Background: Roles of endothelin (ET) receptors (R) and of the endothelium on ET-1-induced pulmonary vasoreactivity are subjects of debate. This stems from endothelial ET_B-R that can release both vasodilators and vasoconstrictors. The aim of this study was to evaluate the roles of the endothelium and of ET-Rs on ET-1-induced pulmonary vasoreactivity. Methods: Pharmacological experiments were performed in isolated rat lungs and in pulmonary resistance arteries. Results: In isolated lungs, ET-1 and the selective ET_B-R agonist sarafotoxin 6c (S6c) induced a similar vasoconstriction. ET-1 constriction was reduced by a selective ET_A-R antagonist; however, the selective ET_B-R antagonist had no significant effect. In preconstricted lungs, ET_B-R stimulation caused mild vasodilation at low concentrations but severe vasoconstriction at higher concentrations. In isolated arteries, responses to ET-1 and S6c were not different and unaffected by removal of endothelium. Interestingly, concentrations of ET_A-R and ET_B-R antagonists that only mildly reduced ET-1 vasoconstriction when used alone, prevented maximal constriction and greatly reduced vascular sensitivity to ET-1 when used in combination. Conclusion: In rat lungs, both ET_A-R and ET_B-R contribute to ET-1-induced pulmonary vasoconstriction with evidence of interaction between receptors. A mild vasodilator role of the endothelial ET_B-R is evident only at low agonist concentration and when baseline vascular tone is increased.

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, ET A and ET B 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 ET A (A-147627), ET B (A-192621) and dual ET A/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 ET B receptor (p < 0.001) gene expressions were reduced, as were ET B receptor protein levels (p < 0.05). ET-1 induced similar vasoconstrictions in both groups. In arteries from sham animals, neither bosentan nor the ET A or the ET B receptor antagonists modified the response. In arteries from PAH rats, however, bosentan and the ET A receptor antagonist potently reduced the maximal contraction, while bosentan also reduced sensitivity (p < 0.01).

Chronic hyperendothelinemia reduces the pulmonary vasodilator reserve in response to nitric oxide. Correction by an antioxidant and L-NNA suggests that this relates to increased production of reactive oxygen species, which may have clinical relevance for conditions associated with chronic increase of ET. Further studies are required to determine if, in the long term, this could contribute to the development of pulmonary hypertension.

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Background Bendamustine is a bifunctional alkylating agent with unique properties that distinguish it from other