Hyperpnea-induced bronchoconstriction is dependent on tachykinin-induced cysteinyl leukotriene synthesis

Yang, X. X., W. S. Powell, M. Hojo, and J. G. Martin.Hyperpnea-induced bronchoconstriction is dependent ontachykinin-induced cysteinyl leukotriene synthesis. J. Appl. Physiol. 82(2): 538-544, 1997.The purposeof the study was to test the hypothesis that tachykinins mediatehyperpnea-induced bronchoconstriction indirectly by triggeringcysteinyl leukotriene (LT) synthesis in the airways. Guinea pigs(350-600 g) were anesthetized with xylazine and pentobarbital sodium and received hyperpnea challenge (tidal volume 3.5-4.0 ml,frequency 150 breaths/min) with either humidified isocapnic gas(n = 6) or dry gas(n = 7). Dry gas challenge wasperformed on animals that received MK-571(LTD₄ antagonist; 2 mg/kg iv; n = 5), capsaicin(n = 4), neurokinin (NK) antagonists[NK₁ (CP-99994) + NK₂ (SR-48968) (1 mg/kg iv);n = 6], or theH₁ antihistamine pyrilamine (2 mg/kg iv; n = 5). We measured thetracheal pressure and collected bile for 1 h before and 2 h afterhyperpnea challenge. We examined the biliary excretion of cysteinylLTs; the recovery of radioactivity in bile after instillation of 1 µCi [³H]LTC₄intratracheally averaged 24% within 4 h(n = 2). The major cysteinyl LTidentified was LTD₄ (32% recoveryof radioactivity). Cysteinyl LTs were purified from bile of animalsundergoing hyperpnea challenge by using reverse-phase high-pressureliquid chromatography and quantified by radioimmunoassay. There was asignificant increase in the peak value of tracheal pressure afterchallenge, indicating bronchoconstriction in dry gas-challenged animalsbut not after humidified gas challenge. MK-571, capsaicin, and NKantagonists prevented the bronchoconstriction; pyrilamine didnot. Cysteinyl LT levels in the bile after challenge weresignificantly increased from baseline in dry gas-challenged animals(P < 0.05) and were higher than inthe animals challenged with humidified gas or dry gas-challengedanimals treated with capsaicin or NK antagonists (P < 0.01). The results indicatethat isocapnic dry gas hyperpnea-induced bronchoconstriction is LTmediated and the role of tachykinins in the response is indirectthrough release of LTs. Endogenous histamine does not contribute to theresponse.

     

Role of tachykinins in airway responses to ozone in rats

Previousstudies that used neonatal capsaicin (Cap) treatment toablate C fibers indicate that C fibers act to inhibit lung damage andairway hyperresponsiveness after ozone(O₃) exposure in rats. Thepurpose of this study was to determine1) the role of tachykinins in theseprotective effects and 2) whetherdifferences in minute ventilation (E)during O₃ exposure might accountfor the effect of Cap. In the first study, male Sprague-Dawley rats were exposed to 1 part/million O₃or air for 3 h. Four hours later, a bronchoalveolar lavage (BAL) wasperformed or airway responsiveness was measured. Rats were treated withCP-99994 and SR-48968, selective neurokinin-1- and -2-receptorantagonists, respectively, or with vehicle (Veh).O₃ caused an increase in thenumber of neutrophils recovered from BAL fluid in both the Veh-treatedand tachykinin-receptor antagonist (TKRA)-treated rats, but the numberof neutrophils was approximately twofold greater in the TKRA-treatedrats. In contrast, TKRA treatment had no effect on baseline pulmonarymechanics or airway responsiveness. AfterO₃ exposure, the number ofneutrophils in BAL fluid was also greater in Cap- than in Veh-treatedrats. O₃ reducedE in both Veh- and Cap-treated rats,but the response was greater (reduction of 44.7 ± 3.7 vs. 27.8 ± 6.8%) and occurred earlier (10 vs. 70 min) in Cap- than inVeh-treated rats (P < 0.02). Theseresults suggest that tachykinins mediate protective effects of C fibersagainst O₃-induced lunginflammation. The results also indicate that the more pronounced effectof O₃ on BAL neutrophils inCap-treated rats is not the result of a greater inhaled dose ofO₃ resulting from greaterE.

