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PubMed1996

Endothelium-dependent and NO-mediated desensitization to vasopressin in rat aorta.

1. The present study was performed to characterize the tachyphylaxis of rat aortae to vasopressin. Isometric tension generated by rat thoracic aorta sliced in 4 mm rings, was recorded. 2. Tension generated by intact rings increased with cumulative additions of vasopressin up to 10 nM (1.51 +/- 0.15 g). After this concentration, most rings lost their tension and relaxed to 1.09 +/- 0.17 g (P < 0.001) despite further addition of vasopressin. This tachyphylaxis was not observed in endothelium-denuded rings (from 2.87 +/- 0.12 g to 2.68 +/- 0.17 g). 3. Repeated administrations of supramaximal concentration (100 nM) of vasopressin confirmed an enhanced desensitization in intact rings, compared to endothelium-denuded rings. No desensitization to phenylephrine was observed in intact or in endothelium-denuded rings. 4. Dose-response curves to a V1 receptor agonist, [Phe2, Ile3, Orn8]-vasopressin, and to a V2 receptor agonist, [deamino-Cys1,D-Arg8]-vasopressin, were performed in intact preparations. An increase in tension, followed by a desensitization was observed with the V1 receptor agonist. In contrast, the V2 receptor agonist did not induce any response. 5. Pretreatment of intact aortic rings with the cyclo-oxygenase inhibitor, diclofenac (1 microM), did not prevent the desensitization to vasopressin. In contrast, NO synthase inhibition with NG-nitro-L-arginine (30 microM) resulted in an attenuated desensitization to vasopressin in intact rings (from 2.46 +/- 0.17 to 2.25 +/- 0.22 g, NS). 6. To confirm the involvement of NO, endothelium-denuded rings were pretreated with sodium nitroprusside (SNP). At a concentration of 10 nM, SNP induced a desensitization to vasopressin comparable with that observed in intact rings. 7. Pretreatment of endothelium-denuded rings with 8-bromo-cyclic GMP (100 microM) reduced maximum contraction to vasopressin without producing any desensitization. In contrast, guanylate cyclase inhibition with either LY 83,583 (10 microM) or methylene blue (10 microM) blocked completely the desensitization of intact rings to vasopressin. 8. The results suggest that the endothelium-dependent tachyphylaxis to vasopressin is due to rapid desensitization and is mediated by NO. However, it is unclear whether this effect of NO involves cyclic GMP.

Animals↗
PubMed2006

Multiple motor effects of ATP and their inhibition by P purinoceptor antagonist, pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid in the small intestine of the guinea-pig.

Adenosine 5'-triphosphate (ATP) may be an important neurotransmitter in the gastrointestinal tract. The present study examined the motor effects of exogenous ATP on longitudinally-oriented preparations of the guinea-pig isolated ileum and the influence of drugs on the ATP-induced responses. High micromolar concentrations of ATP caused two types of contraction, a phasic, cholinergic response and a tonic, tetrodotoxin-resistant contraction. The phasic contraction was reduced by hexamethonium (5x10(-5) M), but left uninfluenced by capsaicin tachyphylaxis or tachyphylaxis to alpha,beta-methylene ATP. The tonic response was resistant to atropine, hexamethonium, capsaicin, omega-conotoxin GVIA, or pretreatment with alpha,beta-methylene ATP. Both types of ATP-induced contraction were diminished or abolished by the P2 purinoceptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS, 3x10(-6) and 3x10(-5) M, respectively). In the precontracted, atropine-treated ileum ATP (10(-6)-10(-4) M) caused guanethidine-resistant relaxation. This response was not influenced by tetrodotoxin, omega-conotoxin GVIA, or NG-nitro-L-arginine, but was abolished by apamin (10(-7) M), and inhibited by PPADS (3x10(-5) M) or reactive blue 2 (10(-5) M), in a surmountable manner. A high degree of tachyphylaxis was observed with the relaxant effect of ATP (10(-5)-10(-4) M). A high concentration (3x10(-4) M) of PPADS failed to influence ileum contractions to exogenous acetylcholine or histamine. It is concluded that, in addition to its direct contractile action in the guinea-pig ileum, ATP can activate (partly preganglionic) cholinergic neurones, an effect whose mechanism is largely different from that of alpha,beta-methylene ATP. ATP also causes relaxation by a direct, probably P2Y-receptor-mediated effect on the smooth muscle. All motor effects of ATP are inhibited by the antagonist PPADS.

