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Endothelin-1-induced responses in isolated mouse vessels: the expression and function of receptor types

¹Department of Physiology and Cell Biology and ²Davis Heart and Lung Research Institute, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio 43210

Submitted 9 December 2003 ; accepted in final form 7 April 2004

Mice have been increasingly used as models for investigating cardiovascular diseases. However, the responsiveness of mouse vasculature to endothelin (ET)-1 has not been clearly established. The goal of this study was to determine the role of ET receptors (ET_A and ET_B) in mouse vessels using isometric force measurements. Results showed that in the abdominal aorta ET-1 induced a concentration-dependent contraction (EC₅₀: 1.4 nM) with maximum reaching 89.5 ± 4.9% (10 nM) of that induced by 60 mM K⁺ [with nitric oxide synthase (NOS) inhibitor N-nitro-L-arginine methyl ester (L-NAME)]. However, in the thoracic aorta or the carotid artery, ET-1 was poorly effective. RT-PCR revealed that in the endothelium-denuded abdominal aorta, the PCR product for ET_B receptors was very low compared with ET_A. Similarly in tissues treated with L-NAME, the ET_B receptor-specific agonist sarafotoxin 6c (S6c; 100 nM) induced only a minimal contraction (<5%). Meanwhile, the ET_A antagonist BQ-123 (1 µM) completely inhibited the maximum ET-1 (10 nM) contractile response. Furthermore, we found that in the abdominal aorta that had not been treated with L-NAME, ET-1-induced contraction significantly decreased. However, in such specimens, S6c was unable to induce any relaxation on phenylephrine-induced contraction. These results indicate that the role of ET receptors differs considerably among mouse vessels. In the abdominal aorta, ET_A receptor mediates a potent vasoconstrictor response, whereas ET_B has, if any, only a minimal functional presence. Also, our data suggest that ET-1 might involve a NOS-dependent vasodilation in the abdominal aorta, which remains to be further defined.

endothelin_A receptor; endothelin_B receptor; vasoconstriction; nitric oxide synthase; vasodilation

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