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PubMed1999

A low individualized GH dose in young patients with childhood onset GH deficiency normalized serum IGF-I without significant deterioration in glucose tolerance.

OBJECTIVE: Many GH deficient (GHD) patients have impaired glucose tolerance and GH substitution in these patients has caused deleterious effects on glucose tolerance with hyperinsulinaemia. This further impairment of glucose tolerance might be due to an unphysiologically high dose of GH. Whether such a deterioration can be avoided by an optimal GH replacement dose is not known. In most previous studies, the GH dose was calculated according to body weight or body surface area and not adjusted according to the serum IGF-I response. DESIGN: The study was of open design and investigations were performed before the start of GH substitution and after nine months of treatment. The GH dose was adjusted according to the response in serum IGF-I, and in patients with sub-normal serum IGF-I levels (all but two) we aimed for a serum IGF-I level in the middle of the normal range. The median GH dose at the end of the study was 0.14 IU/kg/week. PATIENTS: Ten patients, eight males and two females, with childhood onset GHD were examined. Their median age was 27 years (range 21-28). MEASUREMENTS: Overnight and 24-h fasting levels of glucose, insulin and IGFBP-1 were measured. Directly after the 24-h fast an oral glucose tolerance test (OGTT), with measurements of glucose, insulin and IGFBP-1 was performed. An intravenous glucose tolerance test (IVGTT) was performed after overnight fasting. Body composition was measured with bio-impedance analysis (BIA) and quality of life was assessed using a self-rating questionnaire, Qol-AGHDA. RESULTS: After GH treatment, there were no significant changes in glucose tolerance, measured by overnight and 24-h fasting levels of glucose, insulin and IGFBP-1, an oral glucose tolerance test (after 24-h fasting) and an intravenous glucose tolerance test (after overnight fasting). Percentage fat mass and BMI correlated negatively with both the 24 h fasting IGFBP-1 levels and the IGFBP-1 responses after the OGTT. All patients decreased their percentage of fat mass measured by BIA [median -2.9%; range -1.0-(-6.6); P = 0.005]. The administered GH dose correlated negatively with the relative change in whole body resistance (r = -0.66; P = 0.04). All, but one of the patients improved their quality of life score after GH therapy. CONCLUSIONS: In a group of young patients with childhood onset GH deficiency, 9 months of treatment with a low GH dose (median 0.14 IU/kg/week) caused no significant deterioration of glucose tolerance. The strong negative associations between BMI or percentage fat mass and IGFBP-1 suggest that serum IGFBP-1 is more closely related than insulin to body composition in GH deficient patients. It is important to consider which critical endpoints should determine the GH dose. We would suggest that, apart for normalizing the serum IGF-I level, another main endpoint should be normalization of, or at least avoidance of any deterioration in glucose tolerance.

Adult↗
PubMed1999

Toward tolerance: lessons learned from liver transplantation.

*Define the various concepts of transplantation tolerance: Immunologically: unresponsiveness to donor antigens Clinically: ability to discontinue nonspecific immunosuppression Outcome-based: ability to prevent long-term immunologically mediated graft loss (i.e., chronic rejection). *Understand the various possible mechanism(s) involved in developing transplantation tolerance: Central tolerance: clonal deletion Peripheral tolerance: Blocking antibodies Cytokine imbalance Clonal T-cell anergy Active regulation of T- and B-cell proliferation. *Methods to achieve transplantation tolerance: Macrochimerism: recipient cytoablation and donor reconstitution Microchimerism: bone marrow augmentation, growth factors Intrathymic inoculation: central tolerance? T-cell costimulatory blockade: induction of T-cell anergy. *Limitations of achieving transplantation tolerance: No markers to define tolerance Poor understanding of acute and chronic rejection mechanisms (e.g., direct v indirect antigen presentation, high- v low-affinity T cells for alloantigen) What cells are involved in the development of tolerance? How stable is clinical tolerance: are the dynamics influenced by nontransplant factors (e.g., antigenic stimulation by viral factors)? Need for a two-pronged approach: nonspecific phase followed by specific phase?

