BACKGROUND AND PURPOSE: The endothelin (ET) system is activated in pulmonary arterial hypertension (PAH). The therapeutic value of pharmacological blockade of ET receptors has been demonstrated in various animal models and led to the current approval and continued development of these drugs for the therapy of human PAH. However, we currently incompletely comprehend what local modifications of this system occur as a consequence of PAH, particularly in small resistance arteries, and how this could affect the pharmacological response to ET receptor antagonists with various selectivities for the receptor subtypes. Therefore, the purposes of this study were to evaluate potential modifications of the pharmacology of the ET system in rat pulmonary resistance arteries from monocrotaline (MCT)-induced pulmonary arterial hypertension. EXPERIMENTAL APPROACH: ET-1 levels were quantified by ELISA. PreproET-1, ETA and ETB receptor mRNA expressions were quantified in pulmonary resistance arteries using Q-PCR, while protein expression was evaluated by Western blots. Reactivity to ET-1 of isolated pulmonary resistance arteries was measured in the presence of ETA (A-147627), ETB (A-192621) and dual ETA/B (bosentan) receptor antagonists. KEY RESULTS: In rats with PAH, plasma ET-1 increased (p < 0.001) while pulmonary levels were reduced(p < 0.05). In PAH arteries, preproET-1 (p < 0.05) and ETB receptor (p < 0.001) gene expressions were reduced, as were ETB receptor protein levels (p < 0.05). ET-1 induced similar vasoconstrictions in both groups. In arteries from sham animals, neither bosentan nor the ETA or the ETB receptor antagonists modified the response. In arteries from PAH rats, however, bosentan and the ETA receptor antagonist potently reduced the maximal contraction, while bosentan also reduced sensitivity (p < 0.01). CONCLUSIONS AND IMPLICATIONS: The effectiveness of both selective ETA and dual ETA/B receptor antagonists is markedly increased in PAH. Down-regulation of pulmonary resistance arteries ETB receptor may contribute to this finding.
BACKGROUND AND PURPOSE: The endothelin (ET) system is activated in pulmonary arterial hypertension (PAH). The therapeutic value of pharmacological blockade of ET receptors has been demonstrated in various animal models and led to the current approval and continued development of these drugs for the therapy of human PAH. However, we currently incompletely comprehend what local modifications of this system occur as a consequence of PAH, particularly in small resistance arteries, and how this could affect the pharmacological response to ET receptor antagonists with various selectivities for the receptor subtypes. Therefore, the purposes of this study were to evaluate potential modifications of the pharmacology of the ET system in rat pulmonary resistance arteries from monocrotaline (MCT)-induced pulmonary arterial hypertension. EXPERIMENTAL APPROACH: ET-1 levels were quantified by ELISA. PreproET-1, ETA and ETB receptor mRNA expressions were quantified in pulmonary resistance arteries using Q-PCR, while protein expression was evaluated by Western blots. Reactivity to ET-1 of isolated pulmonary resistance arteries was measured in the presence of ETA (A-147627), ETB (A-192621) and dual ETA/B (bosentan) receptor antagonists. KEY RESULTS: In rats with PAH, plasma ET-1 increased (p < 0.001) while pulmonary levels were reduced(p < 0.05). In PAH arteries, preproET-1 (p < 0.05) and ETB receptor (p < 0.001) gene expressions were reduced, as were ETB receptor protein levels (p < 0.05). ET-1 induced similar vasoconstrictions in both groups. In arteries from sham animals, neither bosentan nor the ETA or the ETB receptor antagonists modified the response. In arteries from PAH rats, however, bosentan and the ETA receptor antagonist potently reduced the maximal contraction, while bosentan also reduced sensitivity (p < 0.01). CONCLUSIONS AND IMPLICATIONS: The effectiveness of both selective ETA and dual ETA/B receptor antagonists is markedly increased in PAH. Down-regulation of pulmonary resistance arteries ETB receptor may contribute to this finding.
Authors: G de Nucci; R Thomas; P D'Orleans-Juste; E Antunes; C Walder; T D Warner; J R Vane Journal: Proc Natl Acad Sci U S A Date: 1988-12 Impact factor: 11.205
Authors: Cassandra C Derella; Anson M Blanks; Xiaoling Wang; Matthew A Tucker; Chase Horsager; Jin Hee Jeong; Paula Rodriguez-Miguelez; Jacob Looney; Jeffrey Thomas; David M Pollock; Ryan A Harris Journal: J Appl Physiol (1985) Date: 2021-11-11
Authors: Cassandra C Derella; Anson M Blanks; Andy Nguyen; Jacob Looney; Matthew A Tucker; Jinhee Jeong; Paula Rodriguez-Miguelez; Jeffrey Thomas; Matthew Lyon; David M Pollock; Ryan A Harris Journal: Am J Physiol Endocrinol Metab Date: 2022-04-04 Impact factor: 5.900