QqEMkIRnGegV_fyHSoTNS4QcuYAxmtYDZC610gE.js.gz : fichier présent sur le disque mais absent dans la base de données [1] => public://js/js_YqvqIXMHR_JA_6L7V5VgwgrhCDVtmWC_wCWsaINFQtk.js : fichier présent sur le disque mais absent dans la base de données [2] => public://js/js_YqvqIXMHR_JA_6L7V5VgwgrhCDVtmWC_wCWsaINFQtk.js.gz : fichier présent sur le disque mais absent dans la base de données [3] => public://js/js_NhB8QqEMkIRnGegV_fyHSoTNS4QcuYAxmtYDZC610gE.js : fichier présent sur le disque mais absent dans la base de données)

Introduction One hallmark symptom of post‐traumatic stress disorder (PTSD) is an inability to restrict fear responses to the appropriate predictor. An infusion of glucocorticoids (GCs) after a high‐intensity shock has been shown to induce PTSD‐like memory impairments. In addition to GCs, noradrenergic signalling is also recognized as a key biomarker underlying PTSD symptomatology. Methods To explore the role of the noradrenergic system in PTSD‐like memory impairments, in this study, various doses of the β‐adrenoceptor antagonist propranolol were systemically or bilaterally injected into the dorsal hippocampus immediately after unpaired cue‐shock contextual fear conditioning, and then the rats were tested 24 h later. Results Interestingly, we found that only low‐dose propranolol could induce PTSD‐like memory impairments, as rats showed reduced freezing to the correct predictor and generalized fear responses to the safe cues, accompanied by increased NE levels in the hippocampus and altered neural activity within the frontal‐subcortical circuit. Conclusion These findings demonstrate that the noradrenergic system is involved in regulating the consolidation of contextual fear memory and that propranolol can dose‐dependently induce PTSD‐like memory impairments.

International audience; The influence of cell confluence on the β-adrenoceptor (β-AR)/cAMP/phosphodiesterase (PDE) pathway was investigated in cultured rat aortic smooth muscle cells (RASMCs).Cells were plated either at low density (LD: 3.103 cells/cm2) or high density (HD: 3.104 cells/cm2) corresponding to non-confluent or confluent cells, respectively, on the day of experiment.β-AR-stimulated cAMP was monitored in real-time using the fluorescence resonance energy transfer (FRET)-based cAMP sensor, Epac2-camps. A brief application (15 s) of the β-AR agonist isoprenaline (Iso) induced a typical transient FRET signal, reflecting cAMP production followed by its rapid degradation. The amplitude of this response, which increased with the concentration of Iso (10 or 100 nM), was higher in HD than in LD cells, whatever the Iso concentration used. However, activation of adenylyl cyclase by L-858051 (100 µM) induced a similar saturating response in both LD and HD cells. A β1-AR antagonist (CGP 20712A, 100 nM) reduced the Iso (100 nM) response in HD but not LD cells, whereas a β2-AR antagonist (ICI 118,551, 5 nM) reduced this response in HD cells and almost abolished it in LD cells. Competitive [125I]-ICYP binding experiments with betaxolol, a β-AR ligand, identified two binding sites in HD cells, corresponding to β1- and β2-ARs with a proportion of 11% and 89%, respectively, but only one binding site in LD cells, corresponding to β2-ARs. Total cAMP-PDE activity (assessed by a radioenzymatic assay) was increased in HD cells compared to LD cells. This increase was associated with a rise in mRNA expression of five cAMP-PDEs subtypes (PDE1A, 3A, 4A, 4B and 7B) in HD cells, and a decrease in basal [cAMP]i (assessed by an EIA assay). PDE4 inhibition with Ro-20-1724 (10 µM) strongly prolonged the Iso response in LD and HD cells, whereas PDE3 inhibition with cilostamide (1 µM) slightly prolonged Iso response only in LD cells. Interestingly, inhibition of PDE4 unmasked an effect of PDE3 in HD cells. Our results show that in cultured RASMCs, the β-AR/cAMP/PDE signalling pathway is substantially modulated by the cell density. In HD cells, Iso response involves both β1- and β2-AR stimulation and is mainly controlled by PDE4, PDE3 being recruited only after PDE4 inhibition. In LD cells, Iso response involves only β2-AR stimulation and is controlled by PDE4 and to a lower degree by PDE3. This low density state is associated with an absence of membrane expression of the β1-AR, a lower cAMP-PDE activity and a higher basal [cAMP]i. This study highlights the critical role of the cellular environment in controlling the vascular β-AR signalling.