Humans↗
PubMed2002

Prediction of tolerance on the basis of quantification of egg white-specific IgE antibodies in children with egg allergy.

BACKGROUND: It is thought that the natural evolution of food allergy has a good tolerance prognosis. However, there are few follow-up studies that determine the exact probability of tolerance to a given food or that analyze prognostic factors that can help us to understand the evolution of a child who begins life with a food allergy. OBJECTIVE: We sought to determine the likelihood that children younger than 2 years of age with allergy to egg would eventually have tolerance to it and to analyze several prognostic predictors using egg white-specific IgE level as the main variable. METHODS: We performed a prospective study of 58 children younger than 2 years of age with egg allergy, who were studied periodically until tolerance developed or until the end of the study. During the follow-up period, open challenge tests were carried out according to previously established criteria to verify tolerance to egg. Factors such as egg white-specific IgE level, serum total IgE level, symptoms after egg ingestion, size of skin prick test reactions to egg white, atopic dermatitis, and sex were analyzed as prognostic markers. Kaplan-Meier survival curves were used to calculate cumulative tolerance probability. Predictor influence and relative prognostic importance were estimated with the Cox proportional regression model. RESULTS: The median time from the appearance of the first symptoms to tolerance was 35 months. Cumulative tolerance probability was 16% at 12 months of follow-up, 28% at 24 months, 52% at 36 months, 57% at 48 months, and 66% at 60 months. The relative weight of prognostic factors, expressed as the hazard ratio, was 50.95 for symptoms and 3.74 for the size of skin prick test reactions, with both being independent effects. The hazard ratio was 1.173 for every 0.1-unit decrease in the concentration log (decimal logarithm) of specific IgE level, with this effect being associated with tolerance only in children with cutaneous symptoms. CONCLUSIONS: Half of the children younger than 2 years of age with egg allergy will tolerate the food at 35 months of follow-up, and the proportion could be 66% after 5 years. At that age, the main predictors were the symptoms experienced after egg ingestion, followed by the size of skin prick test reactions. In addition, the specific IgE antibody level is an important prognostic marker in children who only had cutaneous symptoms.

Egg Hypersensitivity↗
PubMed1962

Termination of acquired immunological tolerance to protein antigens following immunization with altered protein antigens.

Acquired tolerance to BSA in rabbits was terminated following the injection of certain preparations of altered BSA. Injections of Freund's adjuvant containing BSA complexed to anti-BSA, heat-denatured BSA, acetyl-BSA, picryl-BSA, or arsanil-BSA failed to terminate the tolerant state. Except in an occasional tolerant rabbit, injections of these preparations failed to cause the production of precipitating antibody to the altered preparation. Similar results were obtained following injections of alum-precipitated preparations of pepsin-degraded BSA, acetyl-BSA, and picryl-BSA. Injections of Freund's adjuvant containing sulfanil-BSA terminated the tolerant state, but only small amounts of non-precipitating anti-BSA were produced. Injections of Freund's adjuvant containing picryl-acetyl-BSA terminated the tolerant state in two of six rabbits, but again, only small amounts of non-precipitating anti-BSA were produced. Injections of an alum-precipitated preparation of picryl-acetyl-BSA failed to terminate the tolerant state. On the other hand, injections of Freund's adjuvant containing arsanil-sulfanil-BSA terminated the tolerant state in eleven of eleven rabbits and caused the production of precipitating anti-BSA in all nine of the rabbits tested. The tolerant state was terminated also in six of six rabbits injected with an alum-precipitated preparation of arsanil-sulfanil-BSA. Only one of these rabbits produced precipitating anti-BSA. In addition, the injection of BGG-tolerant rabbits with arsanil-BGG, sulfanil-BGG, or arsanil-sulfanil-BGG terminated the tolerant state. These results were discussed in relation to both the clonal selection theory of antibody production and autoimmunity.

Animals↗
PubMed1974

Cell-to-cell interaction in the immune response. X. T-cell-dependent suppression in tolerant mice.

