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PubMedDate not supplied

Effect of lipid solubility on the development of chronic cross-tolerance between ethanol and different alcohols and barbiturates.

Tolerance to ethanol and cross-tolerance to other alcohols (n-propanol, n-butanol, t-butanol, isobutanol, t-amyl alcohol, n-amyl alcohol, and benzyl alcohol) and barbiturates (pentobarbital, secobarbital, amobarbital, thiopental, barbital and phenobarbital) that differ in lipid:water partition coefficient was examined in rats after chronic pretreatment with ethanol. Tolerance and cross-tolerance were studied with three different measures (hypothermia, tilt-plane, and rotarod). Tolerance to ethanol resulted in significant cross-tolerance to alcohols with low lipid solubility (n-propanol and t-butanol), whereas no cross-tolerance was seen with alcohols of high lipid solubility (isobutanol, n-amyl alcohol, t-amyl alcohol and benzyl alcohol). Cross-tolerance to n-butanol (which has intermediate lipid solubility) appeared to be metabolic rather than functional. Tolerance to ethanol also resulted in significant cross-tolerance to barbital and phenobarbital, but not to pentobarbital, secobarbital, amobarbital or thiopental. These studies suggest that lipid solubility is an important factor in relation to specificity of cross-tolerance to alcohols and barbiturates.

Alcohols↗
PubMed1998

Noncontingent drug exposure facilitates the development of contingent tolerance to the anticonvulsant effects of ethanol and diazepam in kindled rats.

Tolerance to anticonvulsant drug effects on kindled convulsions can result from drug exposure alone, but convulsive activity during drug exposure has a substantial facilitatory effect on tolerance development. Tolerance produced by drug exposure in the absence of a criterion response (in this case convulsions) has been termed pharmacologic tolerance (10); tolerance produced by drug exposure with concomitant performance of the criterion response has been termed contingent tolerance (1). The present study examines whether noncontingent drug exposure facilitates the development of contingent tolerance to the anticonvulsant effects of ethanol and diazepam. Amygdala-kindled, Long-Evans rats were treated with either ethanol (5.0 g/kg once daily for 21 days) or diazepam (5.0 mg/kg three times daily for 10 days) in the absence of convulsive stimulation to produce pharmacologic tolerance--control rats received treatments of vehicle. Then, all of the rats were rendered contingently tolerant by a series of "bidaily" (once every 2 days) injections (ethanol 2.0 g/kg or diazepam 2.0 mg/kg), each 1 h prior to a kindled convulsion. The rats that had received noncontingent exposure to ethanol or diazepam developed contingent tolerance significantly faster than the control rats. These results suggest that the mechanisms underlying pharmacologic and contingent tolerance to anticonvulsant drug effects are additive.

Animals↗
PubMed1999

Involvement of intracellular calcium in morphine tolerance in mice.

Opioid analgesic tolerance is associated with a disruption in Ca++ homeostasis. Drugs reducing Ca++ influx can prevent and reverse tolerance. The hypothesis was tested that both Ca++ influx and mobilization from intracellular pools maintains the expression of morphine tolerance. Ca++ modulating drugs were injected ICV at doses not affecting morphine's potency in placebo pellet-implanted mice, in order to determine whether tolerance would be reversed in morphine pellet-implanted mice. The Ca++ chelator EGTA significantly reversed tolerance. The Ca++ channel antagonists nifedipine and omega-conotoxin GVIA also reversed tolerance. The role of intracellular Ca++ was investigated using the membrane permeable intracellular Ca++ chelator EGTA-AM. EGTA-AM reversed tolerance at lower morphine doses, but not at higher morphine doses. Thus, mobilization of intracellular Ca++ contributes to the expression of tolerance. Finally, 1,4-dihydropyridine-sensitive Ca++ channels are known to stimulate Ca++-induced Ca++ release (CICR) from Ca++/caffeine-sensitive microsomal pools possessing ryanodine receptors. We examined whether blocking Ca++ mobilization from these pools with ryanodine would reverse morphine tolerance. Ryanodine's effects were similar to EGTA-AM. Tolerance was reversed at lower morphine doses, but not at higher doses. Thus, morphine tolerance appears to be associated with increases in Ca++ influx and mobilization from Ca++/caffeine-sensitive pools.

