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PubMed2005

Loss of K+ATP-channel-mediated vasodilation after induction of tachyphylaxis to peroxynitrite.

Systemic injections of peroxynitrite elicit pronounced vasodilator responses in rats by activation of ATP-dependent K+ channels (K+ATP-channels). The aim of this study was to determine whether development of tachyphylaxis to the vasodilator actions of peroxynitrite involves the loss of K+ATP-channel function. The falls in mean arterial blood pressure (MAP) and mesenteric and hindquarter vascular resistances produced by the K+ATP-channel agonist, cromakalim (3-18 microg/kg, iv), and the nitric oxide (NO) donor, sodium nitroprusside (SNP; 1-4 microg/kg, iv), were determined in pentobarbital-anesthetized rats before and after induction of tachyphylaxis to peroxynitrite induced by the administration of 10 injections of peroxynitrite (10 micromol/kg, iv). The first dose of peroxynitrite elicited pronounced falls in MAP and vascular resistances whereas the tenth injection elicited much smaller responses that were equivalent to those of decomposed peroxynitrite. Before induction of tachyphylaxis to peroxynitrite, cromakalim and SNP produced dose-dependent reductions in MAP and vascular resistances. The hemodynamic actions of cromakalim were markedly attenuated after induction of tachyphylaxis to peroxynitrite whereas the SNP-induced responses were only slightly attenuated. These results suggest that tachyphylaxis to the vasodilator actions of peroxynitrite involves the loss of K+ATP-channel function whereas tachyphylaxis to peroxynitrite minimally affects NO-mediated vasodilation. Taken together, these findings raise the possibility that peroxynitrite inhibits K+ATP-channel function by oxidation and/or nitration of amino acids in these channels.

Adenosine Triphosphate↗
PubMed1982

Tachyphylaxis after repeated dosage of decamethonium in anaesthetized man.

1 The tetanic and single twitch responses to the adductor pollicis muscle were used to study the neuromuscular effects of repeated dosage of decamethonium in nine anaesthetized patients. 2 In two of three patients who received the same total dose of decamethonium in three separate series of injections, blockade of the tetanic response was less after the third administration. In the third patient tachyphylaxis was evident after the second series of injections. 3 In three other patients, tachyphylaxis occurred after the second series of injections when the total dose of decamethonium administered was at least twice that given on the first occasion. 4 In terms of tachyphylaxis the single twitch response followed a similar pattern to that of the tetanic response. 5 Once tachyphylaxis had developed, neuromuscular block of the tetanic response by decamethonium was antagonised by neostigmine (2.5 mg) and enhanced by 2% halothane. 6 In contrast, in three patients who were not exposed to more than one series of injections of decamethonium, and presumably therefore before tachyphylaxis had developed, neuromuscular block of the tetanic response was potentiated by neostigmine. Under these circumstances recovery was unaffected by halothane. 7 Thus, when tachyphylaxis occurs with decamethonium the characteristics of the block change to resemble those of the competitive neuromuscular blocking agents; these findings could be of importance in clinical anaesthesia.

Anesthesia↗
PubMed2000

Inactivation and tachyphylaxis of heat-evoked inward currents in nociceptive primary sensory neurones of rats.