β-Adrenoceptors are important mediators of smooth muscle relaxation in the urinary bladder, but the concomitant presence of a muscarinic agonist, e.g., carbachol, can attenuate relaxation responses by reducing potency and/or efficacy of β-adrenoceptor agonists such as isoprenaline. Therefore, the present study was designed to explore the subtypes and signalling pathways of muscarinic receptors involved in the attenuation of isoprenaline-induced isolated rat detrusor preparations using novel subtype-selective receptor ligands. In radioligand binding studies, we characterized BZI to be a M(3)-sparing muscarinic agonist, providing selective M(2) stimulation in rat bladder, and THRX-182087 as a highly M(2)-selective antagonist. The use of BZI and of THRX-182087 in the presence of carbachol enabled experimental conditions with a selective stimulation of only M(2) or M(3) receptors, respectively. Confirming previous findings, carbachol attenuated isoprenaline-induced detrusor relaxation. M(2)-selective stimulation partly mimicked this attenuation, indicating that both M(2) and M(3) receptors are involved. During M(3)-selective stimulation, the attenuation of isoprenaline responses was reduced by the phospholipase C inhibitor U 73,122 but not by the protein kinase C inhibitor chelerythrine. We conclude that both M(2) and M(3) receptors contribute to attenuation of β-adrenoceptor-mediated relaxation of rat urinary bladder; the signal transduction pathway involved in the M(3) component of this attenuation differs from that mediating direct contractile effects of M(3) receptors.

>Molecular mechanism(s) of action of isoproterenol on the expression of the angiotensinogen gene in opossum kidney proximal tubular cells. Background β-adrenoceptors are present in the renal proximal tubules. We have previously reported that isoproterenol stimulates the accumulation of intracellular cAMP and the expression of the angiotensinogen (ANG) gene in opossum kidney (OK) proximal tubular cells via the β 1 -adrenoceptor. We hypothesized that the molecular mechanism(s) of action of isoproterenol on the expression of the ANG gene is mediated via the interaction of the phosphorylated cAMP-responsive element binding protein (CREB) and the cAMP-responsive element (CRE; that is, ANG N-806/-779) in the 5′-flanking region of the rat ANG gene. Methods The fusion genes containing the putative ANG-CRE of the rat ANG gene inserted upstream of the rat ANG basal promoter (ANG N-53/+18) fused to a human growth hormone (hGH) gene as reporter were stably cotransfected, with or without the plasmid containing the cDNA for 43kDa CREB, into the OK cells. The effect of various agonists and antagonists of adrenoceptors on the expression of the fusion genes was evaluated by the amount of immunoreactive hGH secreted into the culture medium. The interactions of OK cellular nuclear protein(s) with the ANG N-806/-779 were determined by gel mobility shift assays and by Southwestern and Western blot analysis. Results The addition of isoproterenol, forskolin, or 8-BromocAMP (8-Br-cAMP) stimulated the expression of pOGH (ANG N-806/-779/-53/+18) by 135, 150, and 160%, respectively, but not mutants of the ANG N-806/-779. The stimulatory effect of isoproterenol was blocked in the presence of propranolol, Rp-cAMP, and atenolol, but not by the presence of staurosporine, U73122, and ICI 118,551. Transient transfection of the plasmid containing the cDNA for the catalytic subunit of protein kinase A further enhanced the stimulatory effect of 43kDa CREB on the expression of the fusion gene. The gel mobility shift assays revealed that the nuclear protein(s) of OK cells binds to the radioactive-labeled ANG N-806/-779. The binding of the labeled ANG N-806/-779 to the OK cell nuclear protein(s) was displaced by unlabeled ANG N-806/-779, but not by the CRE of the somatostatin gene, the CRE of the tyrosine amino-transferase gene, or the mutants of the ANG N-806/-779. Southwestern blot analysis revealed that the labeled ANG N-806/-779 binds to two nuclear species of 43 and 35kDa proteins. Western blot analysis, however, revealed that rabbit polyclonal antibodies against the 43kDa CREB interacted with only the 43kDa molecular species but not with the 35kDa species. Conclusion These studies demonstrate that the stimulatory effect of isoproterenol on the expression of the ANG gene may be mediated, at least in part, via the interaction of the phosphorylated CREB and the CRE in the 5′-flanking region of the rat ANG gene. The novel 35kDa nuclear protein that is immunologically different from the 43kDa CREB may also play a role in the expression of the ANG gene.

