Selective depletion of spinal noradrenaline abolishes post-decapitation convulsions

Previous data have suggested that spinal noradrenaline (NA) might be important in the normal expression of post-decapitation convulsions. This hypothesis was tested by selective depletion of spinal NA through stereotaxic infusions of 6-hydroxydopamine into the medulla in adult rats. This treatment was found to substantially reduce spinal NA and to abolish the post-decapitation convulsions. The results are discussed in terms of the mechanism underlying the involvement of NA in this reflex.     

Taurine depletion alters vascular reactivity in rats

We recently showed that chronic taurine supplementation is associated with attenuation of contractile responses of rat aorta to norepinephrine and potassium chloride. However, the potential involvement of endogenous taurine in modulation of vascular reactivity is not known. Therefore, we examined the effect of beta-alanine-induced taurine depletion on the in vitro reactivity of rat aorta to selected vasoactive agents. The data indicate that both norepinephrine- and potassium-chloride-induced maximum contractile responses of endothelium-denuded aortae were enhanced in taurine-depleted rats compared with control animals. However, taurine depletion did not affect tissue sensitivity to either norepinephrine or potassium chloride. By contrast, sensitivity of the endothelium-denuded aortae to sodium nitroprusside was attenuated by taurine depletion. Similarly, taurine deficiency reduced the relaxant responses of endothelium-intact aortic rings elicited by submaximal concentrations of acetylcholine, and this effect was associated with decreased nitric oxide production. Taken together, the data suggest that taurine depletion augments contractility but attenuates relaxation of vascular smooth muscle in a nonspecific manner. Impairment of endothelium-dependent responses, which is at least in part associated with reduced nitric oxide generation, may contribute to the attenuation of the vasorelaxant responses. These vascular alterations could be of potential consequence in pathological conditions associated with taurine deficiency.     

Prenatal stress alters reproductive responses of rats in behavioral estrus and paced mating of hormone-primed rats

Adult female offspring of dams exposed to gestational stress (prenatal stress, PNS) may show altered reproductive behavior, exploration in novel environments, and/or social interactions than do their non-PNS counterparts. These behavioral differences may be more readily observed in a seminatural, paced mating paradigm, in which females have greater control of their sexual contacts, than in a standard mating situation. Adult offspring of dams exposed to restraint and lights for 45 min on Gestational Days 14-20 (PNS) were compared with those not subjected to stress (non-PNS, control condition). The motor, reproductive, and sociosexual behaviors of hormone-primed (Experiment 1) or cycling adult offspring in behavioral estrus (Experiment 2) were examined following 20 min of restraint stress under bright lights (postnatal stress). Hormone-primed PNS rats displayed less motor behavior in a novel arena than did non-PNS rats. In a standard mating test, hormone-primed PNS females tended to be more aggressive toward the male than were non-PNS rats. In a seminatural mating situation, hormone-primed PNS females showed increased avoidance behavior, such as longer latencies to the initial intromission, greater return latencies following mounts and intromissions, and more exiting subsequent to mounts and intromissions, than did non-PNS rats. PNS rats in behavioral estrus had decreased incidence and intensity of lordosis, and fewer solicitation behaviors, in both standard or paced mating situations, in which latency to and number of mounts were also increased. Thus, hormone-primed PNS rats exposed to restraint showed more avoidance behaviors in paced mating situations, while cycling PNS rats in behavioral estrus had greater disruption of reproductive responses in standard or paced mating paradigms than did non-PNS control rats.     

Neonatal handling enhances contextual fear conditioning and alters corticosterone stress responses in young rats

Previous studies have indicated that neonatal handling influences development of hypothalamic-pituitary-adrenal (HPA) control of corticosterone. In addition, corticosterone influences memory consolidation processes in contextual fear conditioning. Therefore, neonatal handling may affect hippocampal-dependent memory processes present in contextual fear conditioning by influencing the development of HPA control of corticosterone. To investigate the effects of neonatal handling on early learning, rat pups were either handled (15-min removal from home cage) on the first 15 days after birth or left undisturbed in their home cage. Handled rats and nonhandled rats were fear conditioned at 18, 21, or 30 days of age and then tested at two time points--24 h following conditioning and at postnatal day 45. Subsequently, at approximately postnatal day 60, rats were exposed to restraint stress and corticosterone levels were assessed during restraint and recovery. Handled and nonhandled rats did not differ significantly in their freezing response immediately following footshock on the conditioning day. However, when tested for contextual fear conditioning at 24 h following conditioning and at postnatal day 45, handled rats showed more freezing behavior than nonhandled rats. When exposed to restraint stress, handled rats had a more rapid return of corticosterone to basal levels than nonhandled rats. These results indicate that neonatal handling enhances developmentally early memory processes involved in contextual fear conditioning and confirms previously reported effects of neonatal handling on HPA control of corticosterone.     

