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Nitric oxide (NO) increments in exhaled air and changes in mean arterial pressure of anaesthetised rabbits were measured in order to study the NO generation from NO donors and tachyphylaxis in NO formation from nitroglycerin. Continuous infusions of isosorbide dinitrate, isosorbide-5-mononitrate and 3-morpholino-sydnonimine (SIN-1) evoked dose-dependent increases in exhaled NO, paralleled by decrements in mean arterial pressure. Repeated infusions of nitroglycerin resulted in attenuation (P<0.01) of the NO increase from a given dose. Concurrent infusions of isosorbide dinitrate, isosorbide-5-mononitrate or nitroglycerin reduced the amount of NO emanating from the bioconversion of a given dose nitroglycerin as measured in the expired air (P<0.01 for all drugs), indicating cross-tachyphylaxis. SIN-1 did not exhibit such cross-tachyphylaxis. In conclusion, measurements of exhaled NO can be a useful tool for exploration of nitrovasodilator tachyphylaxis. Cross-tachyphylaxis is only shared between some nitrovasodilators and is possibly not due to feedback from the generated NO.
Vascular leakage induced by intradermal injection of endotoxin, zymosan-activated plasma (ZAP) and platelet-activating factor (PAF) was measured in nine Thoroughbreds using 125-iodine human serum albumin (125I-HSA) as a marker in the blood. ZAP and PAF produced dose-dependent increases in vascular permeability with the maximum occurring within the first 15 min after injection. The vascular leakage induced by endotoxin was also dose-dependent, but the maximum occurred 2 h after intradermal injection. Intradermal sites previously injected with endotoxin were refractory to a second injection of endotoxin for up to 5 days. However, sites injected with endotoxin and re-injected with either ZAP or PAF remained responsive with increased vascular leakage compared to saline injected control sites re-injected with either ZAP or PAF. Diminished response to endotoxin challenge may contribute to the poor prognosis of endotoxaemia in the horse.
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BACKGROUND: Tachyphylaxis to sciatic nerve blockade in rats correlates with hyperalgesia. Spinal inhibition of nitric oxide synthase with N(G)nitro-L-arginine methyl ester (L-NAME) has been shown to prevent hyperalgesia. Given systemically, L-NAME also prevents tachyphylaxis. The action of L-NAME in preventing tachyphylaxis therefore may be mediated at spinal sites. We compared systemic versus intrathecal potency of L-NAME in modulating tachyphylaxis to sciatic nerve block. METHODS: Rats were prepared with intrathecal catheters. Three sequential sciatic nerve blocks were placed. Duration of block of thermal nocifensive, proprioceptive and motor responses was recorded. We compared spinal versus systemic dose-response to L-NAME, and examined effects of intrathecal arginine on tachyphylaxis. An additional group of rats underwent testing after T10 spinal cord transection. In these rats duration of sciatic nerve block was assessed by determining the heat-induced flexion withdrawal reflex. RESULTS: L-NAME was 25-fold more potent in preventing tachyphylaxis given intrathecally than intraperitoneally. Intrathecal arginine augmented tachyphylaxis. Spinalized rats exhibited tachyphylaxis to sciatic block. CONCLUSION: The increased potency of intrathecal versus systemic L-NAME suggests a spinal site of action in inhibiting tachyphylaxis. Descending pathways are not necessary for the development of tachyphylaxis since it occurs even after T10 spinal cord transection. Thus tachyphylaxis, like hyperalgesia, is mediated at least in part by a spinal site of action.
BACKGROUND: Tachyphylaxis, defined as a rapidly decreasing response to a physiologically active agent after administration of a few doses, can be well demonstrated in the experimental setting. However, tachyphylaxis in the clinical setting lacks clear demonstration. OBJECTIVE: Our purpose was to identify dermatologists' perception of the clinical incidence of tachyphylaxis and then design a prospective study that would estimate the clinical incidence of tachyphylaxis. METHODS: Clinical and academic dermatologists completed a survey questionnaire about the incidence of tachyphylaxis and the time course to its occurrence. Subjects with plaque psoriasis applied topical corticosteroid twice daily for 12 weeks to their plaques, leaving an isolated plaque untreated for comparison. Plaques were evaluated every 2 weeks. By means of a 9-point scale, an end point for clinical detection of tachyphylaxis was defined as "an increase in plaque elevation of at least 2 occurring after a detectable decrease in plaque elevation with topical steroid." RESULTS: The survey found that 57% of dermatologists perceived that tachyphylaxis occurred after 8 weeks of therapy with topical corticosteroid. In the 12-week clinical study, none of 32 patients exhibited detectable signs of tachyphylaxis. CONCLUSION: What accounts for the commonly held belief of tachyphylaxis in the clinical setting may be related to the therapeutic efficacy of topical corticosteroids. Failure of topical corticosteroids to clear psoriasis after an initial improvement may give the impression of tachyphylaxis. The common clinical perception of tachyphylaxis may also be related to issues of compliance outside a study setting or a psoriasis flare unrelated to therapy.