Membrane currents evoked by repeated noxious heat stimuli (43-47 degrees C) of 3 s duration were investigated in acutely dissociated dorsal root ganglion (DRG) neurones of adult rats. The heat stimuli generated by a fast solution exchanger had a rise time of 114 +/- 6 ms and a fall time of 146 +/- 13 ms. When heat stimuli were applied to heat-sensitive small (< or = 32.5 microm) DRG neurones, an inward membrane current (I(heat)) with a mean peak of 2430 +/- 550 pA was observed (n = 19). This current started to activate and deactivate with no significant latency with respect to the heat stimulus. The peak of I(heat) was reached with a rise time of 625 +/- 115 ms. When the heat stimulus was switched off I(heat) deactivated with a fall time of 263 +/- 17 ms. During constant heat stimulation I(heat) decreased with time constants of 4-5 s (inactivation). At the end of a 3 s heat stimulus the peak current was reduced by 44 +/- 5 % (n = 19). Current-voltage curves revealed outward rectifying properties of I(heat) and a reversal potential of -6.3 +/- 2.2 mV (n = 6). Inactivation was observed at all membrane potentials investigated (-80 to 60 mV); however, inactivation was more pronounced for inward currents (37 +/- 5 %) than for outward currents (23 +/- 6 %, P < 0.05). When neurones were investigated with repeated heat stimuli (3 to 5 times) of the same temperature, the peak current relative to the first I(heat) declined by 48 +/- 6 % at the 3rd stimulus (n = 19) and by 54 +/- 18 % at the 5th stimulus (n = 4; tachyphylaxis). In the absence of extracellular Ca2+ (buffered with 10 mM EGTA) inactivation (by 53 +/- 6 %) and tachyphylaxis (by 42 +/- 7 % across three stimuli) were still observed (n = 8). The same was true when intracellular Ca2+ was buffered by 10 mM BAPTA (inactivation by 49 +/- 4 %, tachyphylaxis by 52 +/- 7 % across three stimuli; n = 13). Thus, inactivation and tachyphylaxis were mainly independent of intra- and extracellular Ca2+. These results indicate that inactivation and tachyphylaxis of heat-evoked inward currents can be observed in vitro, similar to adaptation and suppression of action potential discharges elicited by comparably fast heat stimuli in vivo. Whereas the voltage dependence of I(heat) resembles that of capsaicin-induced membrane currents (I(Caps)), the independence of inactivation and tachyphylaxis of I(heat) from calcium is in clear contrast to I(Caps). A similar difference in calcium dependence of inactivation has been reported between heat-evoked and capsaicin-induced currents through the cloned capsaicin receptor channel VR1. Thus, the properties of I(heat) and of VR1 largely account for the adaptation and suppression of heat-evoked nociceptor discharges.

Animals↗
PubMed2007

Permeating protons contribute to tachyphylaxis of the acid-sensing ion channel (ASIC) 1a.

The homomeric acid-sensing ion channel 1a (ASIC1a) is a H+-activated ion channel with important physiological functions and pathophysiological impact in the central nervous system. Here we show that homomeric ASIC1a is distinguished from other ASICs by a reduced response to successive acid stimulations. Such a reduced response is called tachyphylaxis. We show that tachyphylaxis depends on H+ permeating through ASIC1a, that tachyphylaxis is attenuated by extracellular Ca2+, and that tachyphylaxis is probably linked to Ca2+ permeability of ASIC1a. Moreover, we provide evidence that tachyphylaxis is probably due to a long-lived inactive state of ASIC1a. A deeper understanding of ASIC1a tachyphylaxis may lead to pharmacological control of ASIC1a activity that could be of potential benefit for the treatment of stroke.

Acid Sensing Ion Channels↗
PubMed1999

Rapid tachyphylaxis to hemodynamic effects of PACAP-27 after inhibition of nitric oxide synthesis.

The vasodilator effects of pituitary adenylate cyclase-activating polypeptide (PACAP)-27 are subject to tachyphylaxis in rats treated with the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME). We examined whether this tachyphylaxis could be prevented by administration of the putative endothelium-derived nitrosyl factor S-nitroso-L-cysteine (L-SNC) and whether L-SNC may exert its effects via increases in cGMP levels in vascular smooth muscle. Five doses of PACAP-27 (2 nmol/kg iv) produced pronounced vasodilator responses in saline-treated rats. These responses were not subject to tachyphylaxis. The first injection of PACAP-27 (2 nmol/kg iv) in L-NAME-treated (50 micromol/kg iv) rats produced vasodilator responses similar to those in saline-treated rats, whereas subsequent injections produced progressively smaller responses. The injection of L-SNC (1,200 nmol/kg iv) before each injection of PACAP-27 prevented tachyphylaxis to the Gs protein-coupled receptor agonist in L-NAME-treated rats, whereas equihypotensive doses of the NO donor sodium nitroprusside (100 micrograms/kg iv) did not. The injection of the membrane-permeant cGMP analog 8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphate (8-CPT-cGMP; 30 micromol/kg iv) to L-NAME-treated rats restored resting hemodynamic values to pre-L-NAME levels but did not prevent the development of tachyphylaxis to PACAP-27. These results suggest that nitrosyl factors prevent the development of tachyphylaxis to the hemodynamic actions of PACAP-27. These nitrosyl factors may act independently of their ability to generate cGMP in vascular smooth muscle.

Animals↗
PubMed1999

Tachyphylaxis to PACAP-27 after inhibition of NO synthesis: a loss of adenylate cyclase activation.

