The Effect of Chronic Hypoxia on Endothelin Receptor Subtype-mediated Responses in Rat Isolated Airways

Abstract

Contractile responses to endothelin-1 (ET-1) were investigated in isolated trachea from rats previously exposed to chronic hypoxia (10% O2) or room air for 14 days. Concentration-response curves were constructed to ET-1 (10−11–3×10−7m) in the presence and absence of the ETAreceptor antagonist FR 139317 (10−8, 10−7and 10−6m), the ETBreceptor antagonist BQ 788 (10−6and 3×10−6m), the non-selective ET receptor antagonist SB 209670 (10−7and 10−6m) and a combination of FR 139317 (10−6m) and BQ 788 (10−6m). Concentration–response curves were also conducted to the ETBreceptor agonist sarafotoxin S6c (10−11–3×10−7m). In addition, responses to ET-1 (10−11–3×10−7m) were examined in the presence and absence of the nitric oxide synthase inhibitor, L-NAME. In control rat trachea, both FR 139317 and BQ 788 failed to inhibit ET-1-induced contractions and, indeed, FR 139317 (10−8m) and BQ 788 actually potentiated responses. In trachea from chronic hypoxic rats, FR 139317 did not alter ET-1 responses whereas BQ 788 again potentiated ET-1-induced contractions. The non-selective ET receptor antagonist SB 209670 attenuated ET-1-evoked contractions in trachea from control and chronically hypoxic rats. A combination of FR 139317 (10−6m) and BQ 788 (10−6m) also attenuated ET-1 responses in control rat trachea, but not trachea from chronically hypoxic rats. In trachea from both control and chronically hypoxic rats, L-NAME significantly potentiated responses to ET-1. To investigate ET receptor-mediated relaxation, tissues were preconstricted with methacholine and concentration–response curves were conducted to ET-1(10−13–10−8m) in the presence and absence of BQ 788 (10−6m) and to the ETBreceptor agonist sarafotoxin S6c (10−13–10−8m). In trachea from control and chronic hypoxic rats, ET-1 and sarafotoxin S6c evoked only very small, non-reproducible relaxatory responses.