     

Reduced lipoprotein lipase activity in postural skeletal muscle during aging.

Lipoprotein lipase (LPL) is a key enzyme for fatty acid and lipoprotein metabolism in muscle. However, the effect of aging on LPL regulation in skeletal muscle is unknown. We report the effect of aging on LPL regulation in the soleus (red oxidative postural) muscle and the tibialis anterior (white glycolytic non-weight-bearing) muscle in 4- and 24-mo-old Fischer 344 rats and 18- and 31-mo-old Fischer 344 x Brown-Norway F1 (F-344 x BN F1) rats. Total and heparin-releasable LPL (HR-LPL) activities were decreased 38% (P < 0.01) and 52% (P < 0.05), respectively, in the soleus muscle of the older Fischer 344 rats. There was a 32% reduction (P < 0.05) of total LPL protein mass in the soleus muscle with aging. The results were confirmed in another strain. A decrease of total LPL activity (-50%, P < 0.05) was also found in the soleus muscle between 18- and 31-mo-old F-344 x BN F1 rats. LPL mRNA concentration in the soleus muscle was not different between ages. Total LPL protein mass was reduced by 46% (P < 0.05) in the soleus muscle of the 31-mo-old F-344 x BN F1 rats. In the tibialis anterior muscle, neither LPL activity nor mRNA concentration was affected by age in either strain. In conclusion, LPL regulation in a non-weight-bearing muscle was not affected by aging. However, there was a pronounced reduction in LPL activity and LPL protein mass in postural muscle with aging.     

Strong and weak immune responses across the same major histocompatibility barrier in rats

Inbred rat strains, Fischer 344 (F-344) and Lewis (LEW), share the serologicalAg-Bl allele and react very weakly in mixed lymphocyte culture (MLC). Despite this apparent identity atAg-B, these strains differ markedly in their immune responses to anAg-B disparate third strain Marshall 520 (M-520) (Ag-B6). F-344 recipients allowed M-520 heart grafts an extended survival, whereas LEW recipients rejected them rapidly. F-344 and M-520 showed a weak response in MLC in contrast to a strong response for LEW and M-520. F-344 produced antisera in response to injection of M-520 cells that had a relatively high antibody titer but low cytotoxic activity. F-344 responded to another strain, Buffalo (BUF) (alsoAg-B6), in a similar fashion. F-344 apparently can produce a strong allogeneic response, as it was able to rapidly reject heart grafts from (LEW x Brown-Norway) F₁ donors (LBN) (Ag-B 1/3). The low response of F-344 to M-520 probably was not due to shared antigens between the two strains because M-520 heart grafts underwent rapid rejection in LEW hosts highly tolerant to F-344. To explain the contrasting response of F-344 and LEW to theAg-B6 disparity, we propose that it is controlled by an immune-response gene(s); that F-344 has a low-responding allele and LEW has a high-responding allele. The data do not reveal a location for this proposed gene. The high-responding allele appears to be dominant, as M-520 hearts were rejected rapidly by (F-344 x LEW) F₁ recipients.     