The vasodilator effects of pituitary adenylate cyclase activating polypeptide (PACAP-27) are subject to tachyphylaxis in rats treated with the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). This study examined whether this tachyphylaxis is due to the loss of vasodilator potency of cAMP generated by activation of the G(s) protein-coupled PACAP receptors. Five successive treatments with PACAP-27 (2 nmol/kg iv) produced pronounced vasodilator responses in saline-treated rats that were not subject to tachyphylaxis. The first injection of PACAP-27 (2 nmol/kg iv) in L-NAME (50 micromol/kg iv)-treated rats produced vasodilator responses of similar magnitude to those in saline-treated rats, whereas four subsequent injections produced progressively and markedly smaller responses. The hemodynamic effects of the membrane-permeable cAMP analog 8-(4-chlorophenylthiol)-cAMP (8-CPT-cAMP; 5-15 micromol/kg iv) were similar in L-NAME-treated rats and in L-NAME-treated rats that had received the five injections of PACAP-27. In addition, five injections of 8-CPT-cAMP (10 micromol/kg iv) produced pronounced vasodilator responses in saline- and L-NAME-treated rats that were not subject to the development of tachyphylaxis. These results suggest that a loss of biological potency of cAMP is not responsible for tachyphylaxis to PACAP-27 in L-NAME-treated rats. This tachyphylaxis may be due to the inability of the G(s) protein-coupled PACAP receptor to activate adenylate cyclase.

Adenylyl Cyclases↗
PubMed1988

Histamine tachyphylaxis in canine airways despite prostaglandin synthesis inhibition.

Tachyphylaxis to aerosolized histamine was studied in dogs anesthetized with thiamylal after pretreatment with prostaglandin synthesis inhibitors. Three consecutive histamine dose-response curves were obtained in nine dogs pretreated with 5 mg/kg indomethacin; two of these nine were also pretreated with 10 mg/kg indomethacin. Seven of the nine dogs were pretreated with 4 mg/kg sodium meclofenamate; four of these seven were also pretreated with 12 mg/kg. All dogs had tachyphylaxis at high concentrations of histamine regardless of inhibitor used. Pretreatment with indomethacin while the dogs were under alpha-chloralose-urethan anesthesia gave similar results. Histamine tachyphylaxis was also studied both in the presence and in the absence of indomethacin in tracheal smooth muscle strips obtained from seven additional dogs. A decrease in the median effective dose to histamine was observed in the indomethacin-treated strips, but tachyphylaxis to histamine remained. We conclude that prostaglandin synthesis inhibition does not reverse histamine tachyphylaxis either in vivo or in vitro. Thus the mechanism of histamine tachyphylaxis remains unexplained.

Airway Resistance↗
PubMed1994

Effect of magnitude of airway responsiveness and therapy with inhaled corticosteroid on histamine tachyphylaxis in asthma.

Histamine challenge testing is used to measure airway responsiveness in asthma. Histamine tachyphylaxis has been demonstrated after repeated challenges in mild asthmatics not using inhaled corticosteroid. Other studies, using subjects with variable severity of asthma, have not demonstrated histamine tachyphylaxis. Forty patients with stable asthma were studied and stratified according to severity of airway hyperresponsiveness and use of inhaled corticosteroid, to examine the effects of these factors on histamine tachyphylaxis. Airway responsiveness was measured as the histamine provocative concentration causing a 20 percent fall in FEV1 (PC20). Twenty subjects had mildly increased airway hyperresponsiveness (PC20 > 1 mg/ml), of whom 10 were using inhaled corticosteroid. Twenty subjects had moderate to severely increased airway hyperresponsiveness (PC20 < 1 mg/ml), of whom 10 were using inhaled corticosteroid. On each of two study days, 1 week apart, two histamine challenges were performed 1 h apart. Histamine tachyphylaxis was found for the entire group on both study days. The geometric mean PC20 increased from 1.0 mg/ml (percent SEM 1.2) to 1.3 mg/ml (percent SEM 1.2) 1 h later on day 1 (p < 0.0005), and 1.1 mg/ml (percent SEM 1.2) to 1.3 mg/ml (percent SEM 1.2) 1 h later on day 2 p < 0.05). Subgroup analysis demonstrated that tachyphylaxis only occurred consistently in subjects with mildly increased airway hyperresponsiveness not receiving inhaled corticosteroid. In this group, the PC20 increased from 2.2 mg/ml (percent SEM 1.2) to 3.2 mg/ml (percent SEM 1.2) on day 1 (p < 0.001), and from 2.5 mg/ml (percent SEM 1.3) to 3.4 mg/ml (percent SEM 1.2) on day 2 (p < 0.05). This study confirms that histamine tachyphylaxis occurs in asthmatics, but is consistently present only in mild, noncorticosteroid-dependent asthmatics.

