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PubMed2004

Effects of repeated injection of local anesthetic on sciatic nerve blocks response.

In order to examine whether repeated sciatic nerve blocks showed tachyphylaxis and continuity of sciatic nerve with spinal cord affected development of tachyphylaxis when assayed in vivo by duration of depression compound action potentials (CAP), rats were anesthetized with halothane, ventilated, monitored and supported with stable hemodynamics and temperature. Posterior tibial nerve distally and sciatic nerve in thigh were exposed, placed on bipolar silver electrodes for stimulation and recording respectively. Three sequential sciatic nerve blocks were performed between these electrodes using 0.15 ml of 3% chloroprocaine. Nine rats were chosen to observe the effects of repeated sciatic nerve blocks on CAP. In another 18 rats, a second investigator exposed the sciatic nerve near its origin at spinal cord and randomly performed nerve cut and sham (n=9), and closed the incision blinding the electrophysiologic investigator. The results showed that electrical stimulated tibial nerve induced sciatic nerve Aalpha/beta, Adelta, C fiber mediated CAP waves. CAP amplitudes were remained stable during whole experimental procedure. CAP amplitudes were decreased completely with 3% chloroprocaine blocked sciatic nerve and recovered fully. The duration of CAP depression were reduced with repeated blocks. There were no selective blocked effects on Aalpha/beta, Adelta, C fiber mediated CAP. With sciatic nerve cut proximally, there was no statistical significant tachyphylaxis with 3% chloroprocaine repeated blocked sciatic nerve, and the duration of first and third blocked Adelta fiber mediated CAP was 108+/-20 and 92+/-14 min respectively (P>0.05). In normal rats the duration of first and third blocked Adelta fiber mediated CAP was 110+/-20 and 75+/-16 min respectively (P<0.05). It was suggested that tachyphylaxis to local anesthetics can occur in rats repeated blocked sciatic nerve when assayed in vivo by duration of depression CAP. The continuity of sciatic nerve with spinal cord is one of the important factors affecting the development of tachyphylaxis.

Anesthetics, Local↗
PubMed2005

Endogenous nitrosyl factors may inhibit the desensitization of 5-HT3 receptors on vagal cardiopulmonary afferents.

The pronounced tachyphylaxis to the Bezold-Jarisch reflex (BJR) responses elicited by systemic injections of the 5-HT(3) receptor (5-HT(3)R) agonists such as phenylbiguanide (PBG) may involve desensitization and/or reduced rate of resensitization of 5-HT(3)Rs on vagal cardiopulmonary afferents. The presence of nitric oxide synthase (NOS) in vagal afferents raises the possibility that endogenous nitrosyl factors regulate the status of 5-HT(3)Rs in these afferents. Accordingly, the aim of this study was to determine whether the inhibition of NOS alters the development of tachyphylaxis to the BJR responses elicited by PBG in conscious rats. The first injection of PBG (100 microg/kg, i.v.) elicited robust reductions in heart rate (HR), diastolic arterial blood pressure (BP(D)), and cardiac output (CO) but minor changes in total peripheral resistance in saline-treated rats. Subsequent injections elicited progressively smaller responses such that the sixth injections elicited minor responses only. The first injection of PBG (100 microg/kg, i.v.) in rats treated with the NOS inhibitor, L-NAME (25 micromol/kg, i.v.) elicited similar reductions in HR, BP(D), and CO as in saline-treated rats. However, the rate of development of tachyphylaxis to PBG was markedly faster in the L-NAME-treated rats. The BJR responses elicited by 5-HT (40 microg/kg, i.v.) were markedly attenuated after the development of tachyphylaxis to PBG in saline- and in L-NAME-treated rats whereas the BJR responses elicited by the S-nitrosothiol, L-S-nitrosocysteine (5 micromol/kg, i.v.), were not attenuated in either group. These findings suggest that tachyphylaxis to PBG was not due to the loss of central or efferent processing of the BJR. Taken together, these findings suggest NOS exists in vagal cardiopulmonary afferents mediating the BJR and that nitrosyl factors influence 5-HT(3)R function.

Adaptation, Physiological↗
PubMed2003

Actions of endothelin and corticotropin releasing factor in the guinea-pig ileum: no evidence for an interaction with capsaicin-sensitive neurons.