Role of tachykinins in ozone-induced airway hyperresponsiveness to cigarette smoke in guinea pigs

Wu, Zhong-Xin, Robert F. Morton, and Lu-Yuan Lee. Roleof tachykinins in ozone-induced airway hyperresponsiveness to cigarettesmoke in guinea pigs. J. Appl.Physiol. 83(3): 958-965, 1997.Acute exposure to ozone(O₃) induces airwayhyperresponsiveness to various inhaled bronchoactive substances.Inhalation of cigarette smoke, a common inhaled irritant in humans, isknown to evoke a transient bronchoconstrictive effect. To examinewhether O₃ increases airwayresponsiveness to cigarette smoke, effects of smoke inhalationchallenge on total pulmonary resistance(RL) and dynamic lungcompliance (Cdyn) were compared before and after exposure toO₃ (1.5 ppm, 1 h) in anesthetizedguinea pigs. Before O₃ exposure,inhalation of two breaths of cigarette smoke (7 ml) at a lowconcentration (33%) induced a mild and reproduciblebronchoconstriction that slowly developed and reached its peak(RL = 67 ± 19%, Cdyn = 29 ± 6%) after a delay of >1 min. After exposure toO₃ the same cigarette smokeinhalation challenge evoked an intense bronchoconstriction thatoccurred more rapidly, reaching its peak(RL = 620 ± 224%, Cdyn = 35 ± 7%) within 20 s, and was sustained for >2min. By contrast, sham exposure to room air did not alter thebronchomotor response to cigarette smoke challenge. Pretreatment withCP-99994 and SR-48968, the selective antagonists of neurokinin type 1 and 2 receptors, respectively, completely blocked the enhancedresponses of RL and Cdyn tocigarette smoke challenge induced byO₃. These results show thatO₃ exposure induces airwayhyperresponsiveness to inhaled cigarette smoke and that the enhancedresponses result primarily from the bronchoconstrictive effect ofendogenous tachykinins.

     

Localization of Eutr2, a locus controlling susceptibility to DES-induced uterine inflammation and pyometritis, to RNO5 using a congenic rat strain

In some rat strains chronic administration of exogenous estrogens induces pyometritis, an inflammation of the uterus associated with infection, suggesting that there is genetic variation in susceptibility to estrogen-induced inflammation and pyometritis. In this article we report that following 10 weeks of treatment with the synthetic estrogen diethylstilbestrol (DES), Fisher 344 (F344) rats exhibit modest uterine inflammation and a 0% incidence of pyometritis. By contrast, under identical experimental conditions, Brown Norway (BN) rats exhibit significant inflammation and a 100% incidence of pyometritis. Similarly, we also observed profound uterine inflammation and a 100% incidence of pyometritis in a congenic rat strain in which a segment of RNO5 from the BN strain is carried on the F344 strain. These data suggest that a locus on RNO5 controls both the magnitude of DES-induced uterine inflammation and susceptibility to DES-induced pyometritis. This locus, designated Eutr2, resides within the same segment of RNO5 as the Eutr1 locus, which confers susceptibility to E2-induced pyometritis in an F2 population generated in a cross between the BN and August × Copenhagen 9935, Irish (ACI) strains. Jyotsna Pandey, Karen A. Gould contributed equally to this work.     

Airway hyperresponsiveness induced by chronic exposure to cigarette smoke in guinea pigs: role of tachykinins.

This study was carried out to determine whether tachykinins released from lung C-fiber afferents play a part in the bronchial hyperreactivity induced in guinea pigs by chronic exposure to cigarette smoke (CS). Two matching groups of young guinea pigs were exposed to either mainstream CS (CS group) or air (control group) for 20 min twice daily for 14-17 days. There was no difference in the baseline total pulmonary resistance (RL) between the two groups, but the baseline dynamic lung compliance was reduced ( approximately 19%) in CS animals. The responses of RL to intravenous injections of ACh, neurokinin (NK) A, and capsaicin were all markedly increased in CS animals; for example, ACh at the same dose of 5.06 microg/kg increased RL by 207% in the control group and by 697% (n = 8; P < 0. 001) in the CS group. The increased responsiveness was accompanied by significant increases in the numbers of neutrophils, eosinophils, and macrophages in the bronchoalveolar lavage fluid in CS animals. Pretreatment with SR-48968 and CP-99994, antagonists of NK(1) and NK(2) receptors, respectively, did not alter the response of RL to ACh in control animals, but it abolished the elevated bronchoconstrictive response in the CS animals. Furthermore, the immunoreactivities of substance P and calcitonin gene-related peptide in the bronchoalveolar lavage fluid collected after capsaicin challenge were significantly increased in CS animals. These results show that chronic exposure to CS induced airway mucosal inflammation accompanied by bronchial hyperreactivity in guinea pigs and that the tachykininergic mechanism plays an important role in this augmented responsiveness.     