Administration, Inhalation↗
PubMed2005

Dual reuptake inhibitors incur lower rates of tachyphylaxis than selective serotonin reuptake inhibitors: a retrospective study.

BACKGROUND: The notion that selective serotonin reuptake inhibitors (SSRIs) may be associated with higher relapse rates than other antidepressants during maintenance treatment (tachyphylaxis) has been discussed for years, but to date there is little or no empirical evidence confirming this phenomenon. In this study, we systematically assessed prior anti-depressant treatment history in a cohort of depressed patients who presented for outpatient psychiatric treatment. Rates of tachyphylaxis were compared in venlafaxine and tricyclic antidepressants (TCAs), which act as dual reuptake inhibitors, versus SSRIs. METHOD: 237 patients who presented for treatment at the Rhode Island Hospital Department of Psychiatry's outpatient practice and were diagnosed with DSM-IV major depressive disorder were interviewed with the semistructured Treatment Response to Antidepressant Questionnaire. This cohort reported having undergone 326 prior SSRI trials, 47 prior venlafaxine trials, and 35 prior trials with a TCA. Rates of tachyphylaxis as a function of antidepressant class were compared. RESULTS: Rates of tachyphylaxis were significantly lower (chi(2) = 6.77, df = 1, p = .01) with the dual reuptake inhibitors venlafaxine and TCAs (3 [3.7%] of 82) compared to rates of tachyphylaxis with SSRIs (46 [14.1%] of 326). CONCLUSION: These results provide preliminary evidence that dual reuptake inhibitors may incur lower rates of tachyphylaxis than SSRIs. By virtue of the retrospective and non-random design of the study, these results warrant confirmation.

Ambulatory Care↗
PubMed1988

[Bronchial adrenergic receptors and asthma. Tachyphylaxis and its prevention].

The majority of the clinical studies in healthy volunteers have shown that chronic inhalation or oral intake of sympathomimetics causes tachyphylaxis of the bronchial beta adrenergic receptors. We have observed in healthy subjects individual differences in the propensity to develop beta-adrenergic tachyphylaxis during a prolonged treatment with sympathomimetics. There was no relation between the development of beta-adrenergic tachyphylaxis and changes in bronchial responsiveness to methacholine. The problem is much more complex in the asthmatic patients. Several well controlled studies have however shown that chronic administration of sympathomimetics results in a significantly decreased sensitivity of the bronchial beta adrenergic receptor. This tachyphylaxis is mainly demonstrable as a shorter duration of action of the sympathomimetics. The clinical relevance of the beta adrenergic tachyphylaxis induced by prolonged treatment with sympathomimetics is probably minimal and has no relation with the relative resistance to sympathomimetics observed during acute severe asthma. Corticosteroids, given orally or parenterally, restore the sensitivity of the beta adrenergic receptors. In a double blind, placebo controlled study in healthy subjects we have observed that ketotifen prevents the development of a tachyphylaxis of the bronchial beta adrenergic receptor during prolonged treatment with inhaled sympathomimetics.

Adrenal Cortex Hormones↗
PubMed1984

Angiotensin tachyphylaxis in the isolated rabbit aorta.

The effect of modifications of the N-terminal end of the angiotensin II (AII) molecule on its ability to induce tachyphylaxis in the isolated rabbit aorta was studied by analyzing the effects of several analogs of AII. No tachyphylaxis to AII was observed, but (1-sarcosine)-AII, (1-guanido-acetic)-AII and (1-glycine)-AII induced marked tachyphylaxis. (1-Betaine)-AII, (2-lysine)-AII, (2-ornithine)-AII and (1-sarcosine,2-lysine)-AII were unable to induce tachyphylaxis in the rabbit aorta. A positively charged N terminus and the guanidino group of the Arg2 side chain appear to be needed for the manifestation of the tachyphylactic property, while the Asp1 side chain is responsible for the absence of tachyphylaxis to AII. It is proposed that the analogs that are able to induce tachyphylaxis, after binding to the receptor to produce the agonistic response, induce a slow conversion of the hormone-receptor complex into a tachyphylactic state, and that this conversion is promoted by the interaction of the N terminus and the guanidino group of the analog with their complementary sites.

