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PubMed1991

Effects of colchicine on the development of tachyphylaxis to calcitonin gene-related peptide in the guinea pig heart.

Calcitonin gene-related peptide (CGRP) induced a concentration-dependent positive inotropic and chronotropic effect on the spontaneously beating right atrium subject to tachyphylaxis upon extended incubation. This stimulatory effect was mimicked by capsaicin. After incubation with colchicine there was a marked attenuation of the decline in the prolonged response to CGRP or capsaicin and no development of CGRP tachyphylaxis. Colchicine incubation did not influence the capsaicin-induced stimulation of the frequency or CGRP outflow in whole heart preparations. Thus, the present data suggest that the development of CGRP tachyphylaxis is a specific receptor-mediated event which can be inhibited by colchicine, probably by disruption of membrane bound proteins.

Animals↗

PubMed1976

A pharmacological study of the angiotensin receptor and tachyphylaxis in smooth muscle.

The interaction of angiotensin with its receptor has been studied on the basis of the tachyphylaxis shown by the rat uterus towards angiotensin II when pH and Ca2+ concentration are below physiological levels. 14C-Angiotensin binding and 45Ca2+-uptake investigations suggest tachyphylaxis to be due to increased binding at low pH and Ca2+ concentration. Studies with alkylating (affinity labeled) angiotensin derivatives containing the N-mustard chlorambucil suggest a "Charnière type" inhibition at the Ca-binding site of receptor and an irreversible inhibition at an anionic site. Angiotensin inhibitors containing chlorambucil do not alkylate tissue but are competitive inhibitors suggesting that the aromatic side chain in angiotensin may induce conformational changes in the receptor. The results obtained lead to a logical model for the angiotensin receptor allowing for normal activation by the hormone as well as for production of tachyphylaxis.

Animals↗

PubMed1976

Tachyphylaxis and angiotensin receptors.

Angiotensin tachyphylaxis was studied in the isolated guinea pig ileum under isometric conditions. 2. In tachyphylactic organs, the initial phasic response to angiotensin was abolished, while the tonic component of the response became faster in its onset and in its reversal (relaxation). 3. The relaxation of non-tachyphylactic organs after angiotensin washout was significantly slower than with bradykinin, des-amino-angiotensin and hexanoyl-angiotensin. This difference did not occur in tachyphylactic organs. 4. There was no correlation between production of tachyphylaxis or rate of relaxation after washout and the partition coefficient of the four peptides in an organic:aqueous solvent system. 5. It is suggested that tachyphylaxis depends on a slowly reversible alteration of a calcium translocation step in the stimulus-response coupling.

Angiotensin II↗

PubMed1997

Pharmacokinetic nature of tachyphylaxis to lidocaine: peripheral nerve blocks and infiltration anesthesia in rats.

Tachyphylaxis to peripheral neural blockade was determined with repeated injections of a constant dose of lidocaine in three experimental models: sciatic nerve block, produced by intraneural or extraneural injections, and infiltration anesthesia. A decrease in the duration of the subsequent blocks was used as the index of tachyphylaxis development. The anesthetic content in the nerve or skin was determined using radiolabeled lidocaine. Repeated injections of a constant dose of lidocaine resulted in a marked decrease in the duration of the blocks. Accelerated decline in lidocaine content of nerve or skin was observed with repeated blocks. Our data show that tachyphylaxis rapidly develops with both sciatic nerve blocks and infiltration anesthesia. The data also suggest that the mechanism is largely pharmacokinetic in nature.

Anesthesia, Local↗

PubMed1997

Inhibitory effect of indomethacin on tachyphylaxis in response to acetaldehyde-induced bronchoconstriction in patients with asthma.

BACKGROUND: Acetaldehyde, a main factor in alcohol-induced asthma, causes bronchoconstriction indirectly through histamine release; and tachyphylaxis in response to repeated inhalation of acetaldehyde is observed in patients with asthma. OBJECTIVE: The study was designed to clarify the mechanism of tachyphylaxis in response to acetaldehyde-induced bronchoconstriction. METHODS: We investigated the bronchial response to inhaled acetaldehyde in 10 patients with asthma who were treated with indomethacin in a double-blind, randomized, placebo-controlled, crossover fashion. RESULTS: The mean acetaldehyde concentration causing a 20% fall in FEV1 with placebo increased significantly from 13.0 mg/ml (geometric SEM = 0.115) to 31.1 mg/ml (geometric SEM = 0.069) over a period of 1 hour (p < 0.01), whereas there was a slight but not significant tachyphylaxis during indomethacin treatment. The tachyphylactic effect, expressed as logarithmic value of the second PC20 minus logarithmic value of the first PC20, was significantly (p < 0.05) reduced from 0.380 (0.066) with placebo treatment to 0.148 (0.094) with indomethacin treatment. CONCLUSION: These results suggest an important role of cyclooxygenase pathway products in decreased response to repeated inhalation of acetaldehyde in patients with asthma.