Ventilation and metabolism among rat strains

Strohl, Kingman P., Agnes J. Thomas, Pamela St. Jean, EvelynH. Schlenker, Richard J. Koletsky, and Nicholas J. Schork. Ventilation and metabolism among rat strains. J. Appl. Physiol. 82(1): 317-323, 1997.We examinedventilation and metabolism in four rat strains with variation in traitsfor body weight and/or blood pressure regulation.Sprague-Dawley [SD; 8 males (M), 8 females (F)], BrownNorway (BN; 10 M, 11 F), and Zucker (Z; 11 M, 12 F) rats were comparedwith Koletsky (K; 11 M, 11 F) rats. With the use of noninvasiveplethysmography, frequency, tidal volume, minute ventilation(E),O₂ consumption, andCO₂ production were derived atrest during normoxia (room air) and during the 5th minute of exposureto each of the following: hyperoxia (100% O₂), hypoxia (10%O₂-balanceN₂), and hypercapnia (7%CO₂-balance O₂). Statistical methods probedfor strain and sex effects, with covariant analysis by body weight,length, and body mass. During resting breathing, strain effects werefound with respect to both frequency (BN, Z > K, SD) and tidal volume(SD > BN, Z) but not to E. Sexinfluenced frequency (F > M) alone. Z rats had higher values forO₂ consumption,CO₂ production, and respiratoryquotient than the other three strains, with no independent effect bysex. During hyperoxia, frequency was greater in BN and Z than in SD orK rats; SD rats had a larger tidal volume than BN or Z rats; Z rats hada greater E than K rats; and M had alarger tidal volume than F. Strain differences persisted duringhypercapnia, with Z rats exhibiting the highest frequency andE values. During hypoxic exposure,strain effects were found to influenceE (SD > K, Z), frequency (BN > K), and tidal volume (SD > BN, K, Z). Body mass was only amodest predictor of E during normoxia, of both E and tidal volume withhypoxia, hypercapnia, or hyperoxia, and of frequency duringhypercapnia. We conclude that strain of rats, more than their body massor sex, has major and different influences on metabolism, the patternand level of ventilation during air breathing, and ventilation duringacute exposure to hypercapnia or hypoxia.

     

Reduced body mass, food intake, and testis size in response to short photoperiod in adult F344 rats

Background  

Although laboratory rats are often considered classic nonseasonal breeders, peripubertal rats of two inbred strains, F344 and BN, have both reproductive and nonreproductive responses to short photoperiods. Unmanipulated adult rats have not been reported to have robust responses to short photoperiod alone, although several treatments can induce photoperiodic responses in adults. In this study, we tested the hypotheses that unmanipulated F344 rats retain responses to short photoperiod as adults and that they have the necessary elements for an endogenous circannual rhythm of sensitivity to short photoperiod.     

Potent NK1 antagonism by SR-140333 reduces rat colonic secretory response to immunocyte activation