The contribution of endothelium-derived mediators and protein kinase C in the tachyphylaxis to arginine vasopressin (AVP) was assessed in the rat aorta. Endothelium-intact (E+) and denuded rings (E-) obtained from the rat thoracic aorta were exposed to three administrations of a supramaximal concentration of AVP (100 nM), lasting 20 min and 45 min apart. N-Omega-nitro-L-arginine (NNLA), a non-selective inhibitor of all isoforms of NO synthase, and AMT, a selective inhibitor for the inducible (iNOS) and neuronal (nNOS) isoforms, diminished the tachyphylaxis to AVP significantly in both E+ and in E- rings. No iNOS could be detected by Western blots in freshly isolated rings or in rings exposed to AVP, despite a strong signal in rings isolated from LPS-treated rats, while nNOS could be constitutively detected. Inhibition of prostaglandins or epoxyeicosatrienoic acids (EETs) synthesis by diclofenac or clotrimazole, respectively, had no effect on tachyphylaxis while combination of these agents diminished tachyphylaxis in E+ only. Combination of NNLA, diclofenac and clotrimazole blocked completely the tachyphylaxis. Inhibition of PKC by either chelerythrine or bisindolylmaleimide I-HCl (BisI) led to a significant diminution of AVP tachyphylaxis only in E-. Activation of PKC with phorbol-12-myristate-13-acetate (PMA) simulated tachyphylaxis to AVP in E- only, effect blocked by the NO donor, SNP. In conclusion, NO produced from constitutive nNOS present in vascular smooth muscle cells participates in tachyphylaxis to AVP. PKC is involved in this tachyphylaxis only in E- rings, the presence of NO probably diminishing the effects of this kinase.
Tachyphylaxis to local anesthetics is defined as a decrease in duration, segmental spread or intensity of a regional block despite repeated constant dosages. However, there is disagreement about the incidence of tachyphylaxis. In contrast to tachyphylaxis, pseudotachyphylaxis denotes time dependent variations in pain or circadian changes in the duration of local anesthetic action. Tachyphylaxis appears neither to be linked to structural or pharmacological properties of the local anesthetics nor to the technique or mode of their administration. The mechanisms underlying tachyphylaxis are open to debate and include changes in pharmacokinetics or pharmacodynamics. Considering pharmacokinetics, local edema, an increased epidural protein concentration, changes in local anesthetic distribution in the epidural space or a decrease of perineural pH could result in decreased diffusion of the local anesthetics from the epidural space to their binding sites at the sodium channel. Increased clearance of local anesthetics from the epidural space may be caused both by increased epidural blood flow or increased local metabolism. Considering pharmacodynamics, antagonistic effects of nucleotides or increased sodium concentration, increased afferent input from nociceptors or receptor down regulation of the sodium channels have been implicated. However, none of these theoretical considerations is supported strongly enough by data to explain tachyphylaxis. A new possibility to maintain for a longer time neural blockade is the design of new ultralong-acting local anesthetics. Liposomal formulations of local anesthetics also appear suitable to provide longer lasting regional anesthesia. The recent observation that NMDA-antagonists as well as NO-synthase-inhibitors prevent the development of tachyphylaxis suggests involvement of the nitric oxide pathway in the development of tachyphylaxis. Accordingly, NMDA-antagonists or NO-synthase-inhibitors may prevent tachyphylaxis.
