Endothelin-receptor mediated responses in pulmonary resistance arteries: Effect of developmental age and left ventricular dysfunction

Abstract

(1) The potent vasoconstrictor endothelin-1 (ET-1) is thought to regulate pulmonary blood flow and play a role in the aetiology of pulmonary hypertension (PHT), as well as in the transition of the pulmonary circulation from fetal to neonatal life. Responses to ET-1, and the receptor subtypes involved, were studied in isolated pulmonary resistance arteries (PRAs) from a rabbit coronary ligation model of left ventricular dysfunction (LVD), and also from fetal and neonatal rabbits. (2) The rabbit coronary ligation model of LVD displayed right ventricular hypertrophy and significant increase in lung weight in animals with coronary artery ligation for 8 weeks compared to age matched sham-operated animals. Also consistent with the development of PHT was significant structural alteration demonstrated in the pulmonary vasculature of the LVD group animals. Small muscular pulmonary arteries were studied 8, 16 and 32 weeks after coronary artery ligation or sham operation. (3) In the rabbit coronary-ligation model, investigation of ET-receptor mediated responses showed an agonist potency profile, according to pEC50 values, of SXS6c > ET-3 = ET-1 in all PRAs from all 8, 16 and 32 week procedure groups. This is indicative of a predominant role of contractile ETB receptor subtypes in these vessels, (4) ET receptor subtypes in this preparation were examined further with the use of several selective antagonists. The results demonstrated a biphasic response to ET-1 in all vessels. In sham-operated rabbit PRAs, the shallow component of the response at lower ET-1 concentrations was resistant to the effects of the non-selective ETA/ETB receptor antagonist SB209670 but sensitive to BQ788, a selective ETB receptor antagonist. The steeper component of the ET-1 response, observed at higher peptide concentrations, was resistant to BQ788 but sensitive to SB209670, These differential effects of the antagonists may provide evidence for a heterogeneous population of ETB-like-receptors. Furthermore, competition radioligand binding studies in rabbit pulmonary artery membranes provided a best fit for a two-site model, thus indicating the existence of two distinct ET receptor populations in this preparation. Ki values of 6.43 x10