The Harderian glands are innervated by sympathetic fibers originating in the superior cervical ganglia. The aim of this study is to characterize the /3-adrenergic receptors in the rat Harderian gland. The characteristics of/3-adrenergic receptors were determined in crude membrane preparations from rat 125 125 Harderian gland, using [ I]iodocyanopindolol ([ I]CYP) as radioligand. The binding of the ligand to the receptor is rapid, reversible, saturable, specific and dependent on time, temperature and membrane concentration. At 30~ stoichiometric data suggest the presence of one binding site with a K a value of 0.29 nM and Bmax of 32 pmol/L. The interaction shows a high degree of specificity for /3-adrenergic agonists and blockers, as suggested by competitive displacement experiments with isoproterenol (ICso = 19.1 nM), propranolol (ICso = 28.1 nM), and norepinephrine (ICso = 96.3 nM). Clonidine, yohimbine, methoxamine, and prazosin are ineffective at concentrations up to 1 IzM. In the other hand, binding of [125I]CYP by Harderian gland membranes exhibits day-night variations. Binding values are low during the daytime and increase progressively late in the evening to reach a maximum at 2200 h (2 h after the onset of dark period), but decreased to the end of the dark period (0600 h). In conclusion, the results presented in this paper show the functional and pharmacological characterization of/3-adrenergic receptors in the rat Harderian gland. This neurotransmitter may play a physiological role at this level regulating, at least, processes such as a thyroid hormone metabolism Comision Interministerial de Ciencia y Tecnología (España) PB94-1434 Fondo de Investigaciones Sanitarias 93/0210

Summary Background MicroRNAs (miRNAs) are noncoding RNAs of 18–25 nucleotides that post-transcriptionally regulate gene expression and are involved in a wide range of physiological and pathological conditions. The β-adrenergic signaling pathway plays a fundamental role in regulation of heart function. The present study was designed to investigate the expression profile of miRNAs and functional implications under conditions of β-adrenoceptor activation or inhibition in rat heart. Material/Methods Hemodynamic parameters were measured to assess heart function in Wistar rats treated with isoproterenol (ISO) or propranolol (PRO). miRNA expression was analyzed by miRNA Microarray and confirmed by real-time quantitative reverse transcription PCR (real-time qRT-PCR). Results Isoproterenol (ISO, a β-adrenoceptor activator) and propranolol (PRO, a β-adrenoceptor inhibitor) induced differential miRNA expression profiles. Out of 349 miRNAs measured, 43 were upregulated and nine downregulated in the ISO group, while five miRNAs were upregulated and 28 downregulated in PRO group. Among these altered miRNAs in both PRO and ISO groups, 11 were cardiac abundant and 11 showed opposite profiles between the PRO and ISO groups. The recognized anti-hypertrophic miRNAs miR-1, miR-21 and miR-27b, and the pro-hypertrophic miRNAs miR-22, miR-24, miR-199a, miR-212 and miR-214, were upregulated in the ISO group. In the PRO group, pro-hypertrophic miRNA miR-30c was upregulated, whereas miR-212 was downregulated. Conclusions β-adrenoceptor intervention alters miRNA expression profile, and miRNAs may be involved in the β-adrenoceptor signaling pathway. Cardiomyocyte hypertrophy is a balanced process between pro-hypertrophic and anti-hypertrophic regulation and involves, at the very least, miRNA participation.