BACKGROUND: Tachyphylaxis to local anesthetics has been shown to be promoted by longer interanalgesic intervals between injections. We hypothesized that thermal hyperalgesia also would accelerate the development of tachyphylaxis. The n-methyl-D-aspartate antagonist ((+)-5 methyl-10,11-dihydro-5H-dibenzo (a,d) cyclohepten-5,10-imine, or dizocilpine) (MK-801) has been shown to prevent thermal hyperalgesia. We therefore also hypothesized that MK-801 would prevent tachyphylaxis. METHODS: Catheters were surgically implanted in rats along the sciatic nerve. After recovery and conditioning to the testing paradigm, they received repeated injections of lidocaine or 2-chloroprocaine followed by motor block testing with or without hot-plate testing at 48, 52, or 56 degrees C. In other experiments, MK-801 or saline was administered by intraperitoneal injection before sciatic nerve local anesthetic injection and sensory and motor testing. RESULTS: Rats receiving repeated lidocaine or 2-chloroprocaine injections, when repeatedly subjected to hot-plate testing at 56 degrees C, developed thermal hyperalgesia and tachyphylaxis to motor and sensory blockade. Rats receiving either no hot-plate exposure or hot-plate exposure at 48 degrees C developed no tachyphylaxis or hyperalgesia. Rats tested at 52 degrees C developed milder hyperalgesia and developed tachyphylaxis more slowly than did rats tested at 56 degrees C. Control experiments excluded artifacts due to circadian rhythm, injection volume, and learning. Rats pretreated with MK-801 showed no tachyphylaxis over a series of three injections. CONCLUSIONS: Thermal hyperalgesia accelerates the development of tachyphylaxis to rat sciatic nerve blockade, and MK-801 prevents tachyphylaxis in this model. n-Methyl-D-aspartate receptor antagonists may have future clinical utility in increasing the duration of effectiveness of prolonged local anesthetic administration.
1. The characteristics of gastrin-stimulated gastric acid secretion were investigated in conscious cats fitted with chronic cannulated gastric fistulae, with particular reference to tachyphylaxis. 2. There is a significant postive correlation between the peak acid secretion in response to pentagastrin 8 microgram kg-1 hr-1 and body weight. Male cats secret significantly greater amounts of acid in response to pentagastrin than females. The difference is lessened, but not eliminated, by expressing the acid out put in terms of body weight. 3. Pentagastrin stimulates a dose-dependent increase in acid secretion in the range 0.5-32 microgram kg-1 hr-1 when the response to each dose is assayed on separate occasions. Pentagastrin 64 microgram kg-1 hr-1 does not produce a further increase in acid secretion. The acid response to pentagastrin 1-16 microgram kg-1 hr-1 assayed on a single occasion by a continuous infusion method shows a dose-response relationship up to 8 microgram kg-1 hr-1 when it reaches a plateau of secretion. There is no difference between the two methods of assaying the gastric acid stimulating activity using doses of pentagastrin up to 8 microgram kg-1 hr-1. 4 The acid secretion in response to pentagastrin 8 microgram kg-1 hr-1 reaches a maximum after 45 min of stimulation and thereafter shows tachyphylaxis. Over a period of 5 hr there are at least two phases of tachyphylaxis distinguishable. During the period 0.75--2.5 hr of stimulation there is a fast phase of tachyphylaxis (-32.0 muequivH+kg-1 15 min-1). This is followed by a slow phase of tachyphylaxis (-9.4 muequivH+kg-1 15 min-1) up to 5 hr of stimulation. 5. The absolute rate of the fast phase of tachyphylaxis of acid secretion (muequivH+kg-1 15 min-1) increases with increasing doses of pentagastrin, but rates of tachyphylaxis are similar when expressed as a percentage of the peak acid response to the particular dose of pentagastrin (5.1--7.8% 15 min-1). Synthetic human gastrin-17, the synthetic C-terminal decapeptide of human gastrin and the C-terminal tetrapeptide of gastrin have comparable rates of tachyphylaxis. The possible receptor models for the tachyphylaxis of gastrin-stimulated acid secretion are discussed.
The bronchoconstriction induced by repeated histamine inhalation tests was studied in eight mild stable asthmatic subjects to determine whether histamine tachyphylaxis occurs in asthmatics. We also studied the specificity of histamine tachyphylaxis by examining for tachyphylaxis in response to inhaled acetylcholine in these subjects. We subsequently investigated whether indomethacin pretreatment inhibited histamine tachyphylaxis. Tachyphylaxis in response to inhaled histamine occurred in all subjects. The mean histamine provocative concentration causing a 20% fall in the forced expiratory volume in 1 s (PC20) increased from 3.04 +/- 1.9 (%SD), to 4.88 +/- 1.9, and to 6.53 +/- 2.2 mg/ml (P less than 0.0005) with successive inhalation tests. Tachyphylaxis was still present at 3 h (P less than 0.01), but not in all subjects at 6 h (P greater than 0.05). Tachyphylaxis, however, did not occur in response to inhaled acetylcholine. In addition, indomethacin pretreatment prevented histamine tachyphylaxis. Thus this study demonstrates that there is a histamine-specific mechanism that can partially protect the airways against repeated bronchoconstriction caused by histamine. This effect may occur through the release of inhibitory prostaglandins in the airway after histamine stimulation. Also when histamine inhalation tests are repeated on the same day, the tests should be separated by greater than 6 h to avoid tachyphylaxis.