The potentneurokinin receptor 1 (NK₁) antagonist SR-140333has previously been shown to reduce castor oil-induced secretion inanimal models. The importance of tachykinins in neuroimmune control ofsecretion and the effect of SR-140333 on key points in this pathwaywere elucidated in the present study to determine the type ofintestinal dysfunction best targeted by this antagonist. Rat colonicsecretion and substance P (SP) release were determined in vitro withthe use of Ussing chamber and enzyme immunoassay techniques.NK₁ receptors played a secretory role as receptor agonistsstimulated secretion and SR-140333 antagonized the response to SPresponse (pK_b = 9.2). Sensory fiber stimulationreleased SP and evoked a large secretion that was reduced by 69% inthe presence of SR-140333 (10 nM). Likewise, mastocytes also released SP. The subsequent secretory response was reduced by 43% in the presence of SR-140333 (50 nM). SP was also released from granulocytes; however, this did not cause secretion. Functional NK₃receptors were present in the colon as senktide stimulated secretion,an effect that was increased during stress. We conclude thatNK₃ receptors may play a role in stress-related disorders,whereas NK₁ receptors are more important in mastcell/afferent-mediated secretion.

     

Differences in response to anaesthetics and analgesics between inbred rat strains

Differences in response to analgesic and anaesthetic drugs can partly be attributed to variations in the genetic background of experimental animals. This study was carried out to determine differences in the response of inbred rat strains to a selection of analgesics and drugs used in anaesthetic protocols. A cross between the most contrasting strains can then be phenotyped in future studies in order to localize quantitative trait loci (QTLs) involved in analgesic/anaesthetic drug sensitivity. Eight inbred strains (n = 6 rats/strain) were selected for the study: the pigmented ACI, BN and COP strains and the albino F344, LEW, SHR, WAG and WKY strains. Each rat was injected intravenously with two analgesics (buprenorphine 0.05 mg/kg and nalbuphine 1 mg/kg) and three drugs used in anaesthetic protocols (propofol 25 mg/kg, medetomidine 50 microg/kg and ketamine 10 mg/kg), respectively, using a crossover design. Analgesic responses were assessed using an analgesiometric procedure. The sleep time of the rat and, where applicable, the interval between injection and loss of righting reflex were used to determine the anaesthetic response. Six out of eight strains responded significantly different from each other to the analgesic effect of buprenorphine with the ACI strain as hyper-responder. The tail withdrawal latency at 55 degrees C of the F344 and WKY rats using buprenorphine was not significantly different from baseline tail withdrawal latencies. In this study, all strains were non-responsive to the analgesic effects of nalbuphine. The response to all three drugs used in anaesthetic protocols differed significantly among the strains. The F344 and BN strains were relatively resistant to the sedative effects of medetomidine. Use of ketamine was abandoned in the ACI and BN strains when the first two animals of both strains died soon after induction. With all three drugs the sleep time of albino rats was significantly longer compared with that of the pigmented ones. We conclude that the results from this study can be used in future studies where QTLs for the sensitivity to anaesthetic/analgesic drugs are localized.     

Angiogenesis and capillary maturation phenotypes associated with the Edpm3 locus on rat chromosome 3

The quantitative trait locus (QTL) Edpm3 is one of a group of additively acting QTL \responsible for the difference in estrogen-induced pituitary tumor growth between the tumor-susceptible F344 and tumor-resistant BN rat strains. The F344.BN-Edpm3^BN rat strain was produced by moving the segment of rat Chr 3 between D3Mgh7 and D3Mgh13, which contains the Edpm3 QTL, from the BN strain into the F344 genetic background. In a previous study, we used this congenic line to find that the BN allele of the Edpm3 QTL reduces tissue mass and S-phase fraction in the estrogen-induced rat pituitary tumor. We now report on the use of this congenic line to investigate the linkage of Edpm3 to tumor angiogenesis. Contrary to expectation, the F344.BN-Edpm3^BN strain has significantly greater angiogenic activity than does F344 in both treated and untreated rats. Microvessel count (MVC), perivascular space, and number of nonattached pericytes/pericapillary fibroblasts are all elevated in the pituitary by chronic estrogen treatment and their values are significantly greater in F344.BN-Edpm3^BN than F344. Thus, although there is greater angiogenic activity in the pituitary of estrogen-treated F344.BN-Edpm3^BN rats, there is a deficiency in capillary maturation compared with F344.     