Analgesia↗
PubMedDate not supplied

Unidirectional cross-tolerance between the carbamate insecticide propoxur and the organophosphate disulfoton in mice.

Previous studies have shown that subchronic treatment of mice with the organophosphate insecticide, disulfoton, or the carbamate insecticide, propoxur, leads to the development of tolerance to their toxicity. Tolerance to disulfoton was due to a decrease in the number of muscarinic cholinergic receptors, while tolerance to propoxur appeared to be due to an induction of hepatic microsomal enzymes. In the present study we investigated if cross-tolerance between disulfoton and propoxur would occur. Cross-tolerance was evaluated by measuring acute toxicities, cholinesterase and carboxylesterase inhibition and hypothermic and antinociceptive effects. Mice tolerant to propoxur were cross-tolerant to the hypothermic and anticholinesterase effects of disulfoton. Similarly, when mice were pretreated with the microsomal enzyme inducer, phenobarbital, the toxicity of disulfoton was decreased. Mice made tolerant to disulfoton were cross-tolerant to the organophosphate chlorpyrifos, but were more sensitive than controls to the toxicity of propoxur. The acute toxicity of the organophosphate malathion was also increased in disulfoton-tolerant mice. Propoxur is metabolized by mixed function oxidases and possibly by a carboxylesterase. While hepatic microsomal enzymes appeared to be unchanged in disulfoton-tolerant mice, brain and liver carboxylesterase activities were significantly inhibited. Pretreatment of mice with the specific carboxylesterase inhibitor triorthotolylphosphate is known to greatly potentiate the toxicity of malathion and also potentiated, to a lesser extent, the toxicity of propoxur.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

Time course for the induction and maintenance of tolerance to Delta(9)-tetrahydrocannabinol in mice.

The time course for the development of tolerance to delta-9-tetrahydrocannabinol (Delta(9)-THC) was studied in an effort to determine the role that length of dosing may have in the onset and maintenance of tolerance. Mice were chronically treated with either vehicle or 10 mg/kg of Delta(9)-THC subcutaneously twice a day. The mice were tested 24 h after the last injection for tolerance as assessed by the production of antinociception and suppression of spontaneous activity. Tolerance was first observed after three injections of Delta(9)-THC (1.5 days) resulting in a 7-fold and 23-fold decrease in potency for the measures of antinociception and hypoactivity, respectively. Seven injections of Delta(9)-THC (3.5 days of dosing) resulted in a 12-fold and 36-fold decrease in potency, respectively, while 13 injections of Delta(9)-THC (6.5 days of dosing) produced a 6.2-fold and 9.8-fold degree of tolerance. The time course for the recovery from Delta(9)-THC-induced tolerance was also determined with a separate group of animals. Mice were dosed for 6.5 days with 10 mg/kg of Delta(9)-THC and were not tested until 4.5, 7.5, and 11.5 days after cessation of drug treatment. After 4.5 days without drug treatment the mice exhibited a 7.5-fold and 2.3-fold degree of tolerance as measured by antinociception and hypoactivity, respectively. After 7. 5 days without drug treatment a 3.4-fold degree of tolerance remained for the measure of antinociception, while no tolerance was detected for the measure of hypoactivity. No tolerance was observed for the measure of antinociception after 11.5 days without drug treatment. This time course indicates that the mechanisms responsible for either the production or maintenance of tolerance differ between the measures of antinociception and suppression of spontaneous activity.

Analgesics, Non-Narcotic↗
PubMed1988

The natural history of tolerance to the benzodiazepines.