Specific immunological tolerance was induced in CBA mice by a single injection of deaggregated fowl immunoglobulin G (FgammaG). The unresponsive state was stable on adoptive transfer and irreversible by pretreatment of tolerant cells with trypsin. Tolerant spleen cells could suppress the response of normal syngeneic recipients. They also suppressed the adoptive primary response of spleen cells to FgammaG in irradiated hosts. The inhibitory effect was on the indirect (7S) plaque-forming cell (PFC) response. Incubation of the tolerant cell population with anti-theta serum and complement reversed the suppressor effect. Furthermore, the addition of purified T cells from normal donors restored the capacity of the anti-theta serum-treated tolerant cells to transfer an adoptive response to FgammaG. The existence of FgammaG-reactive B cells was supported by the demonstration of normal numbers of antigen-binding cells in the spleen and thoracic duct lymph from tolerant animals. Moreover, the formation of caps by these cells implied that they could bind antigen normally. These experiments provided direct evidence for the existence of suppressor T cells in the tolerant population. Further evidence was derived from examination of the effect of antigen "suicide". Tolerant spleen cells were treated with radioactive FgammaG under conditions known to abrogate T-cell helper function. When these cells were transferred together with normal spleen cells into irradiated hosts, suppression of the primary adoptive response to FgammaG was no longer observed. Inhibition of an adoptive secondary response to FgammaG was obtained by transferring tolerant spleen cells with primed B cells provided high doses of tolerant cells were used. By contrast low doses exerted a helper rather than a suppressor effect in this system.

Animals↗
PubMed1983

T cell tolerance to non-H-2-encoded stimulatory alloantigens is induced intrathymically but not prethymically.

The present report has evaluated the differentiation compartment in which T cells are tolerized to non-major histocompatibility complex (MHC)-encoded minor lymphocyte-stimulating locus (MLS) alloantigens. It was observed that T cell precursors are not tolerized prethymically to MLS alloantigens but are tolerized intrathymically and postthymically to MLS alloantigens. The failure of prethymic T cells to be tolerized indicates either that T cell precursors are unable to be tolerized to MLS alloantigens or that cells in the prethymic compartment are unable to induce MLS-specific tolerance. In either case, these results demonstrate that the thymus is the initial site in which T cell tolerance to MLS alloantigen is induced. The present results also demonstrate a striking disparity in the reactivity of thymocytes to MHC and MLS alloantigens expressed in the extrathymic host through which their precursors had migrated. In the experimental mice constructed for these studies, intrathymic T cells were tolerant to the MHC alloantigens but were reactive to the MLS alloantigens expressed by the extrathymic host. This observation is consistent with the concept that T cell precursors may be tolerized to MHC alloantigens at an earlier point in their differentiation than they are tolerized to non-MHC-encoded MLS alloantigens.

Alleles↗
PubMed2001

Clinical isolates of Streptococcus pneumoniae that exhibit tolerance of vancomycin.

The ability of Streptococcus pneumoniae to escape lysis and killing by vancomycin, a property termed "tolerance," has recently been noted in a laboratory strain of the species. Vancomycin tolerance in clinical isolates represents a potential new health risk. We determined the prevalence of vancomycin and penicillin tolerance among 116 clinical isolates of pneumococci by monitoring lysis and viability after exposure to the respective antibiotic for 4 hours. Eight percent of the strains were tolerant to penicillin and 3% were tolerant to vancomycin. The 3 vancomycin-tolerant isolates also had a high ratio of minimum bactericidal concentration to minimum inhibitory concentration, in contrast to nontolerant strains. They were of serotype 9V and had reduced susceptibility to penicillin. Only 1 was also tolerant to penicillin. Growth rate and ability to divide were not affected in the 3 vancomycin-tolerant strains, and they all lysed with deoxycholate, which indicates autolysin production. Vancomycin tolerance among clinical isolates of pneumococci will necessitate tracking to determine the magnitude of the evolving health risk, since tolerance may contribute to treatment failure (in particular, cases of meningitis, in which bactericidal activity is critical for eradication) and since it may also be a favored background for acquisition of resistance of vancomycin.

Amino Acid Sequence↗
PubMed1975

Effects of carbohydrate restriction on glucose tolerance of normal men and reactive hypoglycemic patients.