β-Adrenoceptor antagonists differ in their degree of partial agonism. In vitro assays have provided information on ligand affinity, selectivity, and intrinsic efficacy. However, the extent to which these properties are manifest in vivo is less clear. Conscious freely moving rats, instrumented for measurement of heart rate (β1; HR) and hindquarters vascular conductance (β2; HVC) were used to measure receptor selectivity and ligand efficacy in vivo. CGP 20712A caused a dose-dependent decrease in basal HR (P

Aims Membrane potential is a key determinant of vascular tone and many vasodilators act through the modulation of ion channel currents [e.g. the ATP-sensitive potassium channel (KATP)] involved in setting the membrane potential. Adenylyl cyclase (AC) isoenzymes are potentially important intermediaries in such vasodilator signalling pathways. Vascular smooth muscle cells (VSMCs) express multiple AC isoenzymes, but the reason for such redundancy is unknown. We investigated which of these isoenzymes are involved in vasodilator signalling and regulation of vascular ion channels important in modulating membrane potential. Methods and results AC isoenzymes were selectively depleted (by >75%) by transfection of cultured VSMCs with selective short interfering RNA sequences. AC6 was the predominant isoenzyme involved in vasodilator-mediated cAMP accumulation in VSMCs, accounting for ∼60% of the total response to β-adrenoceptor (β-AR) stimulation. AC3 played a minor role in β-AR signalling, whereas AC5 made no significant contribution. AC6 was also the principal isoenzyme involved in β-AR-mediated protein kinase A (PKA) signalling (determined using the fluorescent biosensor for PKA activity, AKAR3) and the substantial β-AR/PKA-dependent enhancement of KATP current. KATP current was shown to play a vital role in setting the resting membrane potential and in mediating the hyperpolarization observed upon β-AR stimulation. Conclusion AC6, but not the closely related AC5, plays a principal role in vasodilator signalling and regulation of the membrane potential in VSMCs. These findings identify AC6 as a vital component in the vasodilatory apparatus central to the control of blood pressure.

Purpose The human physiological bladder contraction is largely mediated by acetylcholine acting on muscarinic receptors, but in pathophysiological settings the relative role of non-cholinergic stimuli gains importance. beta-Adrenoceptor agonists are currently in clinical development as treatments for the overactive bladder syndrome. Therefore, we have explored the ability of the beta-adrenoceptor agonist isoprenaline to induce rat isolated bladder strip relaxation on pre-contraction with the muscarinic agonist carbachol as compared to bladder tone induced by several non-cholinergic stimuli. Methods Bladder tone was induced by passive tension, receptor independently by KCl, carbachol, bradykinin or serotonin. Concentration-response curves were generated for relaxation by isoprenaline, and a single concentration of the receptor-independent relaxant forskolin was also tested. Results The various contractile stimuli induced different degrees of bladder tone, but the ability of isoprenaline or forskolin to relax rat bladder was not correlated with the degree of tone. Isoprenaline was significantly less potent and effective in causing relaxation against carbachol-induced tone than against any other stimulus, whereas no such relationship was observed for forskolin. Conclusions We conclude that beta-adrenoceptor agonists can induce rat bladder relaxation against a wide range of contractile stimuli and are more potent and/or effective against non-cholinergic stimuli than against muscarinic agonism. This profile appears desirable for agents intended for the treatment of overactive bladder

The role of adrenoceptors in the paraventricular nucleus (PVN) in the exercise-induced changes in plasma norepinephrine (NE), epinephrine (E), corticosterone, free fatty acids (FFA), and blood glucose was investigated in rats. Exercise consisted of strenuous swimming against a countercurrent for 15 min. Before, during, and after swimming, blood samples were withdrawn through a permanent heart catheter for determination of E, NE, corticosterone, FFA, and glucose, In control rats receiving artificial cerebrospinal fluid through permanent bilateral cannulas into the PVN, the levels of all blood components increased during exercise. Infusion of the alpha-adrenoceptor antagonist phentolamine into the PVN completely reduced the exercise-induced increases in blood glucose and plasma corticosterone concentrations. Plasma NE, E, and FFA were not affected. Infusion of the beta-adrenoceptor antagonist timolol into the PVN reduced blood glucose and plasma NE concentrations. Plasma E, corticosterone, and FFA remained unchanged. It is concluded that alpha- and beta-adrenergic receptors in the PVN are involved in the central nervous regulation of blood glucose levels during exercise, partly by influencing sympathetic outflow. alpha-Adrenoceptors in the PVN play an important role in the release of corticosterone during exercise.