Acetylcholine↗
PubMed1989

Sympathetic vascular control of the pig nasal mucosa (III): Co-release of noradrenaline and neuropeptide Y.

The overflows of noradrenaline (NA) and neuropeptide Y like immunoreactivity (NPY-LI) and vascular responses upon sympathetic nerve stimulation were analysed in the nasal mucosa of pentobarbital anaesthetized pigs. In controls, a frequency-dependent increase in NA overflow was observed whereas detectable release of NPY-LI occurred only at 6.9 Hz. Parallel decreases in blood flow in the sphenopalatine artery and vein and in nasal mucosa volume (reflecting blood volume in the venous sinusoids) were observed. The laser Doppler flowmeter signal (reflecting superficial blood flow) increased upon low and decreased upon high frequency stimulation. Twenty-four hours after reserpine pretreatment and preganglionic decentralization, the NA overflow was abolished while a frequency-dependent release of NPY-LI occurred. Forty, 60 and 80% of the vasoconstrictor responses then remained upon stimulation with a single impulse, 0.59 and 6.9 Hz, respectively. Both the vasoconstriction and NPY-LI overflow, however, were subjected to fatigue upon repeated stimulation. In reserpinized animals release of NPY-LI and vasoconstrictor responses were larger upon stimulation with irregular bursts at 0.59 Hz compared to effects seen at stimulation with continuous impulses. Pre-treatment with the alpha-adrenoceptor antagonist phenoxybenzamine or the monoamine reuptake inhibitor, desipramine, enhanced NA overflow by 2-3 and 1.5 times at 0.59 and 6.9 Hz, respectively. Phenoxybenzamine significantly reduced the nerve-evoked vascular responses while the release of NPY-LI at 6.9 Hz was increased. Desipramine increased the functional responses but reduced the NPY-LI overflow. During tachyphylaxis to the vasoconstrictor effects of the stable adenosine 5'-triphosphate (ATP) analogue alpha-beta-methylene ATP (mATP) in controls, the vasoconstrictor responses as well as the NA and NPY-LI overflow to nerve stimulation were unmodified. In reserpinized animals, however, the vascular responses and the overflow of NPY-LI were reduced after mATP tachyphylaxis. These data show that both NA and NPY are released upon sympathetic nerve stimulation in the nasal mucosa in vivo and this release seems to be regulated via prejunctional alpha-adrenoceptors. The lack of effect of mATP tachyphylaxis under control conditions makes it less likely that ATP serves as a major mediator of the large nonadrenergic vasoconstrictor component.

Animals↗
PubMed1989

Capsaicin-induced vasodilatation of human coronary arteries in vitro is mediated by calcitonin gene-related peptide rather than substance P or neurokinin A.

In the present study the possible influence of capsaicin on human arterial coronary tone in vitro was studied in relation to the vasodilatory properties of calcitonin gene-related peptide (CGRP), substance P (SP) or neurokinin A (NKA). In addition, the influence of vasoactive intestinal polypeptide (VIP) and somatostatin (SOM) on the arteries was investigated. CGRP application to potassium-pre-contracted human epicardial coronary arteries (0.4-0.6 mm in inner diameter) induced a concentration-dependent, long-lasting relaxation. SP also relaxed these pre-contracted arteries, but the relaxation was transient and tachyphylaxis developed rapidly upon repeated administration. SP tachyphylaxis did not influence the relaxatory effects of CGRP. Furthermore, pre-incubation with gossypol, an inhibitor of the formation and release of endothelium-derived relaxing factors (EDRF), completely abolished the effects of SP without influencing the dilatory action of CGRP. NKA only induced a very minor relaxation of the pre-contracted arteries. Both VIP and SOM concentration-dependently relaxed the pre-contracted arteries. Capsaicin evoked a relaxation of the potassium-pre-contracted arteries. This effect was not influenced by SP tachyphylaxis or gossypol incubation. Thus, CGRP but not SP mimics the vasodilatory effects of capsaicin on human coronary arteries. This suggests that CGRP rather than SP is likely to mediate the relaxatory effects seen upon activation of cardiac sensory nerves.