Both endothelins and corticotropin releasing factor (CRF) appear in capsaicin-sensitive neurons. We have investigated the effects of human endothelin-1 (ET-1) and CRF in the guinea-pig ileum longitudinal and circular preparations and sought for ways of specific antagonism. With the aid of tachyphylaxis to capsaicin (i.e., rendering capsaicin-sensitive neurons functionally impaired) it was tested if these neurons played a mediating role in the effects of ET-1 or CRF. We also tried to find out whether endogenous endothelin or CRF plays a role in the excitatory and inhibitory effects of capsaicin in the ileum. In preparations at basal tone, both exogenous ET-1 (1-100 nM) and CRF (3-100 nM) caused contraction. These responses were not influenced by capsaicin tachyphylaxis. The contractile effect of ET-1 was not affected by tetrodotoxin (1 microM), atropine (1 microM), methysergide (100 nM), chloropyramine (100 nM) or SR140333 (100 nM) but was significantly inhibited or even abolished by the receptor antagonist BQ123 (3 microM) or BQ788 (3 microM). CRF caused contraction that was fully sensitive to tetrodotoxin (1 microM), tachyphylaxis to CRF or to atropine (1 microM) plus the tachykinin NK1 receptor antagonist SR140333 (200 nM). Atropine alone had a weak inhibitory effect on the contractile action of CRF. Neither the antagonist BQ123 (3 microM) nor CRF tachyphylaxis inhibited the contractile action of capsaicin (2 microM), even in the presence of a mixture of GR82334 (3 microM) and SR142801 (100 nM), for blocking tachykinin NK1 and NK3 receptors, respectively--a treatment that by itself significantly reduced the effect of capsaicin. Exogenous ET-1 (0.3-5 nM), but not CRF (30-100 nM), caused relaxation of the atropine-treated, histamine-precontracted ileum. This effect of ET-1 was significantly inhibited or abolished by BQ123 (10 microM), or BQ788 (3 microM), but was not influenced by capsaicin tachyphylaxis. Likewise, relaxation of the atropine-treated, histamine-precontracted ileum in response to capsaicin was not influenced by the endothelin receptor antagonist BQ788 (3 microM) or BQ788 (3 microM) plus BQ123 (3 microM). Apamin (300 nM) was also without effect on the capsaicin-induced relaxation. In circular muscle strips ET-1 inhibited the indomethacin-induced spontaneous activity. This effect was abolished by BQ123 (3 microM) or BQ788 (3 microM). CRF caused a stimulation of the circular muscle. This stimulatory effect was not influenced by atropine (1 microM) alone, but was inhibited by atropine plus tachykinin NK1 and NK2 receptor antagonists (SR140333 (200 nM) and SR48968 (200 nM)) and also by tetrodotoxin (1 microM). It is concluded that capsaicin-sensitive neurons do not play a role in the effects of exogenous ET-1 or CRF in the guinea-pig ileum. ET-1 can both contract and relax the ileal longitudinal smooth muscle directly, probably via both ETA and ETB receptors. CRF acts by specifically stimulating excitatory (but not inhibitory) neurons of the myenteric plexus. Neither endogenous ET-1 nor CRF seems to play a role in the excitatory or inhibitory effects of capsaicin.

Animals↗
PubMed1983

Is acute tolerance to 5-hydroxytryptamine opioid dependent? Its absence in migraine sufferers.

The human dorsal hand vein, exhausted in vivo (tachyphylaxis) by repeated inoculations of 5-hydroxytryptamine, recovers its capacity to contract in response to the 5HT when naloxone (per se ineffective) is inoculated into the same vein. It would seem, therefore, that in the 5HT tachyphylactic mechanism a role could be played by the progressive excitation of a local opioid modulator apparatus (silent in basal condition); naloxone's capacity for neutralizing the vein's fatigue could be indirect evidence of this. This postulation of an opioid role in the tachyphylactic mechanism differs from the conventional thesis, which explains tachyphylaxis as a progressive exhaustion of NA released from the sympathetic neuron by 5HT (see Table 1). Tachyphylaxis is poor, delayed or absent in migraine sufferers; this anomaly is present even in the period between attacks. The anomaly of inverted tachyphylaxis appears amplified during attacks. The loss or inversion of 5HT-tachyphylaxis is constantly observed in heroin addicts during acute abstinence. The fact that the clinical phenomena of acute heroin abstinence are comparable with those of a migraine attack could be a matter for further investigation.

Endorphins↗
PubMed1988

A new role for histamine H2-receptors in asthmatic airways.