Normal individuals ingesting a low carbohydrate diet frequently develop an impairment of glucose tolerance as measured by the oral glucose tolerance test; most of these diets, however, have been high in fat content. Our present studies demonstrate that a low carbohydrate diet (57 g/day) did not impair the glucose tolerance of normal men if the fat content was similar to values on a standard (301 g/day) carbohydrate diet. However, a low carbohydrate diet did lead to impaired glucose tolerance when the fat content was 16 per cent higher than on the control diet. Thus our present and previous studies demonstrate that normal men maintain normal glucose tolerance on low carbohydrate diets and suggest that the deterioration of the glucose tolerance observed on high fat diets is related to the increased fat content rather than to the reduced carbohydrate content of these diets. Seven patients with reactive hypoglycemia were exquisitely sensitive to carbohydrate deprivation. Whereas the glucose tolerance tests of normal men were not altered by a low carbohydrate, high protein diet, a significant deterioration of glucose tolerance occurred when reactive hypoglycemic patients were changed from control diets to low carbohydrate, high protein diets. These hypoglycemic patients also showed an exaggerated deterioration of the glucose tolerance after a 48-hour fast when compared tothe response of normal men. Our observations suggest that a low carbohydrate, high protein diet is not the best therapeutic diet for certain patients with reactive hypoglycemia because this diet does not provide symptomatic improvement and, in addition, leads to impaired glucose tolerance.

Adolescent↗
PubMed1990

Cardiovascular disease risk factors prior to the diagnosis of impaired glucose tolerance and non-insulin-dependent diabetes mellitus in a community of older adults.

Cardiovascular disease risk factors were measured 10-15 years (mean, 11.9 years) prior to the diagnosis of impaired glucose tolerance and non-insulin-dependent diabetes mellitus in Rancho Bernardo, California. There were 1,847 men and women aged 40-79 years who had no known diabetes or fasting hyperglycemia at baseline (1972-1974). At the follow-up examination (1984-1987), 1,115 men and women (60.4%) had normal glucose tolerance, 513 (27.8%) had impaired glucose tolerance, and 219 (11.9%) had non-insulin-dependent diabetes mellitus as defined by World Health Organization criteria. Rates of impaired glucose tolerance and non-insulin-dependent diabetes mellitus increased with age, and impaired glucose tolerance was approximately twice as common as non-insulin-dependent diabetes mellitus. Those with non-insulin-dependent diabetes mellitus were older and more overweight and had higher levels of blood pressure, fasting plasma glucose, and triglyceride at baseline than those whose glucose tolerance remained normal; those with impaired glucose tolerance generally had intermediate levels of the same risk factors. When it was examined in a prospective fashion, in general, the age-adjusted risk of non-insulin-dependent diabetes mellitus increased with increasing quartile of each risk factor, and the risk of non-insulin-dependent diabetes mellitus in a given quartile was greater than that for impaired glucose tolerance. Logistic regression analyses showed these factors to be positively associated with a subsequent diagnosis of impaired glucose tolerance as well as non-insulin-dependent diabetes mellitus in women, and to a lesser degree in men, independent of baseline age and body mass index (weight (kg)/height (m)2). These data illustrate that a less favorable cardiovascular risk factor profile precedes the diagnosis of both non-insulin-dependent diabetes mellitus and impaired glucose tolerance.

Adult↗
PubMed1992

Studies of morphine and D-ala2-D-leu5-enkephalin (DADLE) cross-tolerance after continuous intrathecal infusion in the rat.

