endothelin-1 and Bronchial-Spasm

Topics: Animals; Arachidonate 5-Lipoxygenase; Asthma, Exercise-Induced; Bronchial Spasm; Bronchoconstriction; Cells, Cultured; Cytokines; Endothelin-1; Endotoxins; Exercise; Female; Gene Expression Regulation; Gonadal Steroid Hormones; Humans; Inflammation; Male; Mice; Physical Endurance; Rats; Receptors, Adrenergic, beta-2; Receptors, Immunologic; Receptors, Prostaglandin; Running; Sex Characteristics; Th1 Cells; Th2 Cells; Up-Regulation

The present study was done to investigate the role of endothelin-1 (ET-1) in hypotension and bronchospasm provoked by anaphylaxis in rabbits in vivo.. Forty-five rabbits sensitized to horse serum were randomly allocated to five groups: Group 1 (n = 10) received 0.5 nmol x kg(-1) of ET-1; Group 2 (n = 10) received 0.5 nmol x kg(-1) of ET-1 and 200 nmol x kg(-1) of a selective ETA receptor antagonist, BQ 610, without anaphylaxis; Group 3 (n = 5) received 200nmol x kg(-1) of BQ 610 alone without anaphylaxis, Group 4 (n = 10) received normal saline alone before being antigen challenged to induce anaphylaxis; Group 5 (n = 10) received 200 nmol x kg(-1) of BQ 610 before antigen challenge.. Mean arterial pressure (MAP) values were significantly different between Groups 1 and 2. Heart rate (HR), central venous pressure (CVP), dynamic pulmonary compliance (C(dyn)), and pulmonary airway resistance (R(L)) did not differ significantly between Groups 1 and 2. MAP values were significantly decreased compared with baseline in both Groups 4 and 5; however, the values were not significantly different between two groups. CVP values were significantly different between Groups 4 and 5 only at the 15-min time point following antigen challenge. HR, R(L), and C(dyn) values were not significantly different between Groups 4 and 5, nor were the survival rates.. BQ 610 does not improve hypotension or survival rates in systemic aggregated anaphylactic rabbits in vivo, implying that circulating ET-1 may not play an important role in anaphylaxis, although direct proof of production of circulating ET-1 or activation of ETA receptors is lacking in this study.

Topics: Anaphylaxis; Animals; Bronchial Spasm; Endothelin-1; Female; Hemodynamics; Hypotension; Male; Oligopeptides; Rabbits; Sodium Chloride; Time Factors

Topics: Animals; Asthma; Biomarkers; Bronchial Spasm; Child; Endothelin-1; Endothelium, Vascular; Epithelial Cells; Fibrosis; Humans; Inflammation; Lung; Mice; Mice, Transgenic

Endothelin-1 (ET-1) has been formerly demonstrated to have potent vasocontractile as well as bronchoconstrictor effects in vitro. This followup study was aimed to evaluate the possible changes in ET-1 levels in the plasma of asthmatic children, according to disease activity and severity.. Plasma ET-1 was estimated by enzyme-linked immunoadsorbent assay in 30 asthmatic patients (6 to 12 years old) during and after remission of an acute attack. Thirty age- and sex-matched healthy children were included as a control group.. Plasma ET-1 immunoreactivity was significantly increased in the asthmatic children during the attacks (17.2+/-6.9 pg/mL) in comparison to the levels during quiescence of symptoms (0.9+/-1.13 pg/mL). Further, both values were significantly higher than the control value (0.22+/-0.29 pg/mL). The severity of attacks as judged clinically and by peak expiratory flow rate measurement did not influence the plasma endothelin status; neither did the family history of atopy nor the absolute eosinophil count. However, serum total IgE levels could be positively correlated to the plasma endothelin concentrations measured after remission of the asthmatic attacks (P < 0.05).. Our findings reinforce the concept that ET-1 may be implicated in the pathogenesis of bronchoconstriction. This may encourage further studies on the value of ET-1 antagonism among alternative therapeutic modalities of childhood asthma.

Topics: Acute Disease; Asthma; Bronchial Spasm; Bronchoconstriction; Capillary Leak Syndrome; Case-Control Studies; Child; Convalescence; Endothelin-1; Enzyme Activation; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Female; Fibronectins; Humans; Hypersensitivity, Immediate; Immunoglobulin E; Male; Phospholipases A; Severity of Illness Index

