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PubMed1981

Chronic amphetamine: tolerance and reverse tolerance reflect different behavioral actions of the drug.

Chronic administration of amphetamine (AMPH) has been reported to produce tolerance to the drug's behavioral effects in some paradigms (self-stimulation, discriminative stimulus, self-administration) and an enhanced effect or reverse tolerance when other behaviors are monitored (locomotor activity, stereotypy). The present study investigated whether the two phenomena are, in fact, related to the particular behavior monitored or reflect the marked differences in the injection regimens (1X vs. 3X daily injections) used to produce the phenomena. The effects of chronic AMPH administered once or three times daily on AMPH facilitation of self-stimulation responding and on the locomotor stimulant and stereotypy-producing effects of the drug were assessed. Regardless of the injection regimen used, chronic AMPH resulted in an enhancement of the locomotor stimulant effects of the drug as well as a more rapid onset and greater intensity of the stereotypy produced. In the self-stimulation paradigm, only the 3X daily regimen significantly reduced the effectiveness of a challenge dose of AMPH (tolerance), although the 1X regimen produced effects that were qualitatively similar but quantitatively less. Perhaps behavioral tasks in which tolerance develops reflect the mood-altering properties of the drug in humans whereas a process similar to reverse tolerance may underlie the increased susceptibility to psychoses elicited by the drug with repeated use.

Amphetamine↗
PubMed1983

Tolerance and cross-tolerance to central nervous system depressants after chronic pentobarbital or chronic methaqualone administration.

This study reports on tolerance and cross-tolerance to the rotarod (RR)-disrupting effects of various central nervous system (CNS) depressants. Female rats trained on the RR were fed ground chow containing pentobarbital (PB, 2.0 mg/g chow) or methaqualone (MQ, 1.0 mg/g chow) and were injected twice daily (PB) or daily MQ) with 30 mg/kg IP for 6 days. Control rats received ground chow and saline injections. On day 7 the subjects were tested with various doses of PB, MQ, diazepam (DZ), or ethanol (ET) for disruption of RR performance over the time-course of the drug effect (up to 12 hours). Control animals demonstrated a dose-dependent duration of impairment for all 4 agents. Both groups receiving chronic drug showed a prominent decrease in duration of RR impairment after PB, a less marked decrease after MQ, and even less of a decrease after DZ. However, neither chronic drug group showed an appreciable tolerance to the RR disruption of ET, relative to the control group. Based on the time of 50% recovery (RR performance recovering to 90 seconds or more), both chronic treatments resulted in a significant shift of the dose-response curves for PB, MQ and DZ to the right. Therefore, the degree of tolerance and cross-tolerance in rats chronically treated with PB or MQ was dramatic for PB and MQ, was significant for DZ, but was not demonstrable for ET.

Animals↗
PubMed1985

Tolerance, cross-tolerance, and receptors after chronic nicotine or oxotremorine.

Saline, 8.0 mg/kg/hr nicotine, or 1.0 mg/kg/hr oxotremorine was continuously infused into the jugular veins of DBA female mice. After 10 days of treatment, respiratory rate, Rotarod performance, Y-maze crossings, Y-maze rears, heart rate, and body temperature were measured after challenge with 2.0 mg/kg nicotine or saline or 0.2 mg/kg oxotremorine. Nicotine-infused mice were tolerant to the effects of nicotine for all six tests and oxtremorine-infused mice were tolerant to the effects of oxotremorine for all six tests and to the effects of nicotine on heart rate and body temperature. Oxotremorine infusion reduced the Bmax for [3H]-L-QNB binding, but had no effect on Bmax for either [3H]-DL-nicotine or [125I]-alpha-BTX binding. Conversely nicotine infusion did not alter the Bmax for [3H]-L-QNB binding, but increased the Bmax for both [3H]-DL-nicotine and [125I]-alpha-BTX binding. These results indicate that tolerance developed to the effects of two cholinergic agents, nicotine and oxotremorine, and that some cross-tolerance to the effects of nicotine occurred in oxotremorine-treated mice. Treatment with oxotremorine caused down-regulation of muscarinic receptors, while treatment with nicotine caused up-regulation of nicotinic receptors. Although some cross-tolerance to the effects of nicotine occurred in oxotremorine-treated mice, this did not appear to result from changes in nicotinic receptors.