Angiotensin II↗
PubMed1977

Requirements for angiotensin tachyphylaxis in smooth muscles.

The ability of angiotensin II (AII) and of seven N-terminally modified peptide analogs to induce tachyphylaxis in isolated preparations of the rat uterus and the guinea-pig ileum was found to correlate well with the degree of amino group protonation. No correlation was found between tachyphylaxis and the affinity for the rat uterus receptors, as measured by the reciprocals of ED50 values. Dissociation between the tachyphylactic property and receptor affinity in the rat uterus was also evident by lowering the calcium concentration in the medium, which resulted in increased tachyphylaxis without significant changes in ED50 values. In the guinea-pig ileum, tachyphylaxis correlated with the reciprocal of ED50, but there was a better correlation with amino group protonation. [6-Pyrazolylalanine] AII was approximately as tachyphylactic as AII in both smooth muscles studied, indicating that protonation of the histidine side-chain may not be important for the manifestation of tachyphylaxis. The recovery of the guinea-pig ileum for AII tachyphylaxis was not affected by repeated treatments with BaCl2, but it was partially impaired by [Suc1]AII, des-Asp-AII, bradykinin and histamine.

Angiotensin II↗
PubMed1982

Fading and tachyphylaxis to the contractile effects of substance P in the guinea-pig ileum.

Substance P (SP) caused an immediate and vigorous contraction of the longitudinal smooth muscle layer of the guinea-pig ileum. The contractile response to SP, unlike that to acetylcholine or histamine was not maintained but faded to baseline levels in about 6 min. When 0.3-1.0 nM SP was added the fading time was shorter than 6 min and tachyphylaxis did not develop. Higher concentrations of SP produced fading times of about 6 min that could not be increased even by adding extremely high concentrations of the peptide, up to 1800 nM. Short fading times and the lack of development of tachyphylaxis are the result of the rapid adsorption and/or metabolism of SP. The addition of exogenous peptidases such as pronase, chymotrypsin and an extract of black widow spider venom gland dramatically increased the rate of degradation of SP, shortened the fading response and blocked the development of tachyphylaxis. Tetrodotoxin and atropine reduced the fading time by 25%, while eserine increased its duration several-fold; these findings are consistent with the existence of a cholinergic nerve component in the mediation of some of the effects of SP receptor and, in part, to adsorption and metabolism of the peptide. The magnitude of the tachyphylaxis to SP was proportional to the concentration of the desensitizing dose of the peptide and was specific to SP and to the related peptide physalaemin; no cross-tachyphylaxis towards other agents was found.

Animals↗
PubMed1988

Angiotensin tachyphylaxis in normal and everted rings of rabbit aorta.

The development of tachyphylaxis to angiotensin II and to [1-sarcosine]angiotensin II ([Sar1]angiotensin II) was studied in rabbit aorta helical strips, normal rings and everted rings, with and without a functional endothelium. Normal rings developed tachyphylaxis to both angiotensin II and [Sar1]angiotensin II, helical strips only to [Sar1]angiotensin II and everted rings did not show tachyphylaxis. The presence or absence of a functional endothelium had no effect on the development of tachyphylaxis in any of the preparations. Measurement of the intraluminal pH of the normal rings with an antimony minielectrode showed that under steady state conditions there was a pH gradient between the intima side of the vessel wall and the outside bath medium. This could be responsible for the greater susceptibility of the normal rings to tachyphylaxis.

Angiotensin II↗
PubMed1996

Tachyphylaxis develops to bradykinin-induced plasma extravasation in the rat.