Differences in time-dependent hypoxic phrenic responses among inbred rat strains.

Hypoxic ventilatory responses differ between rodent strains, suggesting a genetic contribution to interindividual variability. However, hypoxic ventilatory responses consist of multiple time-dependent mechanisms that can be observed in different respiratory motor outputs. We hypothesized that strain differences would exist in discrete time-dependent mechanisms of the hypoxic response and, furthermore, that there may be differences between hypoglossal and phrenic nerve responses to hypoxia. Hypoglossal and phrenic nerve responses were assessed during and after a 5-min hypoxic episode in anesthetized, vagotomized, and ventilated rats from four inbred strains: Brown Norway (BN), Fischer 344 (FS), Lewis (LW), and Piebald-viral-Glaxo (PVG). During baseline, burst frequency was higher in PVG than LW rats (P < 0.05), phrenic burst amplitude was higher in PVG vs. other strains (P < 0.05), and hypoglossal burst amplitude was higher in PVG and BN vs. FS and LW (P < 0.05). During hypoxia, burst frequency did not change in BN or LW rats, but it increased in PVG and FS rats. The phrenic amplitude response was smallest in PVG vs. other strains (P < 0.05), and the hypoglossal response was similar among strains. Short-term potentiation posthypoxia was slowest in FS and fastest in LW rats (P < 0.05). Posthypoxia frequency decline was absent in PVG, but it was observed in all other strains. Augmented breaths were observed during hypoxia in FS rats only. Thus genetic differences exist in the time domains of the hypoxic response, and these are differentially expressed in hypoglossal and phrenic nerves. Furthermore, genetic diversity observed in hypoxic ventilatory responses in unanesthetized rats may arise from multiple neural mechanisms.     

Endogenous vasopressin does not mediate hypoxia-induced anapyrexia in rats

The present study was designed to test the hypothesis thatarginine vasopressin (AVP) mediates hypoxia-induced anapyrexia. Therectal temperature of awake, unrestrained rats was measured before andafter hypoxic hypoxia, AVP-blocker injection, or a combination of thetwo. Control animals received saline injections of the same volume.Basal body temperature was 36.52 ± 0.29°C. We observed asignificant (P < 0.05) reduction inbody temperature of 1.45 ± 0.33°C after hypoxia (7% inspiredO₂), whereas systemic andcentral injections of AVP V₁- andAVP V₂-receptor blockers caused nochange in body temperature. When intravenous injection of AVP blockerswas combined with hypoxia, we observed a reduction in body temperatureof 1.49 ± 0.41°C(V₁-receptor blocker) and of 1.30 ± 0.13°C (V₂-receptorblocker), similar to that obtained by application of hypoxia only.Similar results were observed when the blockers were injectedintracerebroventricularly. The data indicate that endogenous AVP doesnot mediate hypoxia-induced anapyrexia in rats.     

Genetic mapping of loci controlling diethylstilbestrol-induced thymic atrophy in the Brown Norway rat

Chronic estrogen administration can lead to thymic atrophy in rodents. In this article we report that the Brown Norway (BN) rat is sensitive to thymic atrophy induced by the estrogen diethylstilbestrol (DES). By contrast, DES does not induce significant thymic atrophy in the August × Copenhagen-Irish (ACI) strain. The sensitivity of the BN rat to DES-induced thymic atrophy appears to segregate as an incompletely dominant trait in crosses between the BN and ACI strains. In a (BN × ACI)F₂ population, we find strong evidence for three major genetic determinants of sensitivity to DES-induced thymic atrophy on rat Chromosome (RNO) 10 and RNO2. Genotypes at these loci, termed Esta1, 2, and 3, do not have a significant impact on the ability of DES to induce pituitary tumorigenesis or inhibit growth of these F₂ rats. These data indicate that the genetic factors that control DES-induced thymic atrophy are distinct from those that control the effects of DES on pituitary mass and body mass. The Esta intervals on RNO10 and RNO2 overlap with loci that control sensitivity to radiation-induced thymocyte apoptosis, as well as susceptibility to a variety of allergic and autoimmune pathologies, including allergic encephalitis, arthritis, and glomerulonephritis in rodents. These observations suggest that common genetic determinants may control sensitivity to estrogen-induced thymic atrophy, maintenance of thymocyte homeostasis, and immune function.     