Dependence on benzodiazepines following continued use is by now a well-documented clinical phenomenon. Benzodiazepines differ in their dependence potential. The present studies were aimed at examining the possibility that differential rates of tolerance development might account for differences in dependence risk. Four studies are reported. The first three studies concerned normal subjects. The development of tolerance over a fifteen day period was demonstrated for three different benzodiazepines (ketazolam, lorazepam and triazolam) using two paradigms. Tolerance in terms of a reduction in effectiveness of a repeated given dose was most notable for the benzodiazepine with a medium elimination half-life (lorazepam) for physiological, behavioural and subjective measures. In the case of the drug with the longest elimination half-life (ketazolam) reduction in effectiveness could only be assumed to be occurring if account was taken of the steady increase in plasma concentrations of active metabolites. For this drug it seemed that the physiological measures were those most likely to demonstrate the development of tolerance. Although triazolam showed few significant drug effects on this paradigm (testing being 12 hours after ingestion of this short half-life benzodiazepine), tolerance was seen to develop on some subjective measures. Using an alternative method of testing tolerance, assessing responses to a diazepam challenge dose, a high degree of tolerance on two-thirds of the measures was observed in subjects when pretreated with the benzodiazepine with the most marked accumulation of active metabolites (ketazolam). The other two drugs also led to tolerance development on a range of measures; this was more marked for lorazepam than triazolam. Blunting of the growth hormone response to diazepam was the most sensitive and reliable method of detecting tolerance to the benzodiazepines. Symptoms on discontinuation of the two weeks' intake of the benzodiazepines were marked for all the drugs but unrelated to either the tolerance induced or the elimination half-life of the particular drug. A further clinical study revealed that tolerance persisted in a group of long-term benzodiazepine users for between four months and two years following complete abstinence from the drug. These patients appeared to be less affected by diazepam in terms of its commonly observed subjective effects, regardless of their original medication. These ex-long-term users of benzodiazepines were, however, more likely to manifest two specific types of effects--immediate 'symptom' reduction and exacerbation of 'withdrawal symptoms' over the subsequent week.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1989

Tolerance to the antinociceptive effect of morphine in spinally transected rats.

The effect of a spinal transection on morphine-induced tolerance in rats was examined with the tail withdrawal reflex (tail flick; TF), elicited by noxious thermal stimulation. Intact rats became tolerant to sc morphine injections (3.0 mg/kg) if they were tested on the TF after each injection. Morphine administration alone did not produce tolerance; tail flick tests alone did, though not always to a significant extent. However, when morphine only, TF tests only, or both were administered prior to transection (acute spinal rats), all groups were tolerant when tested 1 day after spinalization. When the same treatments were administered to rats 3 weeks after spinal transection (chronic spinal rats), neither morphine nor TF tests alone produced tolerance. Chronic spinal rats became tolerant only if they were tested after each injection. These results suggest, first that tolerance develops at the spinal cord as a result of either chronic opiate exposure or performance of the nociceptive response but that, intact rats, tolerance is inhibited or suppressed by a supraspinal action of morphine. Second, the fact that chronic spinal rats did not become tolerant to morphine or TF tests alone suggests either that such tolerance is mediated by descending input or that spinal transection produces intrinsic changes in the spinal cord that preclude the development of tolerance induced only by opiate or behavioral stimulation.

Animals↗
PubMedDate not supplied

Neonatal T-cell tolerance to minimal immunogenic peptides is caused by clonal inactivation.