Adult↗
PubMed1988

Investigation of mechanism of fade of gastrin-stimulated gastric acid secretion in the cat.

1. In conscious cats prepared with gastric fistulae gastric acid secretion in response to pentagastrin was found to reach a maximum after 45 min of stimulation, and to fade thereafter. Over the period 45-150 min of stimulation the fade was 5.4-7.8% of the maximum response per 15 min. 2. Once the response to pentagastrin had declined, acid secretion could not be restored by doubling the dose of pentagastrin, although an equisecretory dose of histamine could restore it. 3. Low doses of histamine were additive to the pentagastrin acid secretory response; they tended to prolong the peak response, but did not alter the subsequent fade of acid secretion. The histamine H1-receptor antagonist mepyramine did not affect maximal acid secretion or the fade of the pentagastrin response. 4. The beta-adrenoreceptor antagonist propranolol increased the secretory response to pentagastrin, whilst the alpha-adrenoreceptor antagonist phentolamine was without effect. Neither agent altered the fade of the pentagastrin response. Isoprenaline tended to inhibit pentagastrin-stimulated acid secretion and increase the rate of fade of the response. 5. The 5-hydroxytryptamine (5-HT) receptor antagonist methylsergide slightly enhanced the acid secretory response to pentagastrin, but did not alter the fade of the response. A low dose of 5-HT did not alter pentagastrin-stimulated acid secretion, whilst a higher dose of 5-HT inhibited it. 6. Tetra-, penta- and pentadecagastrin demonstrated tachyphylaxis, i.e. progressively reduced responses upon repeated stimulation, whilst histamine did not. A low dose of histamine did not prevent tachyphylaxis of the pentagastrin response. 7. It is concluded that fade of pentagastrin-stimulated acid secretion in the conscious cat cannot be satisfactorily explained by the failure of the acid secretory mechanism, depletion of histamine, release of 5-HT, or activation of histamine H1-, alpha- or beta-adreno-, or 5-HT-receptors. The similar characteristics of fade and tachyphylaxis of gastrin-stimulated acid secretion are consistent with a common gastrin receptor inactivation or desensitization mechanism.

Animals↗
PubMed2002

Mechanisms underlying the contraction induced by bradykinin in the guinea pig epithelium-denuded trachea.

This study investigates some of the mechanisms by which bradykinin (BK) triggers contraction of epithelium-denuded strips of guinea pig trachea (GPT). Cumulative or single additions of BK, T-BK, L-BK, or ML-BK in the presence of captopril (30 microM) produced graded GPT contractions with the following rank order of potency (EC50 level): T-BK (31.3 nM) > BK (40.0 nM) > L-BK (56.0 nM) > ML-BK (77.0 nM). BK-induced contraction (100 nM) in GPT was completely inhibited by either HOE 140 or NPC 17731 with mean IC50 values of 17 and 217 nM, respectively. Addition of BK (100 nM) at 30 min intervals, induced progressive tachyphylaxis, which was complete after 4 h. The tachyphylaxis induced by BK was unaffected by L-NOARG (nitric oxide synthase inhibitor, 100 microM) or valeryl salicylate (a cyclooxygenase-1 (COX-1) inhibitor, 30 microM), but was prevented by a low concentration of indomethacin, diclofenac (non-selective COX inhibitors, 3 nM each) or by NS 398 (a COX-2 inhibitor, 10 nM). Furthermore, higher concentrations of indomethacin, diclofenac, phenidone (a lypooxygenase (LOX) and COX inhibitor), or NS 398, caused graded inhibition of BK-induced contraction, with mean IC50 values of 0.28, 0.08, 46.37, and 0.15 microM, respectively. Together, these results suggest that BK-induced contraction in GPT involves activation of B2 receptors and release of prostanoids from COX-2 pathway. Furthermore, the tachyphylaxis induced by BK was insensitive to the nitric oxide and COX-1 inhibitors, but was prevented by non-selective and selective COX-2 inhibitors, indicating a mediation via COX-2-derived arachidonic acid metabolites.