Animals↗
PubMed1991

Hypothermia: limited tolerance to repeated soman administration and cross-tolerance to oxotremorine.

The effect of repeated administration of the organophosphate anticholinesterases, soman (pinacolyl methylphosphonofluoridate) and DFP (diisopropylfluorophosphate) on core temperature was investigated in mice. Mice were implanted with telemetry transmitters for the monitoring of core temperature. Following repeated administration of soman (3-10 injections), tolerance (as defined by a decrease in the organophosphate-induced hypothermia upon subsequent administration) to the organophosphate-induced hypothermia was evident after the 5th injection; however, there was cross-tolerance to oxotremorine hypothermia as early as after the 3rd injection of soman. Following repeated administration of DFP, there was no tolerance to the DFP-induced hypothermia following 5 injections, whereas cross-tolerance to oxotremorine was evident following the 5th injection. The organophosphate-induced hypothermia may have another component which contributes to the response. It is proposed that the cross-tolerance to oxotremorine hypothermia after subchronic administration of an anticholinesterase is representative of the functionality of muscarinic cholinergic receptor coupling.

Acetylcholinesterase↗
PubMed1991

Tolerance and cross-tolerance with morphine in mice selectively bred for high and low stress-induced analgesia.

Mice selectively bred for high (HA) and low (LA) swim-induced analgesia were exposed to two different stress paradigms; one consisting of a 3-min swim at 20 degrees C daily for 14 days, and the other consisting of 3-min swims repeated at 2-h intervals for 48 h. Both forms of chronic stress resulted in the development of tolerance to swim-induced antinociception to a greater degree in the HA mice than in control (C) mice, but were both ineffective at inducing tolerance in LA mice. Swimming repeated at 2-h intervals for 48 h resulted in cross-tolerance with morphine in HA and C mice. Naloxone (1 and 10 mg/kg, IP) failed to antagonize swim-induced analgesia in mice that had experienced chronic swimming in the 2-h/48-h paradigm. The daily swimming paradigm failed to produce cross-tolerance with morphine analgesia in any line. Differential degree of tolerance in three lines supports a hypothesis that selective breeding for high and low stress-induced analgesia has modified the degree of opioid involvement in the endogenous analgesia mechanisms.

Animals↗
PubMed1993

Development of rapid tolerance to pentobarbital and cross-tolerance to ethanol on a motor performance test with intoxicated practice.

Male Wistar rats given a single moderate dose (1.7 mg/kg, IP) of pentobarbital (PB), followed by six trials on the moving belt apparatus during the next hour, showed tolerance to the motor-impairing effects of a second dose of 17 mg/kg given 24 h later. A control group that received saline before the first test showed the usual initial sensitivity when tested with PB 24 h later. Three weeks later, the first group showed cross-tolerance to the effects of ethanol (1.7 g/kg, IP) on the same test, while the second group did not. These findings support the suggestion that rapid tolerance is closely similar to chronic tolerance and that the contribution of intoxicated practice results in a long-lasting component that applies to cross-tolerance to ethanol on the same test.

Alcoholic Intoxication↗
PubMed1995

Contingent drug tolerance: differential tolerance to the anticonvulsant, hypothermic, and ataxic effects of ethanol.

The kindled-convulsion model of epilepsy was used to study contingent tolerance to ethanol's (1.5 g/kg; IP) anticonvulsant, hypothermic, and ataxic effects in adult male rats. In the present experiments, three groups of amygdala-kindled rats received a series of bidaily (one every 48 h) convulsive stimulations: one group received ethanol 1 h before each stimulation; one group received ethanol 1 h after each stimulation; and another group served as the saline control. Tolerance to ethanol's anticonvulsant effect (Experiments 1 and 2) was greatest in those rats that received ethanol before each convulsive stimulation; whereas, tolerance to ethanol's hypothermic (Experiments 1 and 2) and ataxic (Experiments 2) effects developed in both groups that received ethanol. These results were predicted on the basis of the drug-effect theory of drug tolerance: the theory that functional drug tolerance is an adaptation to the disruptive effects of drugs on concurrent patterns of neural activity, not to drug exposure per se.

Amygdala↗
PubMed1983

Tolerance maintenance depends on persistence of the tolerizing antigen: evidence from transplantation studies on Xenopus laevis.

