Rosiglitazone Attenuated Endothelin-1-Induced Vasoconstriction of Pulmonary Arteries in the Rat Model of Pulmonary Arterial Hypertension via Differential Regulation of ET-1 Receptors

Abstract

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by a progressive increase in pulmonary arterial pressure leading to right ventricular failure and death. Activation of the endothelin (ET)-1 system has been demonstrated in plasma and lung tissue of PAH patients as well as in animal models of PAH. Recently, peroxisome proliferator-activated receptor γ (PPAR γ ) agonists have been shown to ameliorate PAH. The present study aimed to investigate the mechanism for the antivasoconstrictive effects of rosiglitazone in response to ET-1 in PAH. Sprague-Dawley rats were exposed to chronic hypoxia (10% oxygen) for 3 weeks. Pulmonary arteries from PAH rats showed an enhanced vasoconstriction in response to ET-1. Treatment with PPAR γ agonist rosiglitazone (20 mg/kg per day) with oral gavage for 3 days attenuated the vasocontractive effect of ET-1. The effect of rosiglitazone was lost in the presence of L-NAME, indicating a nitric oxide-dependent mechanism. Western blotting revealed that rosiglitazone increased ETBR but decreased ETAR level in pulmonary arteries from PAH rats. ETBR antagonist A192621 diminished the effect of rosiglitazone on ET-1-induced contraction. These results demonstrated that rosiglitazone attenuated ET-1-induced pulmonary vasoconstriction in PAH through differential regulation of the subtypes of ET-1 receptors and, thus, provided a new mechanism for the therapeutic use of PPAR γ agonists in PAH.

Figure 1

(a) Representative recordings of ET-1-induced contractions of pulmonary arteries from normoxia-, chronically hypoxic- (CH-), or rosiglitazone- (RSG-) treated CH-rats. (b) RSG ameliorated ET-1-mediated vasoconstriction in pulmonary arteries from the rats with PAH. Data were mean ± SEM from 5 to 7 rats. *P < 0.05 CH + RSG versus CH group.

Figure 2

(a) Representative recordings of ET-1-induced contractions pretreated with _L-NAME (100 μmol/L) in pulmonary arteries from normoxia-, CH-, or RSG-treated CH-rats. (b) The effect of RSG on ET-1-mediated vasoconstriction was abrogated in the presence of _L-NAME (100 μmol/L). Data were mean ± SEM from 5 to 7 rats.

Figure 3

Rosiglitazone upregulated ET_BR expression in rats with PAH. Western blotting was performed with the protein samples extracted from the pulmonary arteries of normoxia-, CH-, or RSG-treated CH-rats. Data shown are representative of three independent experiments.

Figure 4

The ameliorative effect of RSG on ET-1-induced contractions was abrogated by ET_BR antagonist. Concentration-dependent contractions to ET-1 pretreated with ET_BR antagonist A192621 (10 nmol/L) in pulmonary arteries from normoxia- (a), CH (b), or RSG-treated CH (c) rats. Data were mean ± SEM from 5 to 8 rats. *P < 0.05 versus control.