Controversy exists concerning possible tachyphylaxis of the acute bronchodilating effect of albuterol, especially with regard to the duration of its acute bronchodilating action. We evaluated 140 patients with bronchial asthma in a prospective double-blind controlled study of possible tachyphylaxis to albuterol aerosol as compared to isoproterenol aerosol. We demonstrated statistically significant tachyphylaxis with regard to duration of acute bronchodilating effect. We believe that this tachyphylaxis is not clinically significant because there was no tachyphylaxis with regard to peak bronchodilating effect and because the duration of bronchodilating effect remains significantly greater, both quantitatively and statistically, when compared to isoproterenol aerosol. Moreover, it appeared that most of the tachyphylaxis was present at four weeks of therapy. There was a small increment of tachyphylaxis after eight weeks of therapy, but no further increase in tachyphylaxis was demonstrated after 13 weeks of inhaled albuterol therapy. We therefore feel that clinically significant tachyphylaxis to inhaled albuterol aerosol must be quite unusual and that chronic therapy with inhaled albuterol aerosol is probably both safe and efficacious for bronchospastic disorders.
Rabbit aorta and rat fundus do not display tachyphylaxis to angiotensin II (Asp1)angiotensin II) at 37 degrees C. These tissues do, however, display tachyphylaxis to [Sar1]angiotensin II (N-methylglycine 1 angiotensin II) and [dimethylglycine angiotensin II, respectively, at this temperature. At 22 degrees C, both tissues displayed rapid tachyphylaxis to [Asp1]angiotensin II which was reversed on prolonged incubation in peptide-free medium. At 37 degrees C, but at a lower than normal pH (pH 6.5 instead of 7.4), the rabbit aorta developed rapid tachyphylaxis to [Asp1)angiotensin II; this effect also was reversed on prolonged incubation in peptide-free medium. The rat uterus, at 30 degrees C, displayed tachyphylaxis to [Asp1]angiotensin II and analogs in order of rate of onset: [Sar1]angiotensin II greater than [Asp1]angiotensin II greater than [des-Asp1]angiotensin II. Over half of the individual uterine strips tested displayed no tachyphylaxis to [des-Asp1]angiotensin II. However, at 22 degrees C tachyphylaxis to all three compounds was rapid on onset and was reversed on prolonged incubation. The results indicate a correlation between affinity of the peptide analog for angiotensin receptor and its ability to induce tachyphylaxis. A possible involvement of membrane-bound enzymes in the onset and duration of tachyphylaxis is suggested.
In isolated canine tracheal smooth muscle, repeated administrations of histamine result in a rapid reduction in contractile response to about 15% of the initial contraction (tachyphylaxis). Development of this tachyphylaxis is specific inasmuch as: 1) it does not develop to acetylcholine (10(-6) M or 10(-4) M), or serotonin (10(-5) M; and 2) maximally developed histamine tachyphylaxis is not associated with a parallel reduction in response to acetylcholine. Pretreatment with propranolol (10(-5) M) or phentolamine (10(-4) M) does not prevent tachyphylaxis: however, pretreatment with atropine (10(-4) M) does prevent tachyphylaxis in about 50% of the animals tested. Tachyphylaxis to histamine can be reversed in a dose- and time-dependent fashion with prostaglandin synthesis inhibiting agents. The order of potency obtained with such compounds (indomethacin greater than mefenamic acid greater than oxyphenbutazone greater than acetylsalicylic acid) is consistent with potencies for inhibition of prostaglandin synthesis found in the literature. Also, in indomethacin pretreated strips in which tachyphylaxis to histamine was prevented, exogenous addition of PGE2 (1.42 x 10(1-) M to 2.84 x 10(-9) M) and PGA2 in a high concentration (2.9 x 10(-9) M) are capable of selectively reducing the response to histamine without an effect on acetylcholine-induced contractions. These data suggest that the mechanism of histamine tachyphylaxis in the canine tracheal smooth muscle preparation involves prostaglandin synthesis.