Histamine tachyphylaxis develops with repeated inhalation of histamine in asthmatic subjects, and this appears to be due to the release of inhibitory prostaglandins. The purpose of this study was to determine whether histamine H2-receptors are also involved in the development of this protective effect in the airways. Seven subjects with mild asthma were studied on 2 days separated by at least 1 wk. On both days, three histamine inhalation tests were performed, separated by 1 h. The response was expressed as the provocative concentration of histamine causing a 20% decrease in FEV1 (histamine PC20). Before each study day subjects were pretreated with placebo or cimetidine (300 mg twice a day) for 3 days in a double-blind, randomized, crossover study. Cimetidine pretreatment had no effect on either baseline FEV1 or on baseline histamine PC20 (p = 0.461). After pretreatment with placebo, histamine tachyphylaxis occurred in all subjects; the mean PC20 increased from 3.01 mg/ml (%SD, 1.44) to 4.88 mg/ml (%SD, 1.68) and to 6.84 mg/ml (%SD, 1.68). Cimetidine pretreatment prevented histamine tachyphylaxis; the mean PC20 was 2.72 mg/ml (%SD, 1.77), 3.03 mg/ml (%SD, 1.73), and 3.56 mg/ml (%SD, 1.59) with repeated tests. These values differed significantly from placebo for both the second (p = 0.014) and third (p = 0.001) tests. This study demonstrated that cimetidine pretreatment prevents histamine tachyphylaxis and suggests that histamine tachyphylaxis occurs through stimulation of histamine H2-receptors in the airway.

Asthma↗
PubMed1992

Adaptation of cough reflex with different types of stimulation.

Inhalation cough challenge has become an accepted method of investigating antitussive agents. It is, therefore, important to examine the degree of tachyphylaxis seen with repeated cough challenge. In addition, different types of challenge may reveal important differences in the neuronal pathways involved in the cough reflex. Citric acid, distilled water and capsaicin were examined to determine adaptation of the cough response during acute and long-term inhalation studies in healthy subjects. To study acute tachyphylaxis two separate one minute continuous inhalation challenges (n = 13) were performed. Long-term tachyphylaxis (n = 10) was examined using citric acid and capsaicin inhalation at 10 min intervals for 40 min, and at 4 and 6 h. Cross-tachyphylaxis to citric acid and capsaicin was examined in a separate randomized crossover study (n = 10). Highly significant adaptation occurred between the first and last 10 s of the one minute challenge with citric acid (90-100%) and distilled water (74-84%), but was less pronounced with capsaicin (37-49%, at 2 microM). Cough during the whole of the second test was significantly reduced for citric acid (50%). During long-term challenge cough was attenuated over 40 min both with citric acid (100 mM, p less than 0.05; 300 mM, p less than 0.001; 1 M, p less than 0.001) and with capsaicin (3 microM, p less than 0.01; 10, 30, 100 microM, p less than 0.001 each). With higher doses, tachyphylaxis was still present at 180 min with both citric acid (300 mM, p less than 0.05) and capsaicin (100 microM, p less than 0.008).(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptation, Physiological↗
PubMed1988

Neutrophil leukocyte emigration induced by endotoxin. Mediator roles of interleukin 1 and tumor necrosis factor alpha 1.

The hypothesis that cytokines mediate neutrophil emigration induced by endotoxin (LPS) was studied by examining the potency, the kinetics of neutrophil emigration, and the tachyphylaxis of intradermal sites with IL-1, TNF-alpha and LPS. Human rIL-1 alpha and IL-1 beta, synthetic lipid A, and LPS were several orders of magnitude more potent than human rTNF. The kinetic profiles of neutrophil emigration induced by IL-1 alpha, TNF, and LPS were characterized by minimal emigration in the first 30 min, followed by rapid and transient emigration. After the injection of LPS, the onset and the time at which the rate of emigration was maximal consistently appeared 30 min later than IL-alpha or TNF, suggesting that neutrophil emigration in response to LPS was mediated by a locally generated cytokine. IL-1 and TNF were then examined as potential secondary mediators of LPS-induced emigration by comparing the patterns of tachyphylaxis between LPS and IL-1 alpha or TNF; i.e., the magnitude of neutrophil emigration into inflammatory sites was compared with sites injected 6 h previously (desensitizing injections) with a cytokine or with LPS. Tachyphylaxis was dose dependent with each and also between the IL-1 species; therefore, when tachyphylaxis between the cytokines and LPS was examined, relatively higher doses were selected for the desensitizing injections than for the test injections. With this approach, desensitizing injections of IL-1 alpha diminished the neutrophil accumulation after LPS, and LPS also desensitized sites to IL-1 alpha. However, tachyphylaxis was not observed between TNF and LPS, or between TNF and IL-1 alpha. These data suggest that IL-1, but not TNF, is a potential mediator of LPS-induced neutrophil emigration.