Chronic estrogen depletion alters adenosine diphosphate-induced pial arteriolar dilation in female rats

We examined pial arteriolar reactivity to a partially endothelial nitric oxide synthase (eNOS)-dependent vasodilator ADP as a function of chronic estrogen status. The eNOS-dependent portion of the ADP response was ascertained by comparing ADP-induced pial arteriolar dilations before and after suffusion of a NOS inhibitor, N(omega)-nitro-L-arginine (L-NNA; 1 mM) in intact, ovariectomized (Ovx), and 17beta-estradiol (E2)-treated Ovx females. We also examined whether ovariectomy altered the participation of other factors in the ADP response. Those factors were the following: 1) the prostanoid indomethacin (Indo); 2) the Ca2+-dependent K+ (K(Ca)) channel, iberiotoxin (IbTX); 3) the ATP-regulated K+ (K(ATP)) channel glibenclamide (Glib); 4) the K(Ca)-regulating epoxygenase pathway miconazole (Mic); and 5) the adenosine receptor 8-sulfophenyltheophylline (8-SPT). In intact females, the eNOS-dependent (L-NNA sensitive) portion of the ADP response represented approximately 50% of the total. The ADP response was retained in the Ovx rats but L-NNA sensitivity disappeared. On E2 replacement, the initial pattern was restored. ADP reactivity was unaffected by Indo, Glib, Mic, and 8-SPT. IbTX was associated with 50-80% reductions in the response to ADP in the intact group that was nonadditive with L-NNA, and 60-100% reductions in the Ovx group. The present findings suggest that estrogen influences the mechanisms responsible for ADP-induced vasodilation. The continued sensitivity to IbTX in Ovx rats, despite the loss of a NO contribution, is suggestive of a conversion to a hyperpolarizing factor dependency in the absence of E2.     

Senescence alters blood flow responses to acute heat stress

Renal and splanchnic sympathetic nerve discharge (SND) responses to heating are significantly reduced in senescent compared with young Fischer-344 (F344) rats (Kenney MJ and Fels RJ. Am J Physiol Regul Integr Comp Physiol 283: R513-R520, 2002). However, the functional significance of this finding is not known. We tested the hypothesis that blood flow distribution profiles to heating are altered in senescent (24 mo old) compared with mature (12 mo old) and young (3 mo old) F344 rats. Visceral organ, skeletal muscle, and tail blood flows were determined with the radionuclide-tagged microsphere technique before (control, 38 degrees C) and during heating that increased body temperature to 41 degrees C in anesthetized F344 rats. Vascular conductance in the kidney, stomach, large intestine, pancreas, spleen, and tail was significantly reduced during control before heating in senescent compared with young F344 rats. Heating significantly decreased kidney, stomach, small and large intestine, and pancreas vascular conductance in young and mature but not senescent F344 rats. Vascular conductance at 41 degrees C in the kidney and small intestine was significantly lower and in the stomach tended to be lower in young compared with senescent rats. Splenic conductance increased during heating in young and senescent rats but was highest in young rats. Tail conductance during heating was significantly increased in young rats but remained unchanged in mature and senescent rats. These results demonstrate a marked attenuation in heating-induced vascular conductance changes in senescent rats, suggesting an important functional consequence for the attenuated SND responses to heating in aged rats.     

Acute depletion of heme by succinylacetone alters vascular responses but does not induce hypertension

Heme plays a critical role in blood pressure regulation because it is required by a number of enzymes that synthesize vascular modulators, including nitric oxide (NO), carbon monoxide (CO), guanosine 3',5'-cyclic monophosphate (cGMP), endothelium-derived hyperpolarizing factor (EDHF), and prostacyclin. The goal of this study was to examine the vascular effects of a short-term depletion of heme achieved through administration of the heme-synthesis inhibitor succinylacetone (SA), an irreversible inhibitor of aminolevulinic acid dehydratase (ALAD). Rats were depleted of heme by using a 4-day treatment with SA. This treatment impacted hemoenzyme function, decreasing renal nitric oxide synthase (NOS) activity (as indicated by decreased in vitro NOS activity), and increasing kidney microsomal heme oxygenase (HO) activity by 27%. SA treatment also resulted in enhanced reduction in blood pressure after infusions of exogenous NO donor MAHMA NONOate (at high dose) and acetylcholine (at low doses). Nevertheless, this SA treatment was insufficient to produce an overt elevation of basal arterial pressure. This latter lack of effect may be the result of multiple compensatory mechanisms for the regulation of blood pressure.     