LU 302 872 (racemate LU 224 332) is a new glycerinic acid derivative related to the selective ETA receptor antagonist LU 135 252. LU 302 872 exhibits high and balanced affinity to ETA and ETB receptors (Ki 2.2 and 5.8 nmol/L), whereas LU 135 252 is ETA-selective (Ki 1.4 and 184 nmol/L). Two hours after oral treatment of rats with 10 mg/kg of LU 302 872 or of LU 135 252, the big ET-1-induced (20 micrograms/kg i.v.) blood pressure increase is inhibited by 59 +/- 8% or 52 +/- 2% (n = 6-8; p < 0.05 vs. control), whereas bosentan is without effect (-6 +/- 7%; n = 6). In guinea pigs, 10 mg/kg p.o. of LU 302 872 inhibited the big ET-1 (20 micrograms/kg i.v.)-induced bronchospasm (reduction in respiratory volume) by 78 +/- 7% (n = 6; p < 0.05), whereas the ETA antagonist LU 135 252 was ineffective (0.2 +/- 37%; n = 6). Hence, a high oral effectiveness of the new ETA/B antagonist could be demonstrated in two species for both an ETA- or an ETB-mediated response. In human prostate tissue (excised during cystectomy in bladder cancer patients), ET-1 and in most cases, the ETB agonist sarafotoxin 6c (S6c) caused contractions of similar magnitude but more sustained than that of norepinephrine (10(-6) mol/L). A high concentration (10(-5) mol/L) of the ETA antagonist LU 135 252 only moderately attenuated ET contractions. The ETA/B antagonist LU 302 872 or its racemate, LU 224 332, dose-dependently inhibited ET-1-induced contractions. S6C dose-response curves, too, were shifted to the right or suppressed by the combined ETA/B antagonist (10(-6) mol/L LU 224 332). LU 302 872 may be a suitable candidate for testing in benign prostate hyperplasia (BPH).

Topics: Animals; Blood Pressure; Bronchial Spasm; CHO Cells; Cricetinae; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Humans; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth; Propionates; Prostate; Protein Precursors; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Stereoisomerism

1. IRL 1620 (0.01-0.1 mg kg-1, i.v.), a selective endothelin B (ETB) receptor agonist, induced a dose-dependent biphasic increase in total lung resistance and a decrease in dynamic compliance in anaesthetized and artificially ventilated guinea-pigs. After intravenous injection of IRL 1620 (0.03 mg kg-1), the first phase was observed within 2 min whereas the second phase started between 5 and 10 min after injection and was long lasting. 2. In order to characterize which endothelin receptors are involved in both phases of bronchoconstriction, we studied the effect of ETA and ETB receptor antagonists (BQ 123 and BQ 788, respectively). BQ 788 (0.1-1 mg kg-1, i.v.) inhibited, in a dose-dependent manner, both phases of bronchoconstriction. BQ 123 (3 mg kg-1, i.v.) markedly inhibited (by 76%) the second phase of bronchoconstriction but had no effect on the early component of the response. 3. The effect of atropine, neurokinin-I (NK1) and neurokinin-2 (NK2) receptor antagonists (SR140333 and SR48968, respectively) were tested to investigate the possible involvement of cholinergic and sensory nerve activation, respectively, in the response to IRL 1620. Likewise, the role of arachidonic acid metabolites (leukotriene D4 antagonist, ONO-1078 and thromboxane A2 (TXA2) inhibitor, OKY-046) in this response was also investigated. OKY-046 (1 mg kg-1, i.v.) and atropine (1 mg kg-1, i.v.) partially inhibited the first phase (by 80% and 20%, respectively) without affecting the late phase of bronchoconstriction. Neither ONO-1078 (1 mg kg-1, i.v.) nor the combination of SR140333 (0.2 mg kg-1, i.v.) and SR 48968 (0.2 mg kg-1, i.v.) modified IRL 1620-induced bronchoconstriction. 4. A low dose of IRL 1620 (0.005 mg kg-1, i.v.) induced a monophasic bronchoconstriction. Pretreatment by phosphoramidon (100 mumol kg-1, i.v.) restored the second phase of bronchoconstriction. In this condition, BQ 123 (3 mg kg-1, i.v.) was able to inhibit partially the second phase of bronchoconstriction. 5. These results suggest that both phases of bronchoconstriction induced by IRL 1620 were mediated primarily by ETB receptor activation, the first phase being a consequence of TXA2 and acetylcholine release. The inhibition by an ETA receptor antagonist and the restoration by a neutral endopeptidase (NEP) inhibitor of the second phase of bronchoconstriction suggests that primary activation of ETB receptors leads to autocrine/paracrine endothelin-1 (ET-1) release that would subsequently cause profound b

Topics: Animals; Atropine; Bronchial Spasm; Bronchodilator Agents; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Female; Guinea Pigs; In Vitro Techniques; Male; Methacrylates; Neurokinin-1 Receptor Antagonists; Oligopeptides; Peptide Fragments; Peptides, Cyclic; Piperidines; Receptors, Endothelin; Receptors, Neurokinin-2; Thromboxane A2; Thromboxane-A Synthase

Endothelin (ET-1) caused dose-related contraction of isolated superfused bronchus and pulmonary artery and bronchoconstriction and pulmonary vascular hypertension of the heart lung preparation (HLP) of guinea pig. The specific ETA receptor antagonist BQ 123 completely blocked the responses of the pulmonary artery, but failed to affect those of bronchus and of HLPs. The specific ETB receptor agonist Sarafotoxin S6c caused contractions of bronchus, but not of pulmonary artery, and bronchoconstriction and pulmonary hypertension in HLPs. It is concluded that non-ETA subtype receptors, perhaps ETB, appear to be the main responsible for the potent pulmonary hypertensive effects of ET-1.

Topics: Animals; Bronchi; Bronchial Spasm; Endothelin-1; Guinea Pigs; Hypertension, Pulmonary; In Vitro Techniques; Male; Pulmonary Artery; Receptor, Endothelin B; Receptors, Endothelin; Vasoconstrictor Agents; Viper Venoms