Animals↗
PubMed1992

Differential sensitivity to bradykinin of esophageal distension-sensitive mechanoreceptors in vagal and sympathetic afferents of the opossum.

1. Single-unit activity was recorded from afferent fibers in the cervical vagus and thoracic sympathetic nerves in the opossum. Seventy-six fibers that responded to balloon distension (100 mmHg for 10 s) of the smooth muscle portion of the esophagus were selected for further study. 2. Forty-nine distension-sensitive afferents were identified in the vagus nerve. The stimulus response function (SRF) of 41 fibers behaved as "low-threshold mechanoreceptors" (LTM), with mean threshold value of 0.29 +/- 0.17 mmHg and saturation pressure of 50-70 mmHg. All fibers demonstrated background activity, with a mean rate of 8.83 +/- 0.93 imp/s (range 0.5-31.25). 3. Twenty-seven distension-sensitive afferents were identified in the thoracic sympathetic chain (T6-T8) and splanchnic nerve. The SRF study revealed two types of fibers: 1) a wide-dynamic-range mechanonociceptor (WDRMN) with a mean response threshold of 3.43 +/- 0.90 mmHg (n = 15) and 2) a "high-threshold mechanonociceptor" (HTMN) with a mean response threshold of 34.93 +/- 2.70 mmHg (n = 12). The mean background activities of WDRMN and HTMN fibers were 0.5 +/- 0.13 and 0.20 +/- 0.08 imp/s, respectively. Both of these fibers had saturation pressures of > 120 mmHg. 4. The conduction velocities were measured in 14 LTM, 10 WDRMN, and seven HTMN fibers. The mean conduction velocity of LTM fibers was 5.03 +/- 1.35 m/s (range 0.97-18.00), with five unmyelinated "C"-fibers (< 2.5 m/s) and nine A-delta fibers (> 2.5 m/s). The mean conduction velocity of WDRMN fibers was 3.64 +/- 0.84 m/s (range 1.10-8.25), consisting of five C-fibers and five A-delta fibers. The mean conduction velocity of HTMN fibers was 6.22 +/- 2.35 m/s (range 1.73-24.66); three fibers were unmyelinated C-fibers, and four fibers were A-delta fibers. 5. The sensitivity to bradykinin (BK) administered systemically (1-300 micrograms/kg) was tested in LTM (n = 34), WDRMN (n = 15), and HTMN (n = 8) fibers. Twenty-six (66%) LTM fibers responded to BK, and eight (34%) fibers were insensitive to BK. All 15 WDRMN and eight HTMN fibers tested responded to BK. 6. Tachyphylaxis to repeated application of BK was tested in all three classes of fibers. The vagal LTM fibers did not exhibit tachyphylaxis when BK was given at an intervals of 10 min. The sympathetic WDRMN and HTMN fibers demonstrated partial tachyphylaxis when BK was injected at 10-min intervals, but not when BK was injected at 20-min intervals.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed2005

Interruption of homologous desensitization in cyclic guanosine 3',5'-monophosphate signaling restores colon cancer cytostasis by bacterial enterotoxins.