Animals↗
PubMed1984

Capsaicin and bradykinin-induced substance P-ergic responses in the iris sphincter muscle of the rabbit.

Exogenously applied capsaicin and bradykinin produced contractile responses in the rabbit iris sphincter muscle and responses were suppressed remarkably by [D-Pro2, D-Trp7,9]-substance P, a substance P antagonist, and disappeared in trigeminally denervated preparations. Thus, the responses to capsaicin or bradykinin were considered to be mediated by substance P released from the trigeminal nerve. Repetitive application of capsaicin or bradykinin produced a gradual decline in the responses, thereby indicating the development of tachyphylaxis. Furthermore, bradykinin failed to induce any response after the development of capsaicin-induced tachyphylaxis, but after the development of tachyphylaxis to bradykinin, responses to capsaicin persisted. Electrical transmural stimulation produced cholinergic and substance P-ergic responses in the rabbit iris sphincter muscle. Substance P-ergic response to electrical transmural stimulation also was abolished after development of tachyphylaxis to capsaicin, but not to bradykinin. The contractile response to exogenously applied substance P was not affected by the development of tachyphylaxis to capsaicin and bradykinin. These results suggest that capsaicin and bradykinin produce substance P-ergic contractile responses mediated by the trigeminal nerve and that the mechanisms of action differ between the two drugs. These effects of capsaicin and bradykinin are discussed in relation to occurrence of neurogenic inflammation in the eye.

Animals↗
PubMed1989

Tachykinin receptor subtype that mediates the increase in vascular permeability in guinea pig skin.

To determine the tachykinin receptor subtype that mediates the increase in vascular permeability, we examined the rank order of potency of tachykinins for inducing plasma extravasation in guinea pig skin and the specificity of tachykinin-induced tachyphylaxis of the responses. Plasma extravasation of the skin induced by tachykinins was NK-1 (SP-P)-type response from the rank order of potency of mammalian and nonmammalian tachykinins. Tachyphylaxis of the vascular response was induced by intradermal preinjection of mammalian tachykinins and was tachykinin-specific. In substance P (SP) tachyphylaxis (where SP was preinjected), the response to SP, not to neurokinin A (NKA) or neurokinin B (NKB), was decreased. In NKA tachyphylaxis and NKB tachyphylaxis, the response to NKA, not to SP or NKB, and the response to NKB, not to SP or NKA, were decreased, respectively. Thus, we conclude that the apparent NK-1-type response is mediated through three mammalian tachykinin receptors, NK-1, NK-2, and NK-3, which are specifically stimulated by their preferred agonist, SP, NKA, and NKB, respectively.

Animals↗
PubMed1988

Desensitization to intrathecal substance P in mice: possible involvement of opioids.

Intrathecal (i.t.) injection of substance P (SP) results in a behavioral syndrome characterized by caudally directed biting and scratching. The present results indicate that repeated injections of 10 ng of SP, administered at 60 sec intervals, result in the rapid development of tachyphylaxis to this SP-induced behavioral phenomenon. Three injections of SP produced a greatly attenuated behavioral response compared to that of a single injection of SP. Mice injected with Freund's adjuvant in the hind foot pads to produce an arthritic-like condition exhibited significantly less desensitization to SP after repeated i.t. injection compared to that in saline-injected control mice. While large doses of naloxone (5 mg/kg s.c. or 1 microgram i.t.) combined with each injection of SP completely blocked the desensitization to the effect of SP in naive mice, a smaller dose of naloxone (0.5 mg/kg administered s.c.) failed to alter the apparent tachyphylaxis to SP similar to that seen in saline-treated control mice. Pretreatment with 0.5 micrograms i.t. of beta-funaltrexamine (beta-FNA) also failed to alter the degree of apparent tachyphylaxis to SP. Co-administration of 1 microgram of fluoxetine, a serotonin reuptake inhibitor, or 1 microgram of phentolamine, an alpha-adrenergic antagonist, completely blocked the development of tachyphylaxis to i.t. SP. These results indicate that tachyphylaxis to SP appears to involve activation of the endogenous opioid system. Desensitization also appears to involve activation and inhibition of the descending adrenergic and serotonergic systems respectively.