To provide tissue-specific and developmental characteristics of gene expression of rat heart uncoupling protein-2 (UCP2), we investigated developmental alterations of UCPs mRNA expression in the heart and brown adipose tissue (BAT), and examined possible up-regulators of heart UCP2 expression using in vitro studies. Heart UCP2 mRNA expression was low during the early postnatal days followed by a rapid and significant increase in the 2nd postnatal week. Heart UCP3 mRNA remained undetectable until the 2nd postnatal week when the expression reached a small but significant peak. BAT UCP1 mRNA was abundantly expressed in the neonate, but the expression rapidly decreased to the adult level. The studies using cultured cardiomyocytes demonstrated that both 10 −8 M triiodothyronine and 10 −7 M isoproterenol, but not phenylephrine, increased UCP2 mRNA expression. These results indicate that the sympathetic nervous system and/or thyroid hormones may be involved in the up-regulation of heart UCP2 gene expression during postnatal development. The increase in postnatal heart UCP2 may provide a key link between the postnatal energy shift and adaptation of rat pups to their novel environment.

International audience; (+/-)-3-[11C]Methyl-2-[4-[3-(tert-butylamino)-2-hydroxypropoxy]phenyl]-6 -methoxy-4(3H) quinazolinone ([+/-]-[11C]HX-CH 44) was labeled with carbon-11 using [11C]iodomethane with the corresponding N-demethylated precursor. Then, 30-90 mCi (1.10-3.33 GBq) of pure [11C]HX-CH 44 were obtained 30 min after end of bombardment with specific radioactivities of 500-1,400 mCi/micromol (18.5-51.8 GBq/micromol). Myocardial uptake in dogs was 0.340+/-0.043 pmol/mL tissue per nanomole injected, 10-15 min postinjection. Heart-to-lung ratio was 3 from the 5th to the 30th minute. Only 35% of the myocardial radioactivity could be displaced. Tissue uptake could not be blocked with appropriate compounds. Therefore, (+/-)-[11C]HX-CH 44 does not appear to be a suitable ligand for the study of myocardial beta1-adrenoceptors in positron emission tomography.

Changes in the distribution of beta-adrenoceptors (beta ARs) in the plasma membrane and the light vesicle fractions of rat liver during different phases of sepsis were studied using [3H]dihydroalprenolol binding and photoaffinity labeling with [125I]iodocyanopindolol diazirine. Sepsis was induced by cecal ligation and puncture (CLP). Septic rats exhibit an initial hypermetabolic (hyperglycemic) phase (9 h after CLP; early sepsis) followed by a hypometabolic (hypoglycemic) phase (18 h after CLP; late sepsis). The radioligand studies show that in the plasma membranes, the density of beta ARs was decreased by 28-32% and 46-69% during the early and the late phases, respectively, of sepsis. In the light vesicles, the density of beta ARs was increased by 25-30% and 30-35% during the early and the late phases, respectively, of sepsis. The total number of the receptor binding sites (the sum of that in plasma membrane plus light vesicle) was decreased by 11-12% and 21-35% during the early and the late phases, respectively, of sepsis. These results indicate that beta ARs were progressively internalized from surface membranes to the intracellular sites and, furthermore, they were underexpressed in the rat liver during the progression of sepsis. Since hepatic glucose metabolism is known to be regulated by catecholamines, in part, through beta AR mediation, an internalization/underexpression of hepatic beta ARs may play a role in the altered glucose homeostasis during sepsis, particularly in the late hypometabolic phase of sepsis.