Bacterial diarrheagenic heat-stable enterotoxins induce colon cancer cell cytostasis by targeting guanylyl cyclase C (GCC) signaling. Anticancer actions of these toxins are mediated by cyclic guanosine 3',5'-monophosphate (cGMP)-dependent influx of Ca2+ through cyclic nucleotide-gated channels. However, prolonged stimulation of GCC produces resistance in tumor cells to heat-stable enterotoxin-induced cytostasis. Resistance reflects rapid (tachyphylaxis) and slow (bradyphylaxis) mechanisms of desensitization induced by cGMP. Tachyphylaxis is mediated by cGMP-dependent protein kinase, which limits the conductance of cyclic nucleotide-gated channels, reducing the influx of Ca2+ propagating the antiproliferative signal from the membrane to the nucleus. In contrast, bradyphylaxis is mediated by cGMP-dependent allosteric activation of phosphodiesterase 5, which shapes the amplitude and duration of heat-stable enterotoxin-dependent cyclic nucleotide accumulation required for cytostasis. Importantly, interruption of tachyphylaxis and bradyphylaxis restores cancer cell cytostasis induced by heat-stable enterotoxins. Thus, regimens that incorporate cytostatic bacterial enterotoxins and inhibitors of cGMP-mediated desensitization offer a previously unrecognized therapeutic paradigm for treatment and prevention of colorectal cancer.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1978

Sodium nitroprusside-induced hypotension in dogs. Drug sensitivity and resistance experimentally provoked by circulating blood volume alterations.

The effects of small circulating blood volume alterations on the SNP dosage required to maintain the mean arterial pressure at 70 mm Hg were studied in 6 anesthetized dogs; (A) normovolemia, (B) hypovolemia by arterial bleeding 7 ml/kg, and (C) hypervolemia by infusing 7 ml/kg whole blood. The animals became extremely SNP sensitive during hypovolemia and resistant during hypervolemia (SNP dosage A: 25.8, B: 14.7, C: 70.0 microgram/kg/min); these changes were accompanied by significant changes in cardiac output (A: 193, B: 142, C: 249 ml/kg/min). The intravenous administration of SNP with the aim of inducing hypotension generally causes a balanced pre- and afterload reduction. This balance is rather delicate and easily disturbed by small intravascular fluid changes leading to cardiac output and thus to SNP sensitivity changes. Slowly developing tachyphylaxis can be explained on the basis of such intercompartimental fluid shifts and a case of SNP tachyphylaxis reported in literature is discussed on the basis of overinfusion. SNP tachyphylaxis or resistance might be treated by preload reducing measures like phlebotomy or the administration of nitroglycerin.

Animals↗
PubMed1992

Comparison of the modulatory effect of ketotifen, sodium cromoglycate, procaterol and salbutamol in human skin, lung and tonsil mast cells.

To assess the influence of mast cell heterogeneity on the inhibition of mediator release by drugs, the effects of ketotifen, sodium cromoglycate and beta-adrenoceptor agonists were examined against IgE-dependent histamine and prostaglandin D2 release from enzymatically dispersed human skin, lung and tonsillar mast cells. At high concentrations, ketotifen was an inhibitor of histamine and prostaglandin D2 release from lung and tonsillar mast cells. No cross-tachyphylaxis with sodium cromoglycate was seen. In skin mast cells no inhibition of mediator release was observed with 1.0 microM ketotifen, above which histamine release was induced. Sodium cromoglycate was a weak inhibitor of histamine and prostaglandin D2 release from lung and tonsillar mast cells and showed tachyphylaxis. Sodium cromoglycate did not inhibit histamine and prostaglandin D2 release from skin mast cells. On the other hand, no heterogeneity was observed with the beta-adrenoceptor agonists, procaterol and salbutamol. beta-Adrenoceptor stimulants were significantly more effective in inhibiting prostaglandin D2 than histamine release. No tachyphylaxis was seen with prolongation of the incubation time before challenge. Our results suggest that human mast cells are heterogeneous with respect to the modulation of mediator release by ketotifen and sodium cromoglycate but not beta-adrenoceptor agonists.