Bradykinin, an inflammatory mediator produced from plasma kallikreins, has potent effects on vascular functions, including increasing plasma extravasation and vasodilation. Attenuation in the response (desensitization to maintained exposure or tachyphylaxis to repeated administration) to bradykinin actions on synovial vasculature, a critical variable with respect to the role of bradykinin in sustained or chronic synovial inflammation, has not been elucidated. In the present study, we determined if tachyphylaxis and desensitization for bradykinin-induced plasma extravasation in the knee joint occur. Bradykinin-induced plasma extravasation into the knee joint cavity was determined spectrophotometrically by measuring the concentration of Evans blue dye extravasation into the joint perfusate. To examine for the development of tachyphylaxis, perfusion of bradykinin (160 ng/ml) was repeated after a 40-min wash with normal saline. Continuous intra-articular perfusion of bradykinin produced an increase in plasma extravasation that remained relatively stable with only a small, approximately 15 percent, decrease over 170 min. On the other hand, the levels of plasma extravasation produced by intermittent perfusion of bradykinin were dramatically lower than that induced by the first exposure (i.e., tachyphylaxis). We conclude that bradykinin-induced plasma extravasation develops marked tachyphylaxis but only minimal desensitization.

Animals↗
PubMed1978

Magnitude, dose-requirement and mode of development of tachyphylaxis to suxamethonium in man.

Tachyphylaxis to suxamethonium infused at a constant rate was studied in 15 surgical patients under enflurane-nitrous oxide-oxygen anaesthesia. The compound electromyographic response of the adductor pollicis muscle to stimulation of the ulnar nerve was monitored. A short-lasting and a long-lasting nearly steady state were observed in Phase I and in Phase II, respectively, during both of which a constant infusion resulted in a constant block. Tachyphylaxis occurred during the transition of phases, beginning after infusion of 1.4 +/- 0.6 (SD) mg kg-1 of suxamethonium, and 36 +/- 14 (SD) minutes of exposure. Tachyphylaxis peaked after 2.6 +/- 1.3 (SD) mg kg-1, and 72 +/- 38 (SD) minutes of exposure. The maximum gain in neuromuscular transmission from the initial maintenance level of block as the result of tachyphylaxis was 53 +/- 24 (SD) % of the control. The results are thought to reconcile previously reported conflicting clinical observations on tachyphylaxis.

Adult↗
PubMedDate not supplied

Tachyphylaxis to 5-hydroxytryptamine in perfused kidneys from spontaneously hypertensive and normotensive rats.

Isolated perfused kidneys from 4- to 6-month-old spontaneously hypertensive rats (SHR, Japanese strain) exhibit increased "vascular reactivity" to 5-hydroxytryptamine (5-HT) and a slower rate of development of tachyphylaxis to this substance when compared with kidneys from normotensive Wistar-Kyoto (WKY) rats. We investigated the possibility that the reduced rate of development of tachyphylaxis could be related to a interaction of 5-HT with adrenergic mechanisms or with endogenous 5-HT. Tachyphylaxis was induced by repeated administration of 5-HT to kidneys from SHR and WKY rats. This procedure did not affect vasoconstrictor responses evoked by norepinephrine. The development of tachypylaxis to 5-HT in kidneys from SHR and WKY rats was not changed by chemical sympathectomy with 6-hydroxydopamine. Treatment of SHR with para-chlorophenylalanine did not affect their blood pressure or the development of tachyphylaxis to 5-HT. These results indicate that delayed tachyphylaxis to 5-HT in kidneys of SHR is not due to an interference with adrenergic mechanisms and does not depend on endogenous 5-HT levels. The phenomenon represents an unusual modification of vascular smooth muscle exposed to chronic high pressure, but it is unlikely that the vasoconstrictor effects of 5-HT contribute to the maintenance of hypertension in the SHR.

Animals↗
PubMed1961

Tachyphylaxis to the antitetanus activity of some phenothiazine compounds.

Although chlorpromazine and acepromazine were the most potent suppressants of local tetanus induced in rabbits by intramuscular injection of the toxin of Cl. tetani, repeated injections lost their effect (tachyphylaxis) and sometimes even increased muscle activity, as did single large injections of either of the two drugs. As neither tachyphylaxis nor stimulation occurred in spinal animals, these effects might arise from an action in the brain-stem reticular formation on which chlorpromazine has been shown to have both inhibitory and excitatory effects. The possible cause of the tachyphylaxis is discussed. Evidence is advanced to support the view that tachyphylaxis can occur when chlorpromazine is used in the treatment of tetanus in man. Methotrimeprazine was more potent than chlorpromazine, but less prone to induce tachyphylaxis. These qualities rendered it more desirable for clinical use than the other two compounds.

Animals↗