In order to assess the role of antigen persistence in the tolerant state, tolerance was induced in Xenopus laevis by the embryonic transplantation of whole eyes or tail tissue. Both types of transplants were seen to heal in and persist, with no signs of immunological incompatibility. At metamorphosis, tail resorption occurred and grafted tail tissue was lost. Eye transplants were maintained through metamorphosis in most eye grafted animals. Eye graft recipients which had maintained the transplant were observed to accept challenge skin allografts from donors of the same genotype as the eye donor in all but one case, while recipients which had lost the eye transplant at metamorphosis or had the eye transplant experimentally removed sometimes did not accept the challenge skin graft. Animals tail grafted as embryos did not accept post metamorphic skin grafts from donors of the same genotype as the tail tissue donor, but rejection was not accelerated. It is proposed that tolerance induction is dependent on the presence of appropriately presented antigen at a time when precursor thymocyte cells are migrating to the thymus, prior to their processing into alloreactive cells, and that tolerance maintenance is dependent upon the persistence of the tolerizing antigen.

Age Factors↗
PubMed1992

The value of glycosylated haemoglobin as a substitute for the oral glucose tolerance test in the detection of impaired glucose tolerance (IGT).

In a prospective study of South African Indian subjects with IGT, glycosylated hemoglobin [specifically HbA1 (HbA1(a+b+c)] and its relationship to the oral glucose tolerance test (OGTT) was studied in 128 study subjects who were classified IGT a year previously (Year 0 of study) and in 64 control subjects. At Year 1 of the study, the standard 75-g OGTT was performed on all subjects; study subjects were further divided into three groups based on World Health Organisation criteria [Normal (N), impaired glucose tolerance (IGT), diabetes mellitus (D)]. HbA1, a glycosylated hemoglobin (GHb), was measured by a cation-exchange microchromatographic method. Based on OGTT results, 47 of the 128 study subjects were classified IGT, 41 diabetes (newly-diagnosed diabetes) and 40 subjects had normal glucose tolerance. Mean GHb was significantly higher in the D group (7.61 +/- 1.76%) compared to the control group (6.99 +/- 1.22%) and the N group (6.9 +/- 1.12%), respectively (P less than 0.05); there was no significant difference between the IGT group (7.48 +/- 1.44%) and each of the other three groups. Compared to the OGTT, GHb was relatively insensitive in the diagnosis of IGT or diabetes mellitus: only 17% of the IGT group and 26.8% of the D group has elevated GHb values; the specificity of GHb as a measure of normal glucose tolerance was 85.9%. The majority of subjects, irrespective of the category of glucose tolerance, had GHb levels within the normal range and there was marked overlap between the four groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1980

Tolerance to methadone lethality and microsomal enzyme induction in mice tolerant to and dependent on morphine.

In an attempt to explain a loss of cross-tolerance between morphine and methadone and an increased tolerance to methadone lethality in morphine-dependent mice administered methadone orally for six days, the possibility that methadone was stimulating its own metabolism was investigated. It was found that methadone did enhance its own metabolism two-fold. This increase in activity correlated with the development of tolerance to the lethal effects of methadone as measured by an elevation of the oral methadone LD50. Furthermore, SKF-525A, a potent microsomal inhibitor, abolished this tolerance. The intracerbroventricular methadone LD50 was not altered by six days administration of oral methadone, suggesting that the tolerance observed was dispositional in nature.

Animals↗
PubMed1996

Impaired glucose tolerance with late hypersecretion of insulin during oral glucose tolerance test in patients with vasospastic angina.