Albuterol↗
PubMed1988

Histamine bronchoconstriction reduces airway responsiveness in asthmatic subjects.

Tachyphylaxis occurs to repeated challenges with inhaled histamine but not with inhaled acetylcholine in asthmatic subjects. This study was undertaken to determine whether prior histamine bronchoconstriction reduces airway responsiveness to inhaled acetylcholine in mild asthmatic subjects demonstrating histamine tachyphylaxis. All subjects developed histamine tachyphylaxis with repeated histamine challenge. The mean histamine PC20 increased from 3.74 to 5.92 mg/ml (p less than 0.005) when the histamine challenges were separated by 1 h. Prior acetylcholine bronchoconstriction did not reduce airway responsiveness to subsequent inhalation of either acetylcholine or histamine in these subjects. However, histamine inhalation did reduce airway responsiveness to acetylcholine in all subjects. The mean acetylcholine PC20 following acetylcholine inhalation was 3.37 mg/ml (%SD 2.17) and this increased to 7.76 mg/ml (%SD 1.80) after histamine inhalation (p less than 0.0005). Thus, this study demonstrates that prior histamine, but not acetylcholine, bronchoconstriction can partially protect against bronchoconstriction caused by both histamine and acetylcholine. Therefore, reduced airway responsiveness caused by histamine bronchoconstriction is specific for histamine and is not due to bronchoconstriction per se. However, the reduced airway responsiveness following histamine bronchoconstriction, is nonspecific.

Acetylcholine↗
PubMed2005

Acute sustained hypoxia suppresses the cough reflex in healthy subjects.

RATIONALE: An intact cough reflex is important to protect the lung from injurious substances and to clear excess secretions. A blunted cough reflex may be harmful or even fatal in respiratory disease. Hypoxia is common in respiratory disorders and has been shown to have depressant effects on respiratory sensation and ventilation. We hypothesized that it might also suppress the cough reflex. OBJECTIVES: To determine if acute hypoxia increases cough threshold and cough tachyphylaxis to inhaled capsaicin. METHODS: On two occasions, 16 healthy subjects inhaled a saline control followed by doubling doses of capsaicin aerosol (range, 0.49-500 microM) every minute for 15 s during controlled ventilation (approximately 190% baseline) with isocapnic hypoxia (SpO2, approximately 80%) or isocapnic normoxia, in random order. When a subject responded to a dose with five or more coughs, the next doubling dose of capsaicin was administered continuously for 60 s to assess acute tachyphylaxis. MAIN RESULTS: The capsaicin concentration required to elicit five coughs was significantly higher during isocapnic hypoxia compared with normoxia (29.6 +/- 16.0 vs. 23.4 +/- 15.6 microM, p = 0.01). During continuous capsaicin inhalation, significantly more coughs were evoked in the first 10 s compared with the last (2.3 +/- 0.3 vs. 1.3 +/- 0.3, p < 0.01), indicating cough tachyphylaxis. However, the decrease was the same during hypoxia and normoxia (-1.3 +/- 0.4 vs. -0.9 +/- 0.6, p = 0.54). CONCLUSIONS: Acute isocapnic hypoxia suppresses cough reflex sensitivity to inhaled capsaicin. This finding raises the possibility that the cough reflex may be impaired during acute exacerbations of hypoxic-respiratory disorders.

Acute Disease↗
PubMed2006

In vitro modeling of the clinical interactions between octreotide and 111In-pentetreotide: is there evidence of somatostatin receptor downregulation?