The mechanisms underlying T-lymphocyte tolerance induced in neonatal mice are still unknown. It is unclear whether the tolerant state is the result of inactivation of T cells on exposure to antigen during development or of active suppression by other T cells specific for the same antigen. To distinguish between these two hypotheses, we have analysed the specificity of tolerance to three cytochrome peptides which differ by only a single amino-acid substitution in the epitope recognized by proliferative T cells. The peptides stimulate proliferative responses which are highly specific with minimal cross-reactivity. As antigen-induced clonal inactivation would address the same cells normally activated by that antigen, the specificity of tolerance should exactly match that of the proliferative response to the antigen, and each cytochrome peptide should induce tolerance to itself alone. Conversely, as T-suppressor (Ts) and T-proliferative (Tp) cells almost invariably seem to recognize distinct, non-overlapping determinants on protein antigens, suppressor-mediated tolerance should not be affected by substitutions in the proliferative T-cell epitope. Tolerance would depend solely on the existence of a shared suppressor determinant, so each cytochrome peptide should induce cross-tolerance to the others. We found that the specificity of tolerance matched that of the proliferative response: each peptide induced tolerance for itself but the response to the variants was unaltered. This result strongly supports the hypothesis of clonal inactivation as an important mechanism in induction of neonatal tolerance.

Animals↗
PubMed2000

Hapten-specific tolerance promoted by calcitonin gene-related peptide.

Calcitonin gene-related peptide has been shown to modulate inflammatory and immune responses in various systems. Recent studies in our laboratory and colleagues have shown that intracutaneously injected calcitonin gene-related peptide impairs the induction of contact hypersensitivity in mice, and participates in the pathogenesis of failed contact hypersensitivity induction after acute, low-dose ultraviolet B radiation. In this study we investigated the ability of calcitonin gene-related peptide to induce tolerance in normal and mast cell deficient mice and we examined the extent to which calcitonin gene-related peptide contributes to the tolerance induced by acute, low-dose ultraviolet B radiation. Calcitonin gene-related peptide was injected intradermally followed by application of 2,4-dinitro-1-fluorobenzene to the injected skin surface. Tolerance was assessed by re-exposing the mice 2 wk later to a second, sensitizing dose of 2, 4-dinitro-1-fluorobenzene on uninjected skin. We found that calcitonin gene-related peptide induced tolerance to 2, 4-dinitro-1-fluorobenzene in both normal and mast cell deficient mice. Calcitonin gene-related peptide-induced tolerance was blocked by intradermal injection of a calcitonin gene-related peptide antagonist [CGRP-(8-37)] that selectively blocks the calcitonin gene-related peptide receptor. Tolerance was also abolished by intraperitoneally injected anti-interleukin-10, but not anti-tumor necrosis factor alpha, antibodies. When 2,4-dinitro-1-fluorobenzene was painted on skin into which splenic dendritic cells pretreated with calcitonin gene-related peptide had been injected, tolerance was observed. Calcitonin gene-related peptide- treated dendritic cells mixed with anti-interleukin-10 antibody prior to intradermal injection failed to promote tolerance. Finally, injection of CGRP-(8-37) into skin that was subsequently exposed to acute, low-dose ultraviolet B radiation partially prevented tolerance induced by local application of 2,4-dinitro-1-fluorobenzene. These results indicate that calcitonin gene-related peptide has the capacity to promote cutaneous tolerance through an interleukin-10-dependent mechanism. This mechanism, which does not require the participation of mast cells, contributes to the tolerance promoted by acute, low-dose ultraviolet B radiation. Thus, calcitonin gene-related peptide from cutaneous nerve endings plays a key role in the local immune aberrations caused by ultraviolet B radiation.

Animals↗
PubMed1994

Specific T-cell tolerance may be preceded by a primary response.