OBJECTIVES: This study tested whether patients with vasospastic angina have impaired glucose tolerance or impaired insulin response. BACKGROUND: Hyperinsulinemia has been demonstrated in patients with coronary artery disease and syndrome X. METHODS: We performed an oral glucose tolerance test (75 g) in 30 patients with vasospastic angina in whom severe coronary vasospasm was induced by acetylcholine and in a matched group of 30 patients with atypical chest pain in whom no significant vasospasm was induced. The responses of insulin and glucose were compared between the two groups. No subjects had overt diabetes mellitus, hypertension, dyslipidemia, obesity or angiographically detected significant baseline coronary stenosis. Venous blood samples were taken during fasting and at 30, 60, 120 and 180 min after glucose load to obtain plasma glucose and immunoreactive insulin levels. RESULTS: Impaired glucose tolerance was detected in the 19 (63%) of 30 patients with vasospastic angina and in none of 30 patients with atypical chest pain (p < 0.001). The immunoreactive insulin levels at 60 and 120 min as well as the interval to peak insulin level were significantly greater in patients with vasospastic angina (p < 0.001). Among patients with vasospastic angina, those with acetylcholine-induced multivessel coronary vasospasm showed a significantly higher sum of insulin concentrations than those with single-vessel spasm (p < 0.01). During induction of coronary spasm, 10 patients with vasospastic angina presented ventricular arrhythmias. The sum of insulin concentrations was significantly greater in patients with than in those without ventricular arrhythmias. CONCLUSIONS: Patients with vasospastic angina exhibited a high incidence of impaired glucose tolerance and delayed and significantly higher insulin responses. These findings suggest that impaired glucose tolerance with late hypersecretion of insulin may contribute to the pathogenesis of severe coronary vasospasm.

Adult↗
PubMed1999

Effects of guanylyl cyclase and protein kinase G inhibitors on vasodilatation in non-tolerant and tolerant bovine coronary arteries.

The effects in bovine coronary arteries of the soluble guanylyl cyclase inhibitor 1 H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) were examined in order to establish the relative importance of the enzyme (a) in the vasodilator actions of glyceryl trinitrate and S-nitroso-N-acetylpenicillamine and (b) in induction of tolerance to these agents. ODQ strongly inhibited responses to both relaxants with IC50's of the order of 0.5 microM; in contrast, the protein kinase G inhibitor, 8-bromoguanosine-3',5'-monophosphorothioate (Rp-8-Br-cGMPS) had little effect on the responses. Tolerance after pre-incubation with glyceryl trinitrate (10 microM) was unaffected by co-pre-incubation with ODQ (1.0 microM), but similar experiments with S-nitroso-N-acetylpenicillamine were inconclusive because tolerance was associated with depressed contractile activity. It is concluded that in bovine coronary arteries soluble guanylyl cyclase is essential for vasorelaxation to both glyceryl trinitrate and S-nitroso-N-acetylpenicillamine but is unimportant for induction of tolerance to glyceryl trinitrate. Our results add weight to the hypothesis of impaired biotransformation rather than guanylyl cyclase desensitisation as the mechanism of in vitro nitrate tolerance.

Animals↗
PubMed1990

Induction of tolerance to non-H-2 alloantigens is not restricted by the MHC molecules expressed on the donor cells in cyclophosphamide-induced tolerance.

A long-lasting skin tolerance to non-H-2 alloantigens has been reported to be readily induced, when the recipient mice were primed intravenously (i.v.) with 5 x 10(7) spleen cells (SC) plus 1.5 x 10(7) bone marrow cells (BMC) from the H-2 identical strains of mice, and treated intraperitoneally (i.p.) with 200 mg/kg CP 2 days later. The present study was conducted in order to clarify whether or not tolerance induction to non-H-2 alloantigens in cyclophosphamide (CP)-induced tolerance is restricted by H-2 alloantigens on donor cells. When BALB/c (BALB; H-2d) female mice were primed i.v. with fully allogeneic [H-2 plus minor histocompatibility (H) antigen-disparate C57BL/10 (B10; H-2b) female SC plus BMC and treated i.p. with CP 2 days later, the survival of H-2 identical B10.D2 nSnSlc (B10.D2; H-2d) female skin was moderately prolonged, but the survival of fully allogeneic B10 female skin was not. When semiallogeneic (B10 x B10.D2) (H-2bxd) female cells or H-2 identical B10.D2 female cells were used as the tolerogen, the survival of B10.D2 female skin was prolonged moderately or permanently, respectively. There was no significant difference between the prolongations of B10.D2 female skin graft survival in the BALB mice treated with the B10 cells followed by CP, and the (B10 x B10.D2) cells followed by CP. Similar results were observed in H-Y antigen-disparate combinations. These results strongly suggest that tolerance induction to non-H-2 alloantigens is not restricted by the products of donor MHC in CP-induced tolerance.