Acetaldehyde↗

PubMed2002

Local nitric oxide release does not affect tachyphylaxis to angiotensin II in dorsal hand veins in man in the presence of prostaglandin synthesis inhibition.

AIMS: Local prostaglandin (PG) production contributes to tachyphylaxis to angiotensin II (ANGII) in veins. Our aim was to assess the hypothesis that local nitric oxide (NO) generation is also, in part, responsible for tachyphylaxis to ANGII in veins, using the Aellig dorsal hand vein technique. METHODS: Eight healthy male volunteers received 600 mg of aspirin (orally) to inhibit PG production. The venoconstrictor effects of ANGII and noradrenaline (NA) were then compared in dorsal hand veins during co-infusion of the NO synthase inhibitor L-NMMA or saline, on separate occasions. RESULTS: ANGII and NA produced a similar degree of initial venoconstriction. However, the response to ANGII was significantly attenuated by 12 min compared with NA (AUC 147 +/- 38 vs 196 +/- 40, respectively; [95% confidence interval for difference: 7, 92], P = 0.02). Infusion of L-NMMA did not influence the response to ANGII or NA (P = 0.2 and P = 0.3, respectively). CONCLUSIONS: Tachyphylaxis to ANGII in dorsal hand veins is not dependent on local NO release.

Angiotensin II↗

PubMed1999

Duration of tachyphylaxis in response to methacholine in healthy non-asthmatic subjects.

It is well recognized that bronchial responsiveness to methacholine is reduced after methacholine-induced bronchoconstriction in non-asthmatic subjects, but not in asthmatic subjects. However, it is unknown how long the methacholine tachyphylaxis lasts. The present study was conducted to elucidate duration of the methacholine tachyphylaxis in healthy non-asthmatic subjects. Measurements of methacholine responsiveness were repeated six times at intervals of 1 h and 1, 2, 3 and 7 days in eight healthy non-asthmatic young female subjects in whom methacholine concentrations causing a 20% fall in forced expiratory volume in 1 sec (FEV1; PC20-Meth) were 40 mg/mL or less. Geometric mean value (GSEM) of PC20-Meth was 10.6 (1.44) mg/mL at the first challenge, 63.4 (1.85) at the 1-h interval, 50.2 (1.67) at the 1-day interval, 49.7 (1.68) at the 2-day interval, 17.3 (1.51) at the 3-day interval and 13.1 (1.44) mg/mL at the 7-day interval. The values at intervals of 1 h to 3 days were significantly greater than the initial value. These results indicate that measurements of methacholine responsiveness should be separated by at least 7 days to avoid the tachyphylaxis when the tests are repeated in non-asthmatic subjects.

Adult↗

PubMed2001

Tachykinin-induced bronchoconstriction in sheep is NK-1 receptor mediated and exhibits tachyphylaxis.

OBJECTIVE: Tachykinins are mediators of airway hyper-reactivity and inflammation. There is in vitro evidence that ovine responses to tachykinins correlate closely to human responses. This study was designed to characterize the effect of intravenously administered tachykinins on sheep lung resistance in vivo to determine the effect of dose timing on reproducibility of responses and the induction of tachyphylaxis. We then used this information to help further characterize the response with several pharmacological agents. METHODOLOGY: Substance P (SP) was administered by infusion to conscious merino ewes and lung resistance (RL) was measured. Infusions were given at 30, 60, 120 min and 24 h intervals. The effect of various agents on the response to SP was then assessed. RESULTS: Substance P led to a transient increase in RL, mean (+/- SEM) 754.8 (+/- 139)% of baseline, with marked tachyphylaxis at 30, 60 and 120 min. Phosphoramidon increased the peak response to 1151.5 +/- 196%. Atropine and CP 96 345 abolished the response to SP, while indomethacin, sodium cromoglycate and pyrilamine had no significant effect. Substance P had a greater effect on RL than did neurokinin A. CONCLUSIONS: Substance P increases RL in sheep via a cholinergic mechanism which is mediated by NK-1 receptors, and is subject to tachyphylaxis. These findings have implications for the design of studies using the ovine model in the evaluation of tachykinin antagonists as potential therapeutic agents.