UNLABELLED: Some authors have suggested that chronic octreotide use enhances the efficiency of radiolabeled somatostatin receptor (sst) imaging. Conversely, desensitization of sst on tumor tissue (tachyphylaxis) may occur occasionally in patients on chronic octreotide therapy. Assuming that chronic exposure to octreotide induces tachyphylaxis, we hypothesized that chronic exposure of sst subtype 2 (sst2)-expressing cells to octreotide would downregulate binding of 111In-pentetreotide to sst and that this downregulation would be due to a reduction in the gene copy number for sst2. METHODS: The clinical scenarios of acute (24 h) and chronic (2 wk) octreotide use, followed by either nuclear imaging exposure (8.6 pmol/L) or therapeutic exposure (510 pmol/L) to (111)In-pentetreotide, were modeled in vitro. Receptor binding in IMR-32 human neuroblastoma cells (high sst2 expression) and PANC-1 human pancreatic cancer cells (no detectable sst2 expression) was evaluated. Gene copy numbers for sst subtypes 1-5 in IMR-32 cells were determined by quantitative polymerase chain reaction. RESULTS: Acute or chronic octreotide exposure at low or high doses did not significantly alter sst2 gene copy numbers or binding of either the diagnostic dose or the therapeutic dose of 111In-pentetreotide. CONCLUSION: In vitro exposure of cells to low or high doses of octreotide for 1-14 d does not result in the development of either tachyphylaxis or upregulation of sst as assessed by changes in gene expression or in high-affinity binding.

Cell Line, Tumor↗
PubMed1991

Changes in uterine venous prostaglandin F metabolites following intravenous infusion of ritodrine in sheep.

The effectiveness of the beta-adrenergic receptor agonist ritodrine as a tocolytic agent is limited by the tachyphylaxis that occurs with its sustained usage. In order to understand the nature of this tachyphylaxis, we investigated the effect of ritodrine on uteroplacental prostaglandin (PG)F2 alpha production in pregnant sheep. Using general anesthesia in five pregnant sheep, we placed catheters in the aorta and vena cava and in the uterine vein from the uterine horn. In random order on different days, we infused ritodrine (4 micrograms/kg/minute) or physiologic saline into the maternal vena cava at a rate of 0.184 mL/minute. Uterine venous and maternal arterial blood was sampled 60 minutes before and immediately before the infusion and then at 60, 120, 180, and 240 minutes during the infusion. After centrifugation, the serum was frozen and then assayed for the metabolite of PGF2 alpha (PGFM). Uterine venous PGFM increased significantly after 60 minutes of ritodrine infusion (mean increase 1.164 ng/mL; P less than .05), and this increase was sustained during the 4-hour infusion. The PGFM gradient across the uteroplacental bed (uterine vein - aorta) was also significantly elevated during the infusion, suggesting a uteroplacental or fetal membrane source of the PG. Saline had no effect on uterine venous PGFM or the PGFM gradient. These results suggest that ritodrine stimulates PGF2 alpha production, and this may contribute to the tachyphylaxis that occurs with ritodrine and limits its long-term effectiveness as a tocolytic agent.

Animals↗
PubMed1983

Long-term maintenance of reduced intraocular pressure by daily or twice daily topical application of prostaglandins to cat or rhesus monkey eyes.

Substantial evidence indicates that a single topical application of prostaglandins (PGs) can reduce intraocular pressure (IOP) in the eyes of several species. However, earlier literature, dealing with ocular hypertensive and inflammatory responses, shows the development of tachyphylaxis to subsequent doses of PGs. If similar tolerance developed to the ocular hypotensive effects of PGs, it would preclude the use of these agents in the treatment of chronic glaucoma. The present study shows, however, that although tachyphylaxis to the ocular hypotensive effects of PGs develops in rabbits, this is not a typical response among mammals. Significant IOP reduction was maintained in cats for up to 9 months by topical application of PGE2 at 12-, 24-, or 48-hr intervals. The IOP reduction was jeopardized seriously only when the PG was applied every other day for several days or when, on a few occasions, 3 days were allowed to elapse between PGE2 applications. Ocular hypotension was also maintained during the course of topical treatment of rhesus monkey eyes with PGF2 alpha. Short periods of pupillary constriction followed the application of each dose of PGF2 alpha to cat eyes, but the miotic response of rhesus monkeys to PGF2 alpha and cats to PGF2 was negligible. Other apparent side effects were noted, but none of these were severe or progressive. These results clearly demonstrate that tachyphylaxis, or tolerance, is not expected to present an obstacle to the development of eicosanoids and/or their derivatives as therapeutic agents for the long-term treatment of ocular hypertension and chronic glaucoma.