Animals↗
PubMed2000

Beta-adrenoceptor dysfunction after inhibition of NO synthesis.

G(s) protein-coupled beta-adrenoceptors rapidly desensitize on exposure to agonists in reconstituted membrane preparations, whereas rapid tachyphylaxis to beta-adrenoceptor-mediated vasodilation does not readily occur in vivo. This study examined the possibility that endothelium-derived nitrosyl factors prevent the rapid desensitization of beta-adrenoceptors in the vascular smooth muscle of resistance arteries in pentobarbital-anesthetized rats. The fall in mean arterial blood pressure and in hindquarter vascular resistance produced by the beta-adrenoceptor agonist isoproterenol (ISO, 0.1 to 10 microg/kg IV) was slightly but significantly smaller in rats treated with the NO synthase inhibitor N:(G)-nitro-L-arginine methyl ester (L-NAME, 100 micromol/kg IV) than in saline-treated rats. The ISO-induced fall in mesenteric resistance was similar in L-NAME-treated and in saline-treated rats. The fall in hindquarter vascular resistance and in mesenteric resistance produced by ISO (8 x 10 microg/kg IV) was subject to tachyphylaxis on repeated injection in rats treated with L-NAME (100 micromol/kg IV) but not in rats treated with saline. Injections of L-S:-nitrosocysteine (1200 nmol/kg IV), a lipophobic S:-nitrosothiol, before each injection of ISO (10 microg/kg IV) prevented tachyphylaxis to ISO in L-NAME-treated rats. The vasodilator effects of ISO (0.1 to 10 microg/kg IV) in L-NAME-treated rats that received 8 injections of ISO (10 microg/kg IV) were markedly smaller than in L-NAME-treated rats that received 8 injections of saline. These results indicate that (1) the vasodilator actions of ISO in pentobarbital-anesthetized rats only minimally involve the release of endothelium-derived nitrosyl factors, (2) the effects of ISO are subject to development of tachyphylaxis in L-NAME-treated rats, and (3) tachyphylaxis to ISO is prevented by L-S:-nitrosocysteine. These findings suggest that endothelium-derived nitrosyl factors may prevent desensitization of beta-adrenoceptors in vivo.

Adrenergic beta-Agonists↗
PubMed1987

Pharmacodynamic evaluation of human cerebral arteries in the genesis of vasospasm.

Experiments were performed on isolated human cerebral arteries to evaluate the role desensitization and tachyphylaxis might play in preventing certain agonists from producing prolonged vasoconstriction after subarachnoid hemorrhage. In addition, the antiproteases leupeptin and pepstatin were studied to ascertain whether these peptides might inhibit contraction as does antithrombin III. The maximal contraction to KCl was used as a standard for comparing the responses elicited by the agonists, the decay of the responses to the agonists over 15 minutes was used as an index of desensitization, and the percentage of decrease in response to a second application of the agonist over the first was a measure of tachyphylaxis. The results showed that desensitization and tachyphylaxis greatly reduced or abolished the contractile responses to norepinephrine, serotonin, angiotensin II, arginine vasopressin, substance P, neuropeptide Y, neurotensin, thrombin, uridine triphosphate, linoleic acid, melittin, and cathepsin D. Moreover, some arteries failed to respond to some of these agonists, and no contractile response was elicited by acetylcholine or bradykinin. In contrast, prostaglandins E2, D2, and F2 alpha, as well as plasmin, produced sustained contractions, without tachyphylaxis, but only prostaglandin E2 and plasmin produced contractions at concentrations of 10(-7) M or less that were comparable to those of KCl. None of the antiprotease peptides inhibited the responses to KCl whereas small concentrations (6 X 10(-8) M) of antithrombin III did. The results support the hypotheses that the phenomenon of desensitization and tachyphylaxis would prevent many diverse agents from acting as spasmogens and that substances like antithrombin III present in the cerebrospinal fluid after hemorrhage could immediately protect patients from cerebral vasospasm.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Studies on the desensitization of the central cardiovascular responses of histamine.