Animals↗
PubMed1987

Drug-induced tolerance to allografts in mice. X. Augmentation of split tolerance in murine combinations disparate at both H-2 and non-H-2 antigens by the use of spleen cells from donors preimmunized with recipient antigens.

In a fully allogeneic murine combination of C3H/HeSlc (C3H) (H-2k) and C57BL/6CrSlc (B6) (H-2b), C3H mice were primed i.v. with 1 X 10(8) spleen cells from B6 mice preimmunized i.v. with 5 X 10(7) C3H spleen cells and then were given i.p. 200 mg/kg cyclophosphamide (CP) 2 days later (Im-B6-Sc plus CP group). The tolerant state in those recipient mice was compared with that in mice made tolerant conventionally with 1 X 10(8) naive B6 spleen cells plus 200 mg/kg CP (naive-B6-Sc plus CP group). B6 skin was rejected in an almost normal fashion in both the naive-B6-Sc plus CP group and the Im-B6-Sc plus CP group. However, EL4 tumor allografts (B6 origin) inoculated after complete rejection of B6 skin grafts were specifically accepted in both groups. Moreover, the tumor growth in the Im-B6-Sc plus CP group was faster than that in the naive-B6-Sc plus CP group. Mixed lymphocyte reaction, cytotoxic T lymphocyte activity, and antibody production against the tolerogen were depressed more profoundly in the Im-B6-Sc plus CP group than in the naive-B6-Sc plus CP group. These observations were consistent with the results from tumor allografting. The other immunological parameters examined in the present study, including helper T cell activity and delayed foot-pad reaction, were retained in the Im-B6-Sc plus CP group at the same levels as in the naive-B6-Sc plus CP group. These observations were consistent with the results from skin allografting. In conclusion, tumor allograft tolerance was made more profound by the use of spleen cells from donors preimmunized with recipient antigens as the tolerogen than by the use of naive spleen cells. However, skin allograft tolerance was not achieved at all by these same treatments. The contribution of graft-versus-host disease to this phenomenon was excluded by the chimeric analysis in AKR/JSea (H-2k) mice given the preimmunized (with AKR antigens) B6 spleen cells plus CP. These results strongly support the existence of a less proliferative lymphocyte population which does not evoke cell divisions to mature even after the strong stimulation with the preimmunized spleen cells and is resistant to tolerance induction.

Animals↗
PubMed1998

Analgesic effects of a specific pulsed magnetic field in the land snail, Cepaea nemoralis: consequences of repeated exposures, relations to tolerance and cross-tolerance with DPDPE.

It has been demonstrated previously that a short acute exposure to a specific extremely low frequency pulsed magnetic field (Cnp) can induce significant partly opioid-mediated analgesia in the land snail, Cepaea nemoralis. Here, this Cnp-induced analgesia is examined for the development of tolerance to daily repeated acute exposures of 15 or 30 min duration. Acute cross-tolerance to the delta opioid receptor directed agonist DPDPE, [D-Pen2, D-Pen5]enkephalin, was also found. Before (pre-exposure) and after (0, 15, 30 and 60 min) exposure to either a sham or Cnp magnetic field, snails were tested for an aversive reaction to a warmed surface (40 degrees C), and the latency time to the aversive reaction was recorded. Snails that were exposed to the Cnp showed a significant increase in the latency time (F1.55 = 2856.4; p < 0.001; Eta2 = 0.95), which may be interpreted as an induction of analgesia. During the daily (9 day) repeated acute exposures, the induction of analgesic response was significantly reduced, but not ablated. Altering the environmental conditions of the Cnp exposure restored a significant proportion of the partly developed tolerance, consistent with previous reports of environmental specificity in the development of opioid tolerance. These findings suggest that the partial development of tolerance to the opioid-mediated portion of Cnp-induced analgesia may be countered by altering the specific environmental Cnp exposure conditions.

Analgesia↗
PubMed2000

Motor impairment produced by ethanol and site-selective NMDA receptor antagonists in mice: tolerance and cross-tolerance.