1. Ethanol (EtOH) tachyphylaxis (acute tolerance), a time-dependent decrease in apparent potency, is known in vivo and in some neuronal preparations. The present studies characterize EtOH tachyphylaxis in spinal motorneurons and test the hypothesis that metabotropic glutamate receptors (mGluRs) play a role. 2. Patch clamp studies were carried out in motorneurons in rat spinal cord slices. Currents were evoked by pulses of glutamate, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) or N-methyl-D-aspartic acid (NMDA). 3. In nine of 15 cells, ethanol depression of glutamate-evoked currents was time-dependent. EtOH depressed current area 36.9+/-3% at 8-10 min, but only 16.8+/-3% at 20 min. Mean reduction in depression was 20.1+/-1%, N=9. Tachyphylaxis was less prominent in currents evoked by AMPA or NMDA, appearing in two of 10 AMPA and three of 11 NMDA currents. 4. The mGluR agonist trans-(1S,3R)-1-amino-1,3-cyclopentanedicarboxylic acid (ACPD) increased, the antagonist (+/-)-alpha-methyl-4-carboxyphenylglycine (MCPG) decreased the area of glutamate-evoked currents. ACPD also increased the area of NMDA- and AMPA-evoked currents. 5. ACPD increased the incidence of tachyphylaxis in glutamate-evoked currents to 100% (N=9); MCPG markedly reduced tachyphylaxis. ACPD also increased the incidence of tachyphylaxis in currents evoked by NMDA and AMPA to five of eight and four of seven neurons, respectively. 6. Block of G-protein pathways by intracellular GDP-beta-s abolished tachyphylaxis in glutamate-evoked currents (N=8); however, currents recovered only partially following EtOH washout. 7. Activation of mGluRs contributes to neuronal tachyphylaxis to EtOH in spinal cord motorneurons, probably via G-protein pathways.
A model of local anesthetic tachyphylaxis was developed in our group previously using repeated sciatic nerve blocks in rats. In this model, thermal hyperalgesia accelerated tachyphylaxis, and the noncompetitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, MK-801, prevented both hyperalgesia and tachyphylaxis. Nitric oxide is thought to be a second messenger for NMDA pathways in the spinal cord, and appears to be involved in spinal mechanisms of hyperalgesia. We hypothesized that nitric oxide synthase inhibitors would also inhibit the development of tachyphylaxis. Repeated rat sciatic nerve blocks were placed by percutaneous injection of 2-chloroprocaine. Block duration was tested by measuring hot-plate latency at 56 degrees C. Two hours before the first nerve block, rats received intraperitoneal injections with saline or one of six concentrations of NG-nitro-L-arginine methyl ester (L-NAME) in a randomized, blinded pattern. Control rats developed tachyphylaxis as seen previously: the duration of the third block was 30% that of the first. L-NAME inhibited the development of tachyphylaxis in a dose-dependent manner; tachyphylaxis was inhibited by 50% using L-NAME at 0.2mg/kg and completely abolished by 50 mg/kg. Nitric oxide pathways may be involved in the development of tachyphylaxis to local anesthetic nerve block.
1 The guinea-pig hypogastric ganglion, perfused through its vasculature with physiological saline solutions, will respond repeatedly to nicotinic stimulant drugs injected at 4 min intervals into the perfusion stream. Stimulation is indicated by contraction of the vas deferens. After a varying number of doses of nicotinic stimulants, complete tachyphylaxis usually develops, and normally this persists for at least 1 hour. During this time, however, electrical stimulation of the hypogastric nerve is still fully effective.2 Tachyphylaxis may be reversed for varying periods of time by all of the following procedures: (a) tetanic stimulation of the hypogastric nerve; (b) injection of large doses of histamine, methacholine, or potassium chloride; (c) perfusion with saline containing ouabain 0.1 mug/ml or 80-100 mM lithium chloride, or, to a lesser extent, with potassium-free saline.3 Tachyphylaxis is always re-established with further doses of nicotinic stimulants, except during perfusion with lithium solutions.4 Atropine hastens the onset of tachyphylaxis, but does not prevent its reversal by hypogastric nerve stimulation or by histamine or potassium. However, it does prevent the reversal by methacholine and by lithium.5 Tachyphylaxis occurs in decentralized ganglia, and can be reversed by histamine, methacholine, and by tetanic stimulation of the hypogastric ganglion. Hence tachyphylaxis and its reversal cannot be due to an effect on presynaptic fibres.6 Potassium chloride stimulates the ganglion both before and after tachyphylaxis has developed to nicotinic drugs, and hence this is unlikely to be due to a depolarization block.7 It is concluded that tachyphylaxis could be due to a prolonged ganglionic hyperpolarization.