Intraventricular administration of histamine (HA) in conscious freely moving rats produces a dose-dependent pressor response and bradycardia. These responses are diminished profoundly when a second injection of HA is given within a short time after the first injection. In this study, the specific HA H1 agonist, pyridylethylamine, and the specific H2 agonist, impromidine, were used to examine the nature of this tachyphylaxis. Blood pressure and heart rate were measured directly from indwelling carotid catheters, and drugs were administered in three consecutive intraventricular injections to conscious freely moving rats at 30-min intervals. HA, the H2 agonist, impromidine and the combined injection of pyridylethylamine and impromidine induced tachyphylaxis of the pressor response. The H1 agonist, pyridylethylamine and the HA-N-methyltransferase inhibitor, SKF-91488 (homodimaprit) did not show tachyphylaxis. Heart rate responses were more complex and only HA demonstrated tachyphylaxis of the bradycardia. It is concluded that the tachyphylaxis of the pressor response caused by repeated injections of HA results from the desensitization of central HA H2 receptors.

Animals↗
PubMed1995

Epithelium-derived inhibitory prostaglandins modulate human bronchial smooth muscle responses to histamine.

The role of the bronchial epithelium and inhibitory prostaglandins in the induction of histamine tachyphylaxis in human isolated bronchial smooth muscle was investigated using bronchi obtained from 14 patients who had been treated with non-steroidal anti-inflammatory drugs (NSAID) for > 2 months and from 14 untreated patients. Epithelium-intact bronchial strips from untreated patients demonstrated tachyphylaxis to histamine with the maximum response (Emax) reduced by 30 +/- 5% (P < 0.02) and the EC50 increased 1.86-fold (P < 0.02). Tachyphylaxis was not observed in epithelium-denuded strips. In epithelium-intact bronchial preparations from NSAID treated patients, the mean initial maximum tension generated in response to histamine was significantly greater than that for bronchial preparations from untreated patients (P < 0.05). In NSAID-treated patients, both epithelium-intact and denuded preparations failed to demonstrate tachyphylaxis. The generation of prostaglandin E2 and prostacyclin was assessed by radio-immunoassay using bronchi from untreated patients (n = 8). In epithelium-intact bronchial preparations, the generation of both prostaglandin E2 and prostacyclin was significantly increased by histamine exposure (P < 0.05) and was completely inhibited by indomethacin. However, the selective histamine H2 receptor antagonist, ranitidine, selectively inhibited the synthesis of prostaglandin E2 alone. Production of both prostaglandins was not altered by exposure to acetylcholine. These results suggest that prostaglandin E2 and prostacyclin are released primarily from the epithelium in response to histamine and may be specifically involved in inhibiting human bronchial smooth muscle responsiveness to this mediator. Significantly, the release of prostaglandin E2 appears to be selectively controlled by histamine H2 receptors, resident on the epithelium.

Acetylcholine↗
PubMed1995

Role of positions 9 and 10 in the endothelin molecule for biological activity and discrimination of receptor subtypes.

The importance of residues 9 and 10 in endothelin-1 was assessed by studying the responses of the guinea-pig ileum to [Ala9]endothelin-1 and [Ala10]endothelin-1. Both analogues induced relaxation followed by contraction. [Ala9]Endothelin-1 showed similar ED50 values and maximum response to those of endothelin-1, whereas [Ala10]endothelin-1 showed a larger ED50 value and was a partial agonist. Endothelin-1 and [Ala10]endothelin-1 induced similar degrees of tachyphylaxis, whereas [Ala9]endothelin-1 induced very little tachyphylaxis, indicating that Lys9 is important for inducing tachyphylaxis. Apamin inhibited the relaxation induced by endothelin-1 and [Ala9]endothelin-1 but not that induced by [Ala10]endothelin-1. BQ-123 (cyclo[D-Trp-D-Asp-Pro-D-Val-Leu), a specific endothelin ETA receptor antagonist, inhibited [Ala9]endothelin-1-, but not [Ala10]endothelin-1-induced contraction. Cross-tachyphylaxis and additivity studies indicated that [Ala9]endothelin-1, like endothelin-1, acts at the endothelin ETA receptor, whereas [Ala10]endothelin-1 behaved as an endothelin ETB receptor agonist, like sarafotoxin S6c. Thus, the residue at position 10 plays a significant role in receptor activation and is a candidate for further exploration of receptor antagonism.

Amino Acid Sequence↗
PubMed2002

Evidence for changes in the tachyphylactic property of recombinant angiotensin II AT(1) receptor expressed in CHO cells.