Current perspectives on clinical use of N-methyl-D-aspartate (NMDA) receptor antagonists infer acute and repeated administration schedules for management of different pathological states. Development of tolerance and cross-tolerance between different antagonists may significantly affect their clinical effectiveness. Since ethanol was repeatedly demonstrated to act as NMDA receptor antagonist, ethanol use may also have its impact on the effects of NMDA receptor ligands. Using the rotarod test in mice, the present study evaluated development of tolerance and cross-tolerance between ethanol (3.2 g/kg, p.o.), competitive NMDA receptor antagonist, D-CPPene (5.6 mg/kg, i.p.), and low-affinity NMDA receptor channel blocker, memantine (30 mg/kg, i.p.), that were administered for seven days once a day after the daily rotarod training session. Acute tests with ethanol (0.3, 1, 1.7, 3.2 g/kg), D-CPPene (0.3, 1, 3, 5.6 mg/kg) and memantine (1, 3, 10, 30 mg/kg) revealed that (a) each of these drugs dose-dependently disrupted rotarod performance in drug-naive mice; (b) in ethanol- and D-CPPene-treated mice, tolerance was observed to ethanol and D-CPPene but not to memantine; moreover, effects of memantine were even more pronounced in D-CPPene-treated subjects; and (c) repeated memantine administration decreased acute motor impairing effects of ethanol, D-CPPene and memantine. Thus, the history of ethanol use or abuse may influence pharmacological activity of NMDA receptor antagonists and this effect is dependent on type of the NMDA receptor antagonist applied.

Animals↗
PubMedDate not supplied

Mechanisms of tolerance induction after rat liver transplantation: intrahepatic CD4(+) T cells produce different cytokines during rejection and tolerance in response to stimulation.

Increasing evidence supports the existence of regulatory T cells that may inhibit the allogeneic immune response after transplantation by secreting regulatory cytokines. To determine whether rat liver tolerance is associated with intrahepatic regulatory T cells secreting a characteristic cytokine profile, we analyzed the cytokine production of freshly isolated intragraft CD4(+) T cells at different times postoperatively by semiquantitative reverse transcription-polymerase chain reaction and by enzyme-linked immunosorbent assay before and after in vitro stimulation. Orthotopic arterialized liver transplantation was performed in two allogeneic rat strain combinations, one with fatal acute rejection (DA-to-LEW) and one with long-lasting tolerance (LEW-to-DA) without immunosuppression despite a complete major histocompatibility complex mismatch (spontaneous liver tolerance). Liver allografts of both groups showed continuously increasing cellular infiltration between day 3 and day 7 after transplantation. In this inflammatory situation, very low levels of interleukin-13 were detectable directly after cell isolation, as well as after in vitro stimulation. However, after 30 days, intrahepatic CD4(+)T cells in the tolerance group were then able to express elevated messenger RNA levels of the anti-inflammatory cytokine interleukin-13 in response to stimulation. This result indicates the presence of an intragraft Th2-like CD4(+) T cell population, which may have a regulatory function in the induction of liver tolerance.

Animals↗
PubMed1999

The nitric oxide donor SIN-1 is free of tolerance and maintains its cyclic GMP stimulatory potency in nitrate-tolerant LLC-PK1 cells.

PURPOSE: Using an established cell culture model, the present study investigates whether linsidomine (SIN-1), a spontaneous donor of nitric oxide and active metabolite of the antianginal drug molsidomine, induces tolerance to its own cyclic GMP stimulatory action or shows a diminished response after tolerance induction with glyceryl trinitrate. METHODS: Incubations with nitric oxide donors were carried out in LLC-PK1 kidney epithelial cells. Intracellular levels of cyclic GMP, the vasodilatory second messenger of nitric oxide, were determined by radioimmunoassay. RESULTS: A 5-h preincubation with glyceryl trinitrate (0.01-100 microM) led to complete inhibition of a subsequent cyclic GMP stimulation by glyceryl trinitrate but left the cyclic GMP response to SIN-1 unaltered. Similarly, cyclic GMP elevations by the spontaneous nitric oxide donors sodium nitroprusside and spermine NONOate were not affected after pretreatment with glyceryl trinitrate. Moreover, pretreatment with SIN-1 (1-1000 microM) had no significant effect on SIN-1-dependent cyclic GMP stimulation. CONCLUSIONS: Our results show that in LLC-PK1 cells, SIN-1 is free of tolerance induction and not cross-tolerant to glyceryl trinitrate. This may be due to the spontaneous nitric oxide release from SIN-1, which in contrast to nitric acid esters does not require enzymatic bioactivation and may therefore be unaffected by nitrate tolerance.

Animals↗