Airway Resistance↗

PubMed1992

Alloxan diabetes blocks noradrenergic tachyphylaxis in the isolated rabbit kidney--effects of insulin.

Normal and alloxan treated diabetic rabbit kidneys were perfused with Krebs-Henseleit solution in a non-recirculating system and the effects of norepinephrine (NOR) 10(-6)M were tested by infusion of this drug for three subsequent periods of 20 min each, with an interval of 10 min for drug wash-out. In the control kidneys the infusion of NOR promoted an intense vasoconstriction, which was less intense during the second and the third periods. This was known as tachyphylaxis. In contrast to the controls, kidneys from diabetic animals did not show tachyphylaxis to NOR, but when insulin was added to the perfusate, tachyphylaxis appeared. Normal kidneys perfused with hyperosmolar solutions show, as in controls, the same phenomenon. The data presented here demonstrate a defect of adrenergic vascular receptors in alloxan treated kidneys, which can be acutely reversed by insulin. These facts are of importance for the understanding of the vascular disease in diabetes.

Animals↗

PubMed1989

Tachyphylaxis to local anesthetics does not result from reduced drug effectiveness at the nerve itself.

Possible development of tachyphylaxis to local anesthetics in the nerve itself (time-dependent change in axonal conduction properties) was studied in the aortic nerve of eight rabbits anesthetized with urethane. The nerve was immersed in Tyrode solution with or without bupivacaine at pH 7.4 and 38 degrees C in a trough molded from the surrounding tissues. After control measurements the nerve was exposed to increasing bupivacaine concentrations until complete nerve block at minimal blocking concentration. Subsequently, bupivacaine concentrations were reduced and kept constant for 4 h (partial block). Finally, intact nerve function was confirmed after bupivacaine washout with Tyrode solution. For quantification total nerve activity was recorded continuously and related to drug concentrations. Two findings argue against the occurrence of tachyphylaxis at the nerve itself: 1) nerve activity decreased rather than increased over time in the presence of constant bupivacaine concentrations during partial block; and 2) for the same bupivacaine concentration, nerve activity during partial block was always lower than during the initial blocking experiments. Thus, drug effectiveness increased rather than decreased over time, which cannot be reconciled with the theory that tachyphylaxis might be mediated by changes in axonal conduction properties.

Anesthetics, Local↗

PubMed1983

Naloxone reversal of 5-hydroxytryptamine tachyphylaxis in humans.

The dorsal hand vein, a suitable substrate for testing the effects of spasmogenic amines in vivo, exhibits a rapid tachyphylaxis to 5-hydroxytryptamine (5-HT)-induced vasoconstriction in healthy subjects. In the tachyphylactic vein, naloxone promptly restores and sometimes potentiates the sensitivity to 5-HT. The local opioid system could be excited by the 5-HT-induced release of noradrenaline (NA) into the neuromuscular junction, thereby participating in the 5-HT tachyphylaxis. Naloxone, antagonizing this mechanism, restores the 5-HT spasm. Therefore, the 5-HT tachyphylaxis could be due to an increased opioid modulation and not (or perhaps partially) to a depletion of the NA in the sympathergic neuron.

Adult↗

PubMed1991

Role of prostanoids in the increased vascular responsiveness and delayed tachyphylaxis to serotonin in the kidney of spontaneously hypertensive rats.

The isolated and perfused kidney of the spontaneously hypertensive rat (SHR) exhibits an increased vascular reactivity and a delayed tachyphylaxis to serotonin (5-hydroxytryptamine) when compared with normotensive Wistar-Kyoto (WKY) rats. Experiments were designed to determine the involvement of products of cyclooxygenase in the augmented response and delayed tachyphylaxis to serotonin in the SHR kidney. Kidneys taken from male, 4-month-old SHR and WKY rats were studied in parallel and perfused with Tyrode's solution at constant, optimal flow rates. Vasoconstrictor responses were recorded as increases in perfusion pressure. The vasoconstrictor responses to serotonin, norepinephrine and angiotensin II were exaggerated in the SHR kidney compared with that of the WKY rat. Indomethacin did not affect the responsiveness to serotonin in the kidney of the SHR but increased the responses to the higher doses of the monoamine in the kidney of the WKY rats. Indomethacin accelerated the tachyphylaxis to serotonin in the SHR but delayed it in the WKY rats. Dazoxiben did not alter the responses to serotonin in the SHR. Responses to norepinephrine in the kidneys from both strains were not affected by indomethacin. The inhibitor of cyclooxygenase reduced the responses to angiotensin II in the kidneys from both hypertensive and normotensive animals. The basal and stimulated (serotonin, norepinephrine and angiotensin II) release of prostaglandins were measured by radioimmunoassay. The basal release of prostacyclin was lower, but that of thromboxane A2 higher, in the kidneys of SHR compared with those of WKY rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗

PubMed2004

An investigation of components of variance and tachyphylaxis in a placebo-controlled intravenous tyramine study.