We have evaluated the ability of ovalbumin to induce T-cell-specific tolerance in SJL mice. A significant decrease of interleukin 2 in lymph-node culture supernatants from tolerant mice upon antigen stimulation was seen. Oral tolerization was less effective than i.p.- or s.c.-tolerization protocols. Transfer experiments of either splenic or lymph-node T cells from tolerant mice to naive mice definitely ruled out suppression as a mechanism involved in tolerant mice. Surprisingly, we found that, before the establishment of specific T-cell tolerance to ovalbumin, T cells from mice that will display tolerance were responsive and synthesized interleukin 2 upon antigen challenge in vitro. Thus, we concluded that anergy cannot account solely for the T-cell unresponsiveness in tolerant mice. Furthermore, although we cannot rule out the hypothesis that the T-cell unresponsiveness in tolerant mice can be explained by programmed cell death of ovalbumin-specific T cells, these data led us to speculate that T-cell "refractoriness" could explain the drop of interleukin 2 production in lymph-node T-cell culture supernatant from tolerant mice.

Adjuvants, Immunologic↗
PubMed1996

Low zone tolerance to contact allergens in mice: a functional role for CD8+ T helper type 2 cells.

Normal skin is permeable to low molecular hydrophobic substances, including allergenic chemicals. Whereas such foreign matter appears to enter the skin naturally, it rarely induces contact hypersensitivity. This suggests that immunological tolerance would be the normal state of affairs. In search of a suitable model, we painted picryl chloride or oxazolone once or repeatedly on normal skin of BALB/c or C57B1/6 mice and found subsensitizing doses to be tolerogenic. The most effective doses in inducing tolerance were doses between those at the point of inflection from no responses to threshold sensitivity. But even doses three orders of magnitude lower than these suppressed subsequent sensitization if applied repeatedly. C57B1/6 mice (low responders) were consistently easier to make tolerant than BALB/c mice (high responders). The tolerant state established by a single painting was found to be fully developed at 48 h after initiation and long-lasting (>14 d). It could be adoptively transferred by intravenous injection of total spleen cells (SC), lymph node cells (LNC), or purified T cells and shown to be hapten specific. Pretreatment with cyclophosphamide (Cy) prevented tolerization. The T cells capable of transferring suppressive activity were found to be generated irrespective of the dose applied. On day 2 after painting, tolerance could be transferred with LNC from both tolerant and sensitized animals. On day 5, however, only cells from tolerant donors transferred tolerance. But by action of Cy, suppression was shown to be part of every sensitization, although masked. Production of hapten-specific antibodies was suppressed as well. Through depletion by monoclonal antibody in vitro the T suppressor cells were shown to belong to the murine CD8+ subset (Lyt2+). Upon restimulation in vitro by haptenized and irradiated normal SC, LNC from tolerant donors produced predominantly interleukin (IL)-4, IL-5, and IL-10. In contrast, LNC from sensitized donors produced preferentially IL-2 and interferon-gamma. Thus we demonstrate that painting subsensitizing doses of contact sensitizers on normal murine skin generates CD8+ Th2-like cells that give rise to hapten-specific tolerance. The model may have broader significance and apply to other species, including humans.

Allergens↗
PubMed1990

Abnormalities of glucose tolerance following gestational diabetes.

Glucose tolerance and insulin secretion were studied in 56 women 6-12 years following a pregnancy complicated by gestational diabetes, and in 23 matched controls. At recall 14 women were known to have diabetes and five were again pregnant with recurrent gestational diabetes. The early development of diabetes was associated with a fasting plasma glucose greater than 6 mmol/l during pregnancy and with a high plasma glucose response to oral glucose which persisted after delivery. Obesity was predictive of non-insulin-dependent diabetes whereas those that later required insulin were not obese. At recall, seven of the remaining 37 women were found to have unrecognized diabetes, 13 had impaired glucose tolerance (IGT) and 17 were normal by WHO criteria using a 75 g oral glucose tolerance test. In these 37 women, fasting plasma glucose and the glucose response to oral glucose in pregnancy were not predictive of subsequent diabetes or impaired glucose tolerance. Obesity in pregnancy and subsequent weight gain were associated with non-insulin-dependent diabetes and impaired glucose tolerance at recall. Insulin deficiency was observed during the oral glucose tolerance test in the diabetics (the mean +/- SEM ratio insulin area:glucose area 4.1 +/- 1.3 diabetics, 10.7 +/- 1.8 controls, p less than 0.05), whereas in the group with impaired glucose tolerance insulin levels were high and in proportion to their hyperglycaemia (insulin area:glucose area 10.9 +/- 1.4 IGT, 9.4 +/- 1.4 controls). Women with normal glucose tolerance and previous gestational diabetes had significantly lower insulin responses than their controls, despite mild hyperglycaemia (insulin area:glucose area 4.0 +/- 0.7 normal glucose tolerance, 7.6 +/- 1.1 controls, p less than 0.02). Abnormalities of glucose tolerance and insulin secretion are present following a gestational diabetic pregnancy. Gestational diabetes identifies women at risk for developing diabetes and impaired glucose tolerance, both of which are risk factors for premature vascular disease.