Administration, Topical↗
PubMed2001

Interleukin-2 induced immune effects in human immunodeficiency virus-infected patients receiving intermittent interleukin-2 immunotherapy.

To characterize the immunological effects of intermittent IL-2 therapy, which leads to selective increases in CD4+ T lymphocytes in HIV-infected patients, 11 patients underwent extensive immunological evaluation. While IL-2 induced changes in both CD4+ and CD8+ cell number acutely, only CD4+ cells showed sustained increases following discontinuation of IL-2. Transient increases in expression of the activation markers CD38 and HLA-DR were seen on both CD4+ and CD8+ cells, but CD25 (a chain of the IL-2 receptor) increased exclusively on CD4+ cells. This increase in CD25 expression was sustained for months following discontinuation of IL-2, and was seen in naive as well as memory cells. IL-2 induced cell proliferation, but tachyphylaxis to these proliferative effects developed after 1 week despite continued IL-2 administration. It thus appears that sustained CD25 expression selectively on CD4+ cells is a critical component of the immunological response to IL-2, and that intermittent administration of IL-2 is necessary to overcome the tachyphylaxis to IL-2-induced proliferation.

ADP-ribosyl Cyclase↗
PubMed1991

Comparison of the effects of prostaglandins E2 and I2 on testicular nociceptor activities studied in vitro.

Effects of exogenous prostaglandin (PG) E2 and PGI2 on testicular polymodal receptor activities were compared in in vitro recordings of single- or multi-fiber discharges from canine testis-spermatic nerve preparations. PGI2 up to 1.4 x 10(-6) mol/l (cumulative method) or 1.0 x 10(-5) mol/l (non-cumulative method) excited only weakly some of the receptors, and similar observations were made with PGE2. Both PGs applied cumulatively or non-cumulatively at concentrations above 1.4 x 10(-8) mol/l augmented the response to bradykinin (9.4 x 10(-8) mol/l) in more than half of the cases tested. The augmenting effect of PGE2 lasted longer than that of PGI2 both with the cumulative and the non-cumulative method. The degree of augmentation tended to increase dependent on concentration, but some cases showed no further increase or rather a decrease in augmentation by PGs at a ten times higher concentration, especially when PGs were applied cumulatively. A second challenge by PG after a short interval (2 min) did not induce augmentation. These phenomena were considered to be tachyphylaxis to PGs. Cross-tachyphylaxis to PGE2 and PGI2 was also observed. There was not much difference in excitatory and augmenting potencies between these two PGs, but there was a clear difference in the concentrations of the PGs necessary to induce excitation of polymodal receptors and to facilitate their response to bradykinin.

Animals↗
PubMed1982

The possible existence of multiple receptors for substance P.

1. The possible existence of multiple receptors for substance P (SP) was investigated by examining the relative pharmacological potencies of SP and related peptides in contracting guinea pig ileum, in potentiating electrically evoked contractions of rat vas deferens preparations and in competing for 3H-SP receptor binding in rat brain membranes, and by comparing the extent of cross-tachyphylaxis of various analogues with SP in the guinea pig ileum. 2. Different rank orders of potencies were observed among SP, its C-terminal fragments, analogues and related tachykinins in the different test systems, and these could not be explained by differential access to the target organ receptors. 3. In contrast to SP and physalaemin, both eledoisin and a metabolically stable SP analogue, [pGlu5, MePhe8, Sar9]-SP5-11 exhibited differential recovery from SP tachyphylaxis in the guinea pig ileum, and part of their spasmogenic action in this preparation was atropine-sensitive. 4. The results suggest the possible existence of multiple SP receptors, and the specificity of those in the brain may be different from those in the gut. The structural and pharmacological basis for subdividing tachykinins into SP-physalaemin and eledoisin-kassinin families is also discussed.

Animals↗