Contribution of NK(2) tachykinin receptors to propulsion in the rabbit distal colon

The role of the tachykinin neurokinin (NK)(2) receptors on rabbit distal colon propulsion was investigated by using two selective NK(2)-receptor antagonists, MEN-10627 and SR-48968. Experiments on colonic circular muscle strips showed that contractile responses to [beta-Ala(8)]NKA-(4-10) (1 nM-1 microM), a selective NK(2)-receptor agonist, were competitively antagonized by MEN-10627 (1-100 nM), whereas SR-48968 (0.1-10 nM) caused an insurmountable antagonism, thus confirming the difference in the mode of action of the two compounds. Colonic propulsion was elicited by distending a mobile rubber balloon with 0.3 ml (submaximal stimulus) or 1.0 ml (maximal stimulus) of water. The velocity of anal displacement of the balloon (mm/s) was considered the main propulsion parameter. At low concentrations (1.0-100 nM and 0.1-10 nM, respectively), MEN-10627 and SR-48968 facilitated the velocity of propulsion, whereas at high concentrations (100 nM and 1 microM, respectively) they decelerated propulsion. The excitatory and inhibitory effects of both antagonists were observed only with submaximal stimulus. We focused on the hypothesis that the facilitatory effect on propulsion may result from blockade of neuronal NK(2) receptors and the inhibitory effect from suppression of the excitatory transmission mediated by NK(2) receptors on smooth muscle cells. In the presence of N(G)-nitro-L-arginine (300 microM), a nitric oxide synthase inhibitor, MEN-10627, at a concentration (10 nM) that was found to accelerate propulsion in control experiments inhibited the velocity of propulsion. In the presence of threshold (1-10 nM) or full (1 microM) concentration of atropine, which inhibited to a great extent the velocity of propulsion, the inhibitory effect of MEN-10627 (1 microM) was markedly increased. In conclusion, in the rabbit distal colon NK(2) receptors may decelerate propulsion by activating a nitric oxide-dependent neuronal mechanism and may accelerate it by a postjunctional synergistic interaction with cholinergic muscarinic receptors.     

Ept7 influences estrogen action in the pituitary gland and body weight of rats

Estrogens control many aspects of pituitary gland biology, including regulation of lactotroph homeostasis and synthesis and secretion of prolactin. In rat models, these actions are strain specific and heritable, and multiple quantitative trait loci (QTL) have been mapped that impact the responsiveness of the lactotroph to estrogens. One such QTL, Ept7, was mapped to RNO7 in female progeny generated in an intercross between BN rats, in which the lactotroph population is insensitive to estrogens, and ACI rats, which develop lactotroph hyperplasia/adenoma and associated hyperprolactinemia in response to estrogen treatment. The primary objective of this study was to confirm the existence of Ept7 and to quantify the impact of this QTL on responsiveness of the pituitary gland of female and male rats to 17β-estradiol (E2) and diethylstilbestrol (DES), respectively. Secondary objectives were to determine if Ept7 influences the responsiveness of the male reproductive tract to DES and to identify other discernible phenotypes influenced by Ept7. To achieve these objectives, a congenic rat strain that harbors BN alleles across the Ept7 interval on the genetic background of the ACI strain was generated and characterized to define the effect of administered estrogens on the anterior pituitary gland and male reproductive tissues. Data presented herein indicate Ept7 exerts a marked effect on development of lactotroph hyperplasia in response to estrogen treatment, but does not affect atrophy of the male reproductive tissues in response to hormone treatment. Ept7 was also observed to exert gender specific effects on body weight in young adult rats.     