The manifestation of tachyphylaxis to angiotensin II in Chinese hamster ovary (CHO) cells expressing the rat angiotensin II AT(1) receptor was investigated. The cells were transfected with a cDNA fragment containing the complete coding region of the angiotensin II AT(1A) receptor gene, as well as 56 bp of its 3'- and 52 bp of its 5'-untranslated regions. These cells (CHO-AT(1)) responded to angiotensin II by increases in intracellular Ca(2+) concentration and inositol phosphate turnover, which were inhibited upon repeated administrations, characterizing the tachyphylaxis phenomenon. In contrast to smooth muscle cells, which are rendered tachyphylactic to angiotensin II but not to [2-lysine]angiotensin II ([Lys(2)]angiotensin II), this analogue induced responses in CHO-AT(1) cells that were also inhibited upon repeated administrations. A smooth muscle cell line, which showed tachyphylaxis only to angiotensin II, became tachyphylactic also to [Lys(2)]angiotensin II after transfection with the angiotensin II AT(1) receptor gene. Our findings suggest that posttranscriptional control directed by the 3'- or the 5'-untranslated regions in the angiotensin II AT(1) receptor gene may play a role in modulating the signal transduction pathways involved in the mechanism of angiotensin II tachyphylaxis.

Adenosine Triphosphate↗
PubMed2003

Tachyphylactic properties of angiotensin II analogs with bulky and hydrophobic substituents at the N-terminus.

Tachyphylaxis, defined as the acute loss of response of some smooth muscles upon repeated stimulations with angiotensin II (Ang II), has been shown to be dependent mainly on the N-terminal region of the ligand. To further study the structural requirements for the induction of tachyphylaxis we have synthesized Ang II analogs containing the bulky and very lipophilic substituents 9-fluorenylmethyloxycarbonyl (Fmoc) and 9-fluorenylmethyl ester (OFm) at the alpha-amino (Nalpha-Fmoc-Ang II) or the beta-carboxyl ([Asp(OFm)1]-Ang II) groups of the Asp1 residue, respectively. In binding assays with Chinese hamster ovary cells transfected with the AT1 Ang II receptor, Nalpha-Fmoc-Ang II bound with high affinity, whereas [Asp(OFm)1]-Ang II showed lower affinity. In biological assays, these two analogs were full agonists and showed 30 and 3%, respectively, of the Ang II potency in contracting the guinea-pig ileum smooth muscle. The two analogs induced tachyphylaxis, in spite of the lack of a free amino group in Nalpha-Fmoc-Ang II. Thus, analogs with Fmoc- or OFm-type groups coupled to the Asp1 residue, whether at the amino or carboxyl functions, induce tachyphylaxis through an unreported mechanism. Based in these findings and those available from the literature, an alternate molecular interaction mode between Ang II N-terminal portion and the AT1 receptor is proposed to explain the tachyphylactic phenomenon.

Angiotensin II↗
PubMed1989

The role of cyclic AMP and the dihydropyridine-sensitive channels on the mechanism of action of milrinone (Corotrope).

Milrinone (Corotrope) increased cyclic AMP levels in dog guinea pig and rat cardiac muscle. A correlation between the increase in contractile force and cyclic AMP levels in dog ventricular trabeculae was obtained when measurements were made 60-70 s after the addition of milrinone. When cyclic AMP levels were determined at the time of maximal contractile response, only concentrations of milrinone 200-300 times the inotropic dose had any effects in elevating cyclic nucleotide levels. In dog Purkinje tissue and rat cardiac muscle, milrinone had minimal or no effects on contractile force but increased cardiac cyclic AMP levels. Sequential doses of milrinone to perfused guinea pig hearts resulted in severe tachyphylaxis to the inotropic activity of milrinone. However, under these conditions, milrinone was found to elevate cardiac cyclic AMP upon each administration. Furthermore, in this preparation, cross-tachyphylaxis between Bay K 8644 and milrinone was demonstrated. The mechanism of action of Bay K 8644, which acts on sarcolemmal Ca2+, is not mediated by increases in cyclic AMP. Following development of tachyphylaxis to Bay K 8644, in the guinea pig hearts, addition of milrinone results in no increases in contractile force but a significant increase in cyclic AMP levels. In all of the instances of tachyphylaxis, isoproterenol increased both contractile force and cyclic AMP. The data are discussed and we put forth the hypothesis that increased cardiac force due to milrinone is in part due to a direct or indirect action on sarcolemmal Ca2+ channels.

Animals↗