To determine the cross tolerance to the antinociceptive effects of mu and delta opioids in the spinal cord, rats received a 7-day infusion of one of three concentrations each of morphine (2, 6, or 20 nmol/h) or D-ala2-D-leu5-enkephalin (DADLE) (2, 6, or 20 nmol/h). A constant-rate (1 microliter/h), constant-dose intrathecal infusion pump was used. On day 7, the magnitude of tolerance was assessed by establishing dose-response curves for the effect of the chronic drug given as an intrathecal bolus. Cross-tolerance was assessed in separate groups of animals with identical infusions by establishing morphine dose-response curves in DADLE-tolerant animals and DADLE dose-response curves in morphine-tolerant animals. Each infused animal was used for a single bolus injection. For morphine and DADLE tolerance, a parallel rightward shift in the dose-response curve was produced with the degree of shift proportional to the log of the infusion dose. Thus, at the infusion rate of 6 nmol/h for either morphine or DADLE, the shift of the tolerance dose-response curves was 55- and 33-fold, respectively. Morphine and DADLE cross-tolerance was also detected as shown by rightward shifts of the cross-tolerance dose-response curves; however, these shifts were relatively minor compared to the shifts seen in the tolerance dose-response curves of animals tested with the same agent as infused.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia↗
PubMed2005

Spinal glucocorticoid receptors contribute to the development of morphine tolerance in rats.

BACKGROUND: Opioid analgesic tolerance is a pharmacologic phenomenon involving the mechanisms of cellular adaptation. Central glucocorticoid receptors (GRs) have been implicated in the cellular mechanism of neuronal plasticity that has many cellular steps in common with the mechanism of opioid tolerance. In a rat model of morphine tolerance, the authors examined the hypothesis that spinal GRs would play a significant role in the development of tolerance to the antinociceptive effect of morphine. METHODS: In experiment 1, each group of rats received the GR antagonist RU38486 (0.5 or 1 microg), the mineralocorticoid receptor antagonist spironolactone (3 microg), or a vehicle, given intrathecally with morphine (10 microg) twice daily for 6 days. In experiment 2, four groups of rats were used, and each group received intrathecally 10 microg morphine plus 5 micromol GR antisense oligodeoxynucleotide, sense oligodeoxynucleotide, mixed-base oligodeoxynucleotide, or vehicle. Western blotting was used to examine the expression of GRs within the spinal cord dorsal horn. In experiment 3, the GR agonist dexamethasone (4 microg) was given intrathecally twice daily in combination with 10 microg morphine. For all experiments, the development of morphine antinociceptive tolerance was assessed using the tail-flick test. RESULTS: The development of tolerance to the antinociceptive effect of morphine was substantially attenuated when the GR antagonist RU38486 (1 > 0.5 microg > vehicle) but not spironolactone was coadministered with morphine for 6 days. A single treatment with RU38486 did not affect morphine antinociception, nor did it reverse morphine tolerance on day 7. A similar reduction of morphine tolerance was observed in those rats treated with a GR antisense oligodeoxynucleotide but not a sense or mixed-base oligodeoxynucleotide. The administration of the GR antisense oligodeoxynucleotide also prevented GR up-regulation within the spinal cord dorsal horn. Moreover, the GR agonist dexamethasone facilitated the development of morphine tolerance. CONCLUSIONS: The results indicate an important role of spinal GRs in the cellular mechanisms of morphine tolerance in rats and may have significant implications in clinical opioid therapy.

Analgesics, Opioid↗
PubMed2002

Nitroglycerin tolerance: different mechanisms in vascular segments with or without intact endothelial function.

In vivo tolerance to nitroglycerin seems to be induced by an increase in vascular superoxide anion levels. In rabbits with normal endothelial function, in vivo induced tolerance is functionally reversed by ex vivo removal of the endothelium, probably due to a reduction in superoxide anion levels. However, the impact of in vivo endothelial dysfunction on tolerance development has not been examined. This study investigated how in vivo endothelium denudation affects the development of in vivo nitroglycerin tolerance. The effect of in vivo endothelium denudation was examined ex vivo (myograph experiments) after prolonged continuous nitroglycerin infusion in a conscious rat model. The vascular reactivity to nitroglycerin was studied in vivo in endothelium-denuded and corresponding endothelium-intact arteries. The results show that in vivo endothelium denudation does not affect the degree of tolerance development but significantly alters the effect of interventions targeted to inhibit tolerance development. In endothelium-intact vessels, superoxide dismutase and the angiotensin II receptor blocker losartan significantly inhibited tolerance-inducing properties of the prolonged nitroglycerin infusion (E[max, nitroglycerin] response in % of normal controls: nitroglycerin tolerant 70%, superoxide dismutase 93%, losartan 99%). This effect was absent in in vivo endothelium-denuded segments (nitroglycerin tolerant 57%, superoxide dismutase 72%, losartan 60%). These findings suggest that interventions against in vivo tolerance development, within the same animal, may elicit different results depending on the presence or absence of an in vivo dysfunctional endothelium.