Adult↗
PubMed2001

Sedative but not analgesic alpha2 agonist tolerance is blocked by NMDA receptor and nitric oxide synthase inhibitors.

BACKGROUND: Studies show that the sedative and analgesic effects of alpha2 adrenergic agonists decrease over time, which is a form of synaptic plasticity referred to as tolerance. Because both the N-methyl-D-aspartate (NMDA) receptor complex and nitric oxide synthase are pivotal for some forms of synaptic plasticity, their role in tolerance to the hypnotic and analgesic effects of alpha2 agonists was investigated. METHODS: After institutional approval, rats were made tolerant to the hypnotic or analgesic action of an alpha2 agonist, dexmedetomidine. The hypnotic response to dexmedetomidine was assessed by the duration of loss of righting reflex, and the analgesic response to dexmedetomidine was assessed by the tail-flick assay. In separate cohorts, either the NMDA receptors or nitric oxide synthase was antagonized by coadministration of MK-801, ketamine, or NO2-arginine, respectively, during induction of tolerance. In a separate series of experiments, after tolerance was induced, the hypnotic and analgesic responses to dexmedetomidine were assessed in the presence of acutely administered MK-801 or NO2-arginine. RESULTS: Induction of tolerance to the hypnotic effect of dexmedetomidine is blocked by coadministration of MK-801, ketamine, and NO2-arginine. However, after tolerance developed, acute administration of MK-801, ketamine, or NO2-arginine did not prevent the expression of tolerance. Coadministration of MK-801 or NO2-arginine neither prevents the development nor reverses the expression of tolerance to the analgesic action of dexmedetomidine. CONCLUSION: The underlying processes responsible for the development of tolerance to the hypnotic and analgesic actions of systemically administered alpha2 agonists were different, with only the sedative tolerance involving the NMDA receptor and nitric oxide synthase system.

Adrenergic alpha-2 Receptor Agonists↗
PubMed1989

Determinants of in vitro nitroglycerin tolerance induction and reversal: influence of dose regimen, nitrate-free period, and sulfhydryl supplementation.

The influence of dose regimen on the induction and reversal of tolerance to nitroglycerin (NTG) is not well understood despite the current widespread clinical use of both sustained and intermittent modes of NTG administration. In an isolated coronary artery preparation both the NTG preexposure concentration and the duration of the NTG preexposure period were positive and independent determinants of the extent of NTG tolerance induction. During a "nitrate-free" or washout period, NTG tolerance was at least partially reversible. The apparent rate of NTG tolerance reversal during a "nitrate-free" period was not dependent on the absolute degree of NTG tolerance induced or on the dose regimen used to induce NTG tolerance. In this isolated vascular preparation, sulfhydryl (SH) supplementation with 1 mM N-acetylcysteine produced no significant augmentation of NTG-induced relaxations in either NTG tolerant or non tolerant tissues. N-acetylcysteine was ineffectual in attenuating the development of NTG tolerance in coronary artery preparations incubated in either Krebs bicarbonate buffer or in 10% human plasma. We conclude that in this model the NTG preexposure concentration, the duration of the NTG preexposure period, and the duration of the "nitrate-free" period are critical and independent determinants of the extent of NTG tolerance but that NTG tolerance is not significantly attenuated by SH supplementation.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1996

Studies of vascular tolerance to nitroglycerin: effects of N-acetylcysteine, NG-monomethyl L-arginine, and endothelin-1.