Amiloride alters lick rate responses to NaCl and KCl in rats

The role-of cation channels on taste cell membranes to salttaste sensation was assessed in rats. We measured the numberof licks during multiple 10-s presentations of NaCl and KClconcentrations (0.05, 0.09, 0.16, 0.28, 0.5 M) dissolved ineither water or in 100 µM amiloride, a sodium-channelblocker. The number of licks to water and 0.3 M sucrose wasalso measured. The number of licks to NaCl was significantlylower and the number of licks to KCl was significantly higherwhen these test solutions were dissolved in amiloride than inwater. There were no differences in lick responses to waterand sucrose. These results suggest that amiloride may have alteredthe taste of NaCl and KCl. The results are discussed in relationshipto prior electrophysiological studies characterizing the effectof amiloride in blocking salt responses of the chorda tympaninerve.     

Role of glutamine depletion in directing tissue-specific nutrient stress responses to L-asparaginase

L-asparaginase is important in the induction regimen for treating acute lymphoblastic leukemia. Cytotoxic complications are clinically significant problems lacking mechanistic insight. To reveal tissue-specific molecular responses to this drug, mice were administered asparaginase from either Escherichia coli (clinically used) or Wolinella succinogenes (novel, glutaminase-free form). Both enzymes abolished serum asparagine, but only the E. coli form reduced circulating glutamine. E. coli asparaginase reduced protein synthesis in liver and spleen but not pancreas via increased phosphorylation of the translation factor eIF2. In contrast, treatment with Wolinella caused no untoward changes in protein synthesis in any tissue examined. Treating mice deleted for the eIF2 kinase, GCN2, with the E. coli enzyme showed eIF2 phosphorylation to be GCN2-dependent, but only initially. Furthermore, although eIF2 phosphorylation was not increased in the pancreas or by Wolinella asparaginase, expression of the amino acid stress response genes, asparagine synthetase and CHOP/GADD153, increased as a result of both enzymes, even in tissues demonstrating no change in eIF2 phosphorylation. Finally, signaling downstream of the mammalian target of rapamycin kinase was repressed in liver and pancreas by E. coli but not Wolinella asparaginase. These data demonstrate that the nutrient stress response to asparaginase is tissue-specific and exacerbated by glutamine depletion. Importantly, increased expression of asparagine synthetase and CHOP does not require eIF2 phosphorylation, signifying alternate or auxiliary means of inducing gene expression under conditions of amino acid depletion in the whole animal.     

花生幼苗对重复干旱胁迫的生理响应

防雨棚内设盆栽试验,设置对照(Control,75%田间持水量)、干旱胁迫(D,35%)、重复干旱胁迫(D_D,35%)3个处理,探讨花生幼苗对预干旱胁迫的适应和记忆响应,分析预干旱对缓解重复干旱胁迫危害的生理作用。结果表明,与干旱胁迫处理相比,重复干旱胁迫提高了叶片的相对含水量,减少脯氨酸的积累,降低MDA和O·_2~-含量;抗氧化酶SOD、CAT活性降低,其中POD活性降低最为明显,并在复水后恢复到与对照相同水平或低于对照。与正常水分的对照相比,干旱胁迫显著降低叶片光合速率(P_N)、最大光合势能(P_C)、最大光量子产量(Y_Q),但重复干旱处理在重复干旱胁迫时期和复水后P_N、P_C和Y_Q均高于干旱处理。预干旱胁迫导致光合和气孔导度滞后面积、滞后率(H_P和H_g)增加,经过预干旱胁迫后,重复干旱显著降低光合和气孔导度滞后面积和滞后率。预干旱胁迫提高植株在重复干旱胁迫下叶片含水量,减轻重复干旱对植株造成的生理伤害,在光合作用上提高对重复干旱的抵御能力,并在复水后快速恢复到正常水分条件下植株生长水平,减少干旱对植株的不利影响。因此,预干旱胁迫促使花生幼苗具备适应或可记忆初始胁迫的能力,重复干旱胁迫时表现更为迅速和强烈的生理防御和快速的生理恢复机制。     