Suppressor cell influence in selected strains of inbred rats. III. Evidence for nonspecific suppression by a lymphocyte-macrophage cooperation.

Lewis (LE) and Brown-Norway (BN) rats treated in vivo with rabbit anti rat thymocyte serum demonstrate a reversal in relative responsiveness when assayed to mitogens and antigens via lymphocyte transformation, i.e., the BN rat now responds to a greater magnitude than the LE rats. Spleen cells, from both strains, that have been eluted from glass wool columns, demonstrate elevated responses to mitogens and antigens when compared to unfractionated spleen cells. The responses by these unfractionated and nonadherent populations can 1) be further enhanced subsequent to the treatment with anti-thymocyte serum and 2) suppressed after addition of macrophages from either strain, but especially by BN derived macrophages. The adherent cells from LE spleens respond to the above treatments in a similar fashion as the other populations. The responsiveness of adherent BN cells is only partially restored following treatment with anti-thymocyte serum, and is not further suppressed upon the addition of macrophages. These data are indicative of a lymphocyte-macrophage cooperation in this mechanism of suppression.     

Breath ethane as a marker of reactive oxygen species during manipulation of diet and oxygen tension in rats

Breath ethane, O₂consumption, and CO₂ productionwere analyzed in 24-mo-old female Fischer 344 rats that had been fedcontinuously ad libitum (AL) or restricted 30% of AL level (DR) dietssince 6 wk of age. Rats were placed in a glass chamber that was first flushed with air, then with a gas mixture containing 12%O₂. After equilibration, a sampleof the outflow was collected in gas sampling bags for subsequentanalyses of ethane and CO₂. TheO₂ andCO₂ levels were also directlymonitored in the outflow of the chamber. O₂ consumption andCO₂ production increased for DRrats. Hypoxia decreased O₂consumption and CO₂ production forthe AL-fed and DR rats. These changes reflect changes in metabolic ratedue to diet and PO₂. A significantdecrease in ethane generation was found in DR rats compared with AL-fedrats. Under normoxic conditions, breath ethane decreased from 2.20 to1.61 pmol ethane/ml CO₂. Duringhypoxia the levels of ethane generation increased, resulting in aDR-associated decrease in ethane from 2.60 to 1.90 pmol ethane/mlCO₂. These results support thehypothesis that DR reduces the level of oxidative stress.     

不同品系大鼠RTI基因抗原表达数量的研究

目的研究不同品系大鼠RT1A、RT1B和RT1D基因表达的抗原总数量,以及在CD4＋T细胞和CD8＋T细胞上表达的数量,为免疫学研究提供数据支持。方法采集四种品系BN、Lewis、F344、SHR大鼠的静脉血,制备淋巴细胞,与有荧光标记的单克隆抗体反应,应用流式细胞术检测抗原数量。结果发现RT1A、RT1B和RT1D基因表达的抗原在不同品系大鼠体内表达的数量不同,其中F344大鼠表达的RT1A抗原最多,BN大鼠表达的RT1B抗原和RT1D抗原均为最多。RT1A、RT1B和RT1D基因表达的抗原在CD4＋T细胞和CD8＋T细胞上表达的数量也不同,Lewis大鼠在CD4＋T细胞上表达的RT1A抗原最多,BN大鼠在CD4＋T细胞上表达的RT1B和RT1D抗原最多。F344大鼠在CD8＋T细胞上表达的RT1A抗原最多;F344大鼠在CD8＋T细胞上表达的RT1B和RT1D抗原最多。同一品系大鼠之间雌雄动物RT1A、RT1B和RT1D基因表达的抗原也不同。结论不同品系大鼠RT1A、RT1B和RT1D基因的抗原总表达数量之间差异有显著性,在CD4＋T细胞上和CD8＋T细胞上表达的数量差异也有显著性。