Development of vascular tolerance to nitroglycerin (NTG) has been attributed to sulfhydryl (SH) depletion, guanylate cyclase desensitization, or both. Controversy regarding the precise contribution of these mechanisms may be due to variations in experimental design. To examine further the biochemical basis of NTG tolerance, norepinephrine (NE)-precontracted rat aortic rings were exposed to NTG (10(-5)M), which resulted in 84 +/- 6% relaxation. Other rings were first superfused with NTG (10(-6)M) and then contracted with NE. These rings showed a marked tolerance to the vasorelaxant effects of NTG (maximal relaxation 20 +/- 5%, n = 15, p < 0.001 vs. control rings). Similar tolerance to NTG was observed when the vascular rings were first superfused with acetylcholine (ACh 10(-6)M), indicating cross-tolerance between ACh and NTG. Treatment of NTG-tolerant rings with N-acetylcysteine (NAC) (10(-5)M) did not restore vascular smooth muscle (VSM) relaxation in response to NTG (maximal relaxation 23 +/- 5%, n = 8), suggesting that SH depletion may not be the basis of NTG tolerance in these experiments. Parallel sets of NTG-tolerant aortic rings were contracted with endothelin-1 (ET-1, n = 5) or the endothelium-derived relaxing factor (EDRF) synthase inhibitor NG-monomethyl L-arginine (L-NMMA, 10(-4)M, n = 8). In both ET-1- and L-NMMA-contracted rings, vascular relaxation in response to NTG was preserved (80 +/- 6 and 88 +/- 8% relaxation, respectively). Measurement of cyclic GMP in aortic rings showed marked accumulation on initial exposure of tissues to NTG (310 +/- 10 fmol/mg), whereas the NTG-tolerant rings showed much less cyclic GMP accumulation (48 +/- 29 fmol/mg). Rings contracted with L-NMMA or ET-1, but not NE, accumulated cyclic GMP when exposed to NTG (280 +/- 20 fmol/mg). These data indicate that NTG tolerance develops on exposure of vascular rings superfused with NTG or ACh and is probably not related to tissue SH depletion. Contraction of NTG-tolerant rings with ET-1 or L-NMMA restores NTG-mediated relaxation.

Acetylcysteine↗
PubMed1998

Thymus-dependent, anti-CD4-induced tolerance to rat cardiac allografts.

BACKGROUND: Treatment with anti-CD4 monoclonal antibodies (mAbs) leads to induction of transplant tolerance in rodent models, but the cellular mechanisms responsible are poorly defined. In this study, we used a rat model of cardiac transplantation to examine the contribution of the thymus gland to anti-CD4 mAb-induced tolerance. METHODS: Pretransplant administration of OX38 mAb partially depletes peripheral CD4 T cells and induces tolerance to fully allogeneic Lewis (RT1l) heterotopic cardiac allografts in DA (RT1a) recipients. Using this experimental model, the contribution of the adult thymus gland and of recent thymic emigrants to tolerance induction was assessed, and the cellular and humoral alloimmune responses accompanying tolerance defined. RESULTS: OX38 mAb selectively depleted mature CD4 T cells but spared CD4 T cells that had recently emerged from the thymus. Pretransplant thymectomy abrogated tolerance induction, but the data suggested a role for recent thymic emigrants rather than for the thymus gland per se. Both nonrejecting cardiac allografts in OX38-treated recipients and rejecting grafts in control animals were infiltrated to a similar extent by mononuclear cells, including activated T cells. Intragraft mRNA transcripts for interleukin (IL)-2, interferon-gamma, IL-4, IL-10, and IL-13 were similar in non-rejecting and rejecting allografts although, with the exception of IL-2, there was a trend towards reduced cytokine transcripts in tolerant grafts. CD4 T cells from long-term tolerant recipients proliferated normally to donor alloantigen in vitro, and produced IL-2, interferon-gamma, and IL-4 in amounts comparable to normal CD4 T cells. Tolerant recipients also developed a strong alloantibody response comprising both IgG1 (Th2-dependent) and IgG2b (Th1-dependent) subclasses. CONCLUSIONS: The results of this study suggest that the thymus, through the production of recent thymic emigrants, plays an important role in facilitating the induction of transplant tolerance after anti-CD4 mAb. Tolerant animals displayed strong cell-mediated and humoral alloimmune responses with no evidence of selective deviation from a Th1 to a Th2-like cytokine pattern.