Maternal stress alters endocrine function of the feto-placental unit in rats

Prenatal stress (PS) can cause early and long-term developmental effects resulting in part from altered maternal and/or fetal glucocorticoid exposure. The aim of the present study was to assess the impact of chronic restraint stress during late gestation on feto-placental unit physiology and function in embryonic (E) day 21 male rat fetuses. Chronic stress decreased body weight gain and food intake of the dams and increased their adrenal weight. In the placenta of PS rats, the expression of glucose transporter type 1 (GLUT1) was decreased, whereas GLUT3 and GLUT4 were slightly increased. Moreover, placental expression and activity of the glucocorticoid "barrier" enzyme 11beta-hydroxysteroid dehydrogenase type 2 was strongly reduced. At E21, PS fetuses exhibited decreased body, adrenal pancreas, and testis weights. These alterations were associated with reduced pancreatic beta-cell mass, plasma levels of glucose, growth hormone, and ACTH, whereas corticosterone, insulin, IGF-1, and CBG levels were unaffected. These data emphasize the impact of PS on both fetal growth and endocrine function as well as on placental physiology, suggesting that PS could program processes implied in adult biology and pathophysiology.     

Head-down bed rest alters sympathetic and cardiovascular responses to mental stress

Astronauts usually work under much mental stress. However, it is unclear how and whether or not an exposure to microgravity affects physiological response to mental stress in humans. To examine effects of microgravity on vasomotor sympathetic and peripheral vasodilator responses to mental stress, we performed 10 min of mental arithmetic (MA) before and after 14 days of 6 degrees head-down bed rest (HDBR), a ground-based simulation of spaceflight. Total muscle sympathetic nerve activity (MSNA, measured by microneurography) slightly increased during MA before HDBR, and this increase was augmented after HDBR. Calf blood flow (measured by venous occlusion plethysmography) increased and calf vascular resistance (calculated by dividing mean blood pressure by calf blood flow) decreased during MA before HDBR, but these responses were abolished after HDBR. Increases in heart rate and mean blood pressure during MA were not different between before and after HDBR. These findings suggest that HDBR augmented vasomotor sympathoexcitation but attenuated vasodilatation in the calf muscle in response to mental stress.     

Chemical sympathectomy alters food intake and thermogenic responses to catecholamines in rats

It has been suggested that the sympathetic nervous system contributes to the short-term control of feeding. The adrenergic innervation of some splanchnic organs seems to be especially involved in such processes, since catecholamines reduce feeding only when injected intraperitoneally or intraportally. In this work, the effects of neonatal sympathetic denervation with guanethidine (Gnt) upon food intake were assessed in adult rats. Gnt-treated male rats had lower body weight gain. The hypophagic response to intraperitoneal (ip) norepinephrine was 70% higher in Gnt-treated animals as compared to controls (P < 0.05); that of epinephrine (E) by 33% (P < 0.05) and that of isoproterenol was not significantly modified. As in normal rats, the hypophagic effect was much stronger after ip than after intramuscular (im) administration (P < 0.05). On the other hand, resting oxygen consumption (VO2) was consistently lower in denervated animals. Ip E administration did not modify VO2, while im E caused increased motor activity and VO2 (P < 0.05). In contrast to control rats, the respiratory exchange ratio in ad libitum fed Gnt rats did not decrease after Ip E administration, suggesting a lack of effect upon lipid mobilization. The lower rate of body weight gain induced by neonatal Gnt sympathectomy might be due to lower daily food intake possibly related, in part, to the sensitization of the alpha-adrenergic porto-hepatic response to endogenous catecholamines. Compared with controls, Gnt-treated rats also showed a limited thermogenic capacity not related to feeding, and a greater degree of carbohydrate oxidation, possibly due to a defect in E-induced lipolysis, which is beta-adrenergic.     