AIMS: To explore inter- and intra-volunteer variability for the dose of intravenous tyramine eliciting a 20 mmHg increase in systolic blood pressure from baseline (TYR20) and to evaluate potential tachyphylaxis. METHODS: Twelve healthy volunteers received blinded placebo-controlled ascending and descending sequences of intravenous tyramine injections on two separate occasions. The TYR20 was derived by linear interpolation, using three interventions to deal with missing data. RESULTS: Analysis of covariance (ancova) demonstrated no significant difference in TYR20 between sequences, regardless of the missing data methodology applied. Inter-volunteer variability was 2.4-3.4 times larger than within-volunteer variability. No evidence of tachyphylaxis was seen using either the sign test or generalized additive models. CONCLUSIONS: Since inter-volunteer variability was greater than intra-volunteer variability, a crossover study design would be a more efficient study design, and the descending sequence of injections could be omitted since tachyphylaxis was not demonstrated.

Adult↗

PubMed1992

Patterns of development of tachyphylaxis in patients with haemophilia and von Willebrand disease after repeated doses of desmopressin (DDAVP).

When patients with mild haemophilia or von Willebrand disease (vWD) are repeatedly treated with desmopressin (DDAVP) at relatively short time intervals, some of them may become less responsive or unresponsive. The development of tachyphylaxis would limit the usefulness of DDAVP in clinical management of these patients. On the other hand, tachyphylaxis is not consistent, and its patterns of development are unknown. The aim of this study was to evaluate in controlled conditions the occurrence of tachyphylaxis by giving intravenous DDAVP (0.3 microgram/kg) on four consecutive days to a selected group of patients with mild haemophilia A (n = 22) and type I vWD (n = 15). After each dose, we measured parameters known to change after DDAVP, i.e. factor VIII coagulant activity, bleeding time, von Willebrand factor antigen, ristocetin cofactor and tissue-type plasminogen activator antigen. We found that on average the responses obtained after the second dose of DDAVP were approximately 30% less than those obtained after the first, but were not further reduced after the third and fourth dose. At all time intervals after DDAVP, patients with vWD responded relatively better than patients with haemophilia, and there were fewer vWD patients who responded poorly or became unresponsive. In vWD patients there were no significant changes in the bleeding time responses and in blood pressure and heart rate. The clinical implications of these findings are that repeated doses of DDAVP can be given efficaciously to many patients (particularly to those with vWD), even though responses lower than those seen after the first dose should be expected.

Adult↗

PubMed1975

Lack of cardiac or bronchodilator tachyphylaxis to isoprenaline in the dog.

1. Tachyphylaxis to heart rate and bronchodilator effects of (plus or minus)-isoprenaline was studied in anaesthetized open-chest dogs by 5 procedures. 2. Heart rate responses to a series of intravenous injections of isoprenaline were essentially unchanged before and after a 15 min infusion of isoprenaline (at 3 doses). 3. Heart rate and bronchodilator responses in the same animal to an intravenous injection of isoprenaline were not significantly different before and after a 30 min infusion of isoprenaline (at 2 doses). 4. Heart rate responses were relatively constant to an isoprenaline injection given every 30 min during a 4 h infusion of isoprenaline (at 3 doses), but the magnitude of the response was smallest for the largest infusion dose (highest background heart rate) and greatest for the smallest infusion dose (lowest background heart rate). 5. Heart rate and bronchodilator responses in the same animal to isoprenaline were relatively constant during a 5 h infusion of isoprenaline (at 2 doses). 6. Bronchodilator responses to intratracheally administered isoprenaline aerosol were essentially unchanged during a 4-5 h period using various doses and procedures. 7. Tachyphylaxis to the heart rate of bronchodilator effects of isoprenaline was not observed. The present data give no support to the hypothesis that tachyphylaxis to isoprenaline aerosols is an important mechanism in asthma mortality.

Aerosols↗

PubMed2005

Effects of acute administration of and tachyphylaxis to alpha,beta-methylene ATP in the guinea-pig small intestine.