Acetylcholine↗
PubMed1985

The role of donor lymphoid cells in the transfer of allograft tolerance.

Tolerance to murine skin allografts across a MHC disparity was induced by conditioning primary hosts with sublethal fractionated total-body irradiation (FTBI) and transfusion of allogeneic bone marrow (BM). Tolerance could be adoptively transferred to secondary hosts conditioned by FTBI with infusion of spleen cells from hosts bearing intact skin allografts greater than 60 days. Tolerance could not be transferred by tolerant host spleen (THS) preparations from which cells of the donor genotype had been deleted by cytotoxic alloantisera. Deletion of host genotype cells, however, did not diminish the capability of THS to transfer tolerance. All of the tolerizing activity of THS appeared to reside within cells of the donor genotype. Small numbers of normal donor spleen cells could induce tolerance in FTBI hosts but only at the expense of very high mortality, in contrast to the low mortality observed with tolerizing injections of allogeneic donor cells from THS or injections of normal semiallogeneic F1 hybrid spleen cells. If an active immune response is responsible for tolerance induction/transfer in this model, allogeneic donor lymphoid cells derived from BM, in contrast to donor spleen cells, must be capable of mounting this response without concomitant severe GVHD. In future experiments, cells of donor genotype can be isolated from THS and purified in sufficient numbers to compare their tolerizing efficiency vs. that of normal donor cells, detect possible suppression of normal host cell alloreactivity in vitro and identify the donor cell phenotypes involved.

Animals↗
PubMed2001

Tolerance to musculoskeletal allografts with transient lymphocyte chimerism in miniature swine.

BACKGROUND: Although transplantation of musculoskeletal allografts in humans is technically feasible, the adverse effects of long-term immunosuppression subject the patient to high risks for correcting a non-life-threatening condition. Achieving immunologic tolerance to musculoskeletal allografts, without the need for chronic immunosuppression, could expand the clinical application of limb tissue allografting. Tolerance to musculoskeletal allografts has been accomplished previously in miniature swine in our laboratory. Although stable, mixed chimerism has been suggested as the mechanism underlying long-term tolerance in a rat limb model, the mechanism of this tolerance induction has not been established. This report explores the possible relationship between hematopoietic chimerism and tolerance to musculoskeletal allografts in swine. METHODS: Twelve miniature swine underwent vascularized musculoskeletal allograft transplantation from histocompatibility complex (MHC) matched, minor antigen-mismatched donors. Eight animals received a 12-day coprse of cyclosporine, one of which was excluded due to subtherapeutic levels. Four recipients were not immunosuppressed. Serial biopsies to assess graft viability and flow cytometry to assess chimerism were performed. Donor and third-party skin grafts were placed on recipients with surviving allografts greater than 100 days to validate tolerance. RESULTS: Both groups developed early peripheral chimerism, but this chimerism became undetectable by postoperative day 19 in the cyclosporine group and by day 13 in the control group. Animals receiving cyclosporine developed permanent tolerance to their allografts, whereas those not receiving cyclosporine rejected their allografts in 6-9 weeks. Animals demonstrating tolerance to their bone allografts also demonstrated prolonged donor skin graft survival. CONCLUSIONS: Induction of tolerance to musculoskeletal allografts can be achieved in the MHC matched swine. Although hematopoietic chimerism is present in the immediate postoperative period, persistent, long-term chimerism does not seem to be necessary for maintenance of such tolerance.

Animals↗
PubMed2003

The cyclic AMP/protein kinase A signal transduction pathway modulates tolerance to sedative and hypothermic effects of ethanol.