1-Isoproterenol has equal affinity for beta 1- and beta 2-adrenoceptors and is a full agonist at both subtypes. However, when infused in vivo into the rat brain, it has been shown to induce a preferential reduction of central beta 2-adrenoceptors. To investigate this phenomenon further, in the present study rats were infused centrally with higher doses of 1-isoproterenol (15 or 45 micrograms/h). Furthermore, isoproterenol was infused into rats lesioned neonatally with 6-hydroxydopamine (6-OHDA). Subtypes of beta-adrenoceptors were measured by quantitative autoradiography of the binding of [125I]iodopindolol ([125I]IPIN). In sham lesioned rats, infusions of isoproterenol at both doses caused comparable reductions in the density of [125I]IPIN binding sites in many brain regions. The binding to beta 2-adrenoceptors was decreased in a larger number of brain areas than the binding to beta 1-adrenoceptors and the magnitude of the reduction was greater for beta 2- than for beta 1-adrenoceptors. However, isoproterenol at these doses did produce greater effects on the beta 1-subtype than those found previously with a lower dose. Treatment with 6-OHDA induced significant increases in the binding of [125I]IPIN to both beta 1- and beta 2-adrenoceptors in cerebral cortical and hippocampal areas, indicating that endogenous norepinephrine may regulate both subtypes in these regions. Even in the 6-OHDA-lesioned rats, the binding of [125I]IPIN to beta 2-adrenoceptors was reduced to a greater extent that the binding to beta 1-adrenoceptors. Thus, these studies demonstrate that the non-selective beta-adrenergic agonist isoproterenol induces a preferential regulation of beta 2-adrenoceptors, even at relatively high doses and in norepinephrine-depleted animals.

The role of hypothalamic adrenoceptors in the exercise-induced alterations of plasma norepinephrine (NE), epinephrine (E), and corticosterone concentrations was investigated in rats. Exercise consisted of strenuous swimming against a counter-current for 15 min. Before, during, and after swimming, blood samples were withdrawn through a permanent heart catheter for determination of E, NE, and corticosterone. In control rats E, NE, and corticosterone levels were all increased during exercise. Infusion of the alpha-adrenoceptor antagonist phentolamine through permanent bilateral cannulas into the ventromedial hypothalamus (VMH) immediately before exercise reduced the exercise-induced increase in plasma E without affecting NE. Infusion of the beta-adrenoceptor antagonist timolol into the VMH enhanced plasma E and attenuated plasma NE increases. Infusion of phentolamine into the lateral hypothalamic area (LHA) led to enhanced NE and unchanged E concentrations, whereas infusion of timolol into the LHA caused a potentiation of the increase in plasma E without an effect on NE. Plasma corticosterone concentrations were not affected. The results suggest that 1) alpha- and beta-adrenoceptors in the hypothalamus influence peripheral catecholamine release, and 2) E and NE responses to exercise can be dissociated by interference of the central nervous system.

The peroxidation of lipids in biological membranes is a destructive phenomenon that can be elicited in various ways. Surface receptor molecules that allow cells to respond to hormones are possibly inactivated during lipid peroxidation. Effects of lipid peroxidation on receptors have not been extensively examined thus far. This investigation shows that there is a decrease in beta-adrenoceptor density (measured as specific (-)-[125I]iodocyanopindolol binding) during lipid peroxidation, in both lungs and erythrocytes of the rat. To this end, lung membranes (containing both beta 1- and beta 2-adrenoceptors) and intact erythrocytes (containing a homogeneous beta 2-adrenoceptor population) were pretreated with cumene hydroperoxide (lung membranes with 0.1 mM and erythrocytes with 1 mM) and Fe2+ (1 X 10(-5) M) for 60 min which resulted in extensive lipid peroxidation measured as malondialdehyde formation. The ration beta 1-:beta 2-adrenoceptor density in lung membranes after treatment with cumene hydroperoxide did not change and remained at 30%:70%. A single injection (i.p.) with the herbicide paraquat (50 mg/kg, 24 h), which is known to cause lung damage via lipid peroxidation, resulted in similar alterations in receptor density to those caused by cumene hydroperoxide in the in vitro experiments.