The aim of the present study was to assess the acute motility effects and desensitizing activity of the stable ATP analogue and P(2X) purinoceptor agonist alpha,beta-methylene ATP (alpha,beta-meATP) and the effect of alpha,beta-meATP desensitization on nerve-mediated cholinergic responses in the guinea-pig ileum in vitro. It was confirmed that alpha,beta-meATP (1-30 microM) causes neurally-mediated, cholinergic (tetrodotoxin- and atropine-sensitive) longitudinal contractions. These responses were not influenced by the ganglionic blocking drug hexamethonium (50 microM), or a combination of the adrenergic neurone blocking drug guanethidine (3 microM), the opioid receptor antagonist naloxone (0.5 microM) and the nitric oxide synthase inhibitor N(G)-nitro-L-arginine (L-NOARG; 100 microM), but were strongly reduced or abolished by the P2 purinoceptor antagonist PPADS (30 microM) or by tachyphylaxis evoked by 10 microM alpha,beta-meATP. The contractile effect of alpha,beta-meATP (3 microM) was moderately inhibited by 10 microM and strongly suppressed by 30 microM of NF 279, an antagonist predominantly affecting P2X1 purinoceptors, but left uninfluenced by the P2X(5,7) receptor antagonist Brilliant blue G. No relaxant effect of alpha,beta-meATP was detected in the concentration range of 1-30 microM. Tachyphylaxis to alpha,beta-meATP (1-10 microM) caused a moderate inhibition of the cholinergic (atropine-sensitive) contractile response of the ileum to electrical field stimulation (5 Hz for 5 sec.). This reduction was unaltered in the presence of guanethidine, naloxone and L-NOARG. Responses to nicotine (1 or 2 microM) were not reduced by alpha,beta-meATP tachyphylaxis. It is suggested that alpha,beta-meATP-sensitive P(2X) purinoceptors are involved in the prejunctional modulation of cholinergic neurotransmission between the myenteric plexus and longitudinal smooth muscle in the guinea-pig small intestine.

Adenosine Triphosphate↗

PubMed2005

Characterization of agonist-induced motilin receptor trafficking and its implications for tachyphylaxis.

The motilin receptor (MR) is a member of the seven-transmembrane receptor family and is expressed throughout the gastrointestinal tract of humans and other species. Motilin, the natural MR peptide ligand, has profound stimulatory effects on gastrointestinal contractility, indicating a therapeutic potential for MR modulators. However, long-term clinical use of certain MR agonists is limited by tachyphylaxis, a reduced responsiveness to repeated compound exposure. This study was meant to characterize the ligand-induced endocytosis of MR and to test whether receptor trafficking contributes to tachyphylaxis. A cell-based assay was developed by fusing a green fluorescent protein (GFP) moiety to the motilin receptor, and high-content biology instrumentation was used to quantify time and dose dependence of MR-GFP endocytosis. Maximal internalization of MR-GFP was induced after 45 min of constant exposure to 80 nM motilin. This process was disrupted by nocodazole, suggesting an essential role for microtubules. Internalized MR-GFP vesicles disappeared within 15 to 45 min of motilin withdrawal but did not overlap with the lysosomal compartment, indicating that MR-GFP escaped degradation and was recycled back to the plasma membrane. It is noteworthy that the kinetics of MR-GFP redistribution varied substantially when stimulated with motilin, erythromycin, 6,9-hemiacetal 8,9-anhydro-4''-deoxy-3'-N-desmethyl-3'-N-ethylerythromycin B (ABT-229), or N-[(1S)-1-[[[(1S)-1-(aminocarbonyl)-3-phenylpropyl]amino]carbonyl]-3-phenylpropyl]-2'-(1,3-benzodioxol-5-ylmethyl)tetrahydro-1',3'-dioxo-spiro[piperidine-4,5'(6'H)-[1H][1,2,4]triazolo[1,2-a]pyridazine]-8'-carboxamide (BMS-591348) at equipotent doses for Ca(2+)-mobilization. Retardation of the intracellular MR-GFP sorting cycle seemed to correlate with the tachyphylaxis-inducing properties of each compound, but not its EC(50). These results indicate that MR internalization, desensitization, and resensitization are ligand-dependent and that appropriate screening strategies may enable the development of small molecule agonists with ideal combinations of these distinct properties.

Base Sequence↗

PubMed1977

Studies on the mechanism of tachyphylaxis to disodium cromoglycate.

The tachyphylaxis to disodium cromoglycate's (DSCG) inhibition of antigen-induced histamine release is readily demonstrable utilizing passively sensitized rat lung fragments. This tachyphylaxis to DSCG is evident whether or not calcium is present during drug preincubation. An attempt to relate the mechanism of tachyphylaxis to the DSCG-induced release of an endogenous cellular inhibitory material was unsuccessful insofar as could be demonstrated by an effect on mediator release.

Animals↗