Animals↗
PubMed2003

Identification and characterization of aluminum tolerance loci in Arabidopsis (Landsberg erecta x Columbia) by quantitative trait locus mapping. A physiologically simple but genetically complex trait.

Aluminum (Al) toxicity, which is caused by the solubilization of Al3+ in acid soils resulting in inhibition of root growth and nutrient/water acquisition, is a serious limitation to crop production, because up to one-half of the world's potentially arable land is acidic. To date, however, no Al tolerance genes have yet been cloned. The physiological mechanisms of tolerance are somewhat better understood; the major documented mechanism involves the Al-activated release of Al-binding organic acids from the root tip, preventing uptake into the primary site of toxicity. In this study, a quantitative trait loci analysis of Al tolerance in Arabidopsis was conducted, which also correlated Al tolerance quantitative trait locus (QTL) with physiological mechanisms of tolerance. The analysis identified two major loci, which explain approximately 40% of the variance in Al tolerance observed among recombinant inbred lines derived from Landsberg erecta (sensitive) and Columbia (tolerant). We characterized the mechanism by which tolerance is achieved, and we found that the two QTL cosegregate with an Al-activated release of malate from Arabidopsis roots. Although only two of the QTL have been identified, malate release explains nearly all (95%) of the variation in Al tolerance in this population. Al tolerance in Landsberg erecta x Columbia is more complex genetically than physiologically, in that a number of genes underlie a single physiological mechanism involving root malate release. These findings have set the stage for the subsequent cloning of the genes responsible for the Al tolerance QTL, and a genomics-based cloning strategy and initial progress on this are also discussed.

Aluminum↗
PubMed1991

Development of tolerance to kava in mice.

1. The development of tolerance to the aqueous extract of kava, and to the lipid soluble extract (kava resin) was tested in mice. 2. Tolerance to the unknown pharmacologically active ingredient(s) developed very rapidly, given parenterally, in the aqueous extract. A minimally effective daily dose (50 mg/kg) of the aqueous extract for 3 days was sufficient to produce tolerance to a test dose of 150 mg/kg, which is close to the ED50. As tolerance was evident at the first test period it can be assumed to be physiological tolerance. 3. Kava resin decreased spontaneous motility and caused a loss of muscle control. A minimally effective daily dose of kava resin (100 mg/kg) did not produce tolerance to the above effects of a weekly test dose of kava resin (166 mg/kg) within 7 weeks. In a further experiment the dose was raised to 150 mg/kg twice daily and this schedule caused partial tolerance to occur within 3 weeks, but very little further tolerance developed over the ensuing 2-week period. 4. To try to induce learned (behaviourally acquired) tolerance a dose of 166 mg/kg kava resin was injected daily and animals were tested each day while under the influence of the drug. However, even under these conditions, there was no tolerance evident within 3 weeks, when the experiment was terminated. 5. It appears difficult to induce the development of physiological or learned tolerance to kava resin in mice.

Animals↗