Effect of sodium depletion on peripheral vascular responses to heat stress in baboons

The cutaneous vasodilation and renal vasoconstriction in baboons during environmental heating (EH) appear to be produced predominantly by sympathetic vasoconstrictor withdrawal and activation of the renin-angiotensin system, respectively. Since these mechanisms may be influenced differently by sodium depletion, this study examined the hypothesis that sodium depletion would have a differential effect on cutaneous and renal vascular responses to EH. Sodium depletion was produced in chronically instrumented baboons by placing them on low-salt intake for 8-19 days along with diuretic administration. EH consisted of exposing the baboon to an ambient temperature of 40-42 degrees C until core temperature (Tc) reached 39.8-40.0 degrees C. Both control plasma renin activity (PRA) and the rise in PRA with Tc during EH were considerably larger in sodium-depleted baboons. However, the magnitudes of the progressive increases in iliac vascular conductance (used as an index of hindlimb cutaneous vasodilation) and renal vascular resistance with rising Tc during EH were unaltered by sodium depletion. Therefore, neither cutaneous nor renal vascular responses to EH are influenced by elevated PRA and other changes accompanying sodium depletion in the baboon.     

Nonsynaptic noradrenaline release in neuro-immune responses

Evidence has recently been obtained that the branches of the autonomic nervous system, mainly, the sympathetic [25], regulate cytokine production. Not only the primary (thymus, bone marrow) and secondary (spleen, tonsils, and lymph nodes) lymphoid organs, but also many other tissues are involved in immune responses and are heavily influenced by noradrenaline (NA) derived from varicose axon terminals of the sympathetic nervous system [25, 100]. Besides NA released from nonsynaptic varicosities of noradrenergic terminals [92], circulating catecholamines (adrenaline, dopamine, NA) are also able to influence immune responses, the production of pro- and anti-inflammatory cytokines by different immune cells. The sympathetic nervous system (catecholamines) and the hypothalamic-pituitary-adrenal (HPA) axis (cortisol) are the major integrative and regulatory components of different immune responses. In our laboratory convincing evidence has been obtained that NA released non-synaptically [90, 92] from sympathetic axon terminals and enhanced in concentration in the close proximity of immune cells is able to inhibit production of proinflammatory (TNF-alpha, IFN-gamma, IL-12, IL-1) and increase antiinflammatory cytokines (IL-10) in response to LPS [25, 91], indicating a fine-tuning control of the production of TNF-alpha and other cytokines by sympathetic innervation under stressful conditions. This effects are mediated via beta2-adrenoceptors expressed on immune cells and coupled to cAMP levels.     

Cardiovascular and sympathoadrenal responses to stress in swim-trained rats

Chronic exposure to swim stress (i.e., training) is associated with functional adaptations of the cardiovascular system. On the other hand, repeated exposure to tail shock, an emotional stress, often results in deleterious changes in resting blood pressure and myocardial pathology. We hypothesized that the pathological adaptation following chronic exposure to tail shock was associated with a larger acute physiological response compared with swim stress. Therefore, acute responses to swim and shock stress were compared. A second concern of this study examined the extent to which adaptation to swim training influences responses to predictable tail shock stress. The cardiovascular and sympathoadrenal responses to swim stress, using 1% body wt attached to the tail, were compared with predictable tail shock (0.2-0.4 mA intensity, 1-s duration, 1/min) in two groups of Long-Evans male rats. In the first, 11 rats were studied following 5-7 wk of swim training, consisting of daily 1-h sessions of swimming with 2% body wt attached to their tails. They were compared with an age-matched nontrained (NT) group (n = 8). During swimming, the trained animals showed significantly lower heart rate (387 +/- 10 vs. 449 +/- 18 beats/min) and significantly lower lactate (0.9 +/- 0.09 vs. 2.0 +/- 0.24 mmol/l), epinephrine (332 +/- 57 vs. 739 pg/ml), and corticosterone (32 +/- 10 vs. 62 +/- 9 micrograms/dl) responses. Systolic and diastolic blood pressures were elevated in swim stress by the same degree in trained (167/110 mmHg) and NT (177/116 mmHg) rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Selective depletion of nonspecific T cells during the early stage of immune responses to infection

Transient T cell depletion occurs before the development of an effective immune response to infection. In this study we show that most T cells, regardless of specificity, are induced to express early activation markers soon after infection with Listeria monocytogenes or lymphocytic choriomeningitis virus. Ag-specific T cells are further activated to display late activation markers and undergo extensive proliferation. As Ag-specific T cells begin to expand, nonspecific T cells are depleted en masse and exhibit no sign of further activation or proliferation before their depletion. This selective depletion of nonspecific T cells is due to in situ death via apoptosis, as visualized by confocal microscopy. Thus, early activation and subsequent depletion of nonspecific T cells are integral parts of the immune response to proinflammatory infections. These results have important implications for our understanding of early events in the development of a robust T cell response.