BACKGROUND: An expanding body of literature indicates the important role of the cAMP/PKA signaling pathway in establishing initial sensitivity to alcohol as well as being involved in certain forms of tolerance to ethanol. The use of mice with heterozygous inactivation of the Gnas gene encoding Gsalpha allowed us to explore the relationship between tolerance to ethanol and cAMP/PKA signaling. METHODS: Mice with the targeted disruption of one Gsalpha allele were compared with wild-type littermates in their initial sensitivity to ethanol-induced sedation and hypothermia and then monitored for the development of tolerance during two subsequent bouts of intoxication. Components of the cAMP/PKA signaling pathway were analyzed in ethanol-naïve mice and again following the development of tolerance to ethanol to better understand the contribution of this signaling pathway to the acquisition of tolerance. RESULTS: During the initial exposure to ethanol, mice with the targeted disruption of one Gsalpha allele (Gnas) were more sensitive to the sedative effects of ethanol compared with wild-type littermates. Wild-type mice developed within-session tolerance to ethanol-induced hypothermia whereas Gnas mice did not. Following the subsequent ethanol treatments, wild-type mice developed between-session tolerance to the sedative effects of ethanol to a greater degree than mice with heterozygous inactivation of the Gnas gene. The development of tolerance to the sedative effects of ethanol was accompanied by increased expression of phospho-CREB in the cerebellum, hippocampus, and frontal cortex. No changes in phospho-CREB expression were detected in these brain regions in mice with heterozygous inactivation of the Gnas gene. CONCLUSION: The results show that cAMP/PKA signal transduction modulates sensitivity to sedative and hypothermic effects of ethanol. This signal transduction system also influences the acquisition of within-session and between-session tolerance. The mechanism through which cAMP/PKA signaling modulates the development of tolerance remains to be elucidated but may involve changes in phospho-CREB expression.

Animals↗
PubMed2004

Role of endothelin in neonatal morphine tolerance.

Management of neonatal opioid tolerance and withdrawal symptoms remains a major challenge in neonatal intensive care units. We provide evidence that central endothelin (ET) mechanisms are involved in the development of morphine tolerance in neonatal rats. Pregnant rats were rendered tolerant to morphine and rat pups were delivered by cesarean section. The effect of morphine tolerance on characteristics of ET receptors in neonatal rats was determined. The affinity (Kd) and density (Bmax) of [I]ET-1 binding in the brain was found to be similar in placebo and morphine-tolerant neonatal rats. Morphine and ET-1-induced G-protein stimulation was determined in placebo and morphine-tolerant neonatal rats by [S]GTPgammaS binding assay. Morphine produced significantly lower (P < 0.05) maximal stimulation in morphine-tolerant neonatal rats (33.10%) when compared with placebo-treated neonatal rats (90.90%). Maximal stimulation produced by ET-1 in morphine-tolerant neonatal rats (41.26%) was also significantly lower (P < 0.05) as compared with placebo-treated neonatal rats (92.23%). This is the first report indicating the involvement of ET in neonatal morphine tolerance as evidenced by attenuation of ET-1-induced stimulation of GTP binding in neonatal rats tolerant to morphine.

Analgesics, Opioid↗
PubMed2006

Nitroglycerin-induced release of calcitonin gene-related peptide from sensory nerves attenuates the development of nitrate tolerance.

The present study was designed to determine if endogenous calcitonin gene-related peptide (CGRP) affects the process of nitrate tolerance development in blood vessels. Rat aortic rings were suspended in organ chambers and relaxations to nitroglycerin (10(-9) -10(-6) M) were obtained in nitrate tolerant and nontolerant rings contracted with norepinephrine (10(-7) M). Tolerance was induced by incubating the rings with (tolerant) or without (nontolerant) nitroglycerin (10(-4) M) for 90 minutes, followed by repeated rinsing for 1 hour. Some rings were treated with CGRP8-37 (10(-6) M), glyburide (10(-6) M), or iberiotoxin (10(-7) M) during the 90-minute desensitization period with nitroglycerin (10(-4) M), and were then washed out during the 1-hour rinsing period. Other rings were treated with capsaicin (10(-5) M) prior to the 90-minute desensitization period. Calcitonin gene-related peptide release was measured by radioimmunoassay. Relaxation to nitroglycerin was markedly reduced in tolerant rings, as compared with nontolerant. Incubation with CGRP8-37 (10(-6) M) specifically during the 90-minute desensitization period with nitroglycerin resulted in even greater impairment in the response to nitroglycerin in tolerant rings, even though the calcitonin gene-related peptide antagonist had been washed out before completion of the nitroglycerin dose-response curve. Similar results were obtained following depletion of calcitonin gene-related peptide stores in sensory nerves by treatment with capsaicin (10(-5) M) prior to the 90-minute desensitization period with nitroglycerin. Prior treatment with CGRP8-37 or capsaicin had no effect on the response to nitroglycerin in nontolerant rings. Incubation with glyburide (10(-6) M), but not iberiotoxin (10(-7) M), specifically during the 90-minute desensitization period, mimicked the effect of CGRP8-37 and capsaicin in tolerant rings, suggesting a role for KATP channels in the effect of calcitonin gene-related peptide. Nitroglycerin (10(-4) M) caused a greater than twofold increase over basal levels in calcitonin gene-related peptide release in nontolerant rings, which was abolished in rings treated with capsaicin and in nitrate tolerant rings. These results suggest that nitroglycerin releases calcitonin gene-related peptide from sensory nerves during the process of desensitization to nitrovasodilators, and that interference with either the release or action of endogenous calcitonin gene-related peptide during this period enhances the extent to which nitrate tolerance occurs. The finding that nitroglycerin-induced release of calcitonin gene-related peptide from sensory nerves attenuates the desensitizing effect of nitroglycerin represents a heretofore unknown event in the development of nitrate tolerance, and demonstrates a novel role for calcitonin gene-related peptide in the vasculature.

Animals↗
PubMed2006

Effect of resveratrol on nitrate tolerance in isolated human internal mammary artery.

The present study aims to examine whether resveratrol, a natural antioxidant present in red wine, restores the tolerance to nitroglycerin (GTN) on isolated human internal mammary artery (IMA), using an in vitro model of nitrate tolerance. IMA rings were obtained from 53 male patients undergoing coronary bypass operation. Nitrate tolerance was induced by incubating the artery ring with 100 microM GTN for 90 minutes. Concentration-response curves to GTN (10(-9) to 10(-4) M) were obtained on IMA rings precontracted with noradrenaline. A low concentration (5 microM) of lucigenin was used as a tool to measure superoxide production in IMA segments. GTN produced concentration-dependent relaxation in isolated human IMA rings. Preexposure of artery rings to GTN reduced the relaxations to GTN [E(max) values: 105 +/- 2% and 76 +/- 3%, n = 10 to 12, P < 0.05; EC(50) values (-log M): 6.72 +/- 0.05 and 4.95 +/- 0.06, P < 0.05, respectively]. Relaxation to sodium nitroprusside remained unchanged. Diminished relaxation to GTN is partially restored after removing endothelium or L(G)-nitro-L-arginine (L-NOARG, 10 M) or superoxide dismutase (20 and 200 U/mL) or catalase (200 U/mL) pretreatments. Pretreatments with resveratrol (1, 10, and 20 microM) for 20 minutes relatively improved the reduced relaxation to GTN in tolerant IMA rings. Coadministration of L-NOARG with resveratrol did not abolish the beneficial effect of resveratrol on nitrate tolerance. The inhibitory effect of resveratrol on GTN-induced tolerance was not abolished in arterial rings without endothelium. Exposure to GTN increased superoxide production in IMA segments with endothelium. Endothelium denudation, L-NOARG, or superoxide dismutase pretreatments markedly inhibited the increased superoxide production in tolerant arteries. Resveratrol (1 and 10 microM) almost completely abolished basal or NAD(P)H-stimulated superoxide production in tolerant and nontolerant arteries. Vascular tolerance to GTN, in in vitro tolerant human IMA rings, can be induced by endothelial superoxide anions. Resveratrol partially restored the reduced relaxation to GTN by inhibiting NAD(P)-derived superoxide production in endothelium.

Catalase↗