Functional characterization of endothelin receptors in hypertensive resistance vessels

Objective The physiological and pathophysiological functions of endothelin- 1 in modulating the regional blood flow of normal and spontaneously hyperte nsive rats (SHR) were studied in the perfused mesenteric vascular bed, a us eful model for investigating resistance vessels. Design and methods We used 15-week-old SHR and Wistar-Kyoto (WKY) rats. End othelin A (ETA) receptor responsiveness was evaluated by endothelin-1 (0.2- 2 mu mol/l) concentration-response curves, and repeated in the presence of indomethacin and the ETA and endothelin B (ETB) receptor antagonists BQ-485 and BQ-788, respectively. ETB receptor responsiveness was tested by sarafo toxin S6c concentration-response curves, obtained in the noradrenaline-prec ontracted mesenteric vascular bed, and repeated after treatment with BQ-788 and after endothelial denudation. Results In both groups, endothelin-1 induced concentration-dependent contra ction; SHR exhibited a markedly increased maximal effect compared with WKY rats (P < 0.01). BQ-485 produced a shift to the right for endothelin-1 conc entration-response curves in both groups, with a higher pA(2) (negative com mon logarithm of the antagonist that produces an agonist dose ratio of 2) v alue in SHR than in WKY rats (P < 0.01). The increase in the maximal effect produced by endothelin-1 in SHR was prevented by indomethacin, which also induced a significant increase in the endothelin-1 concentration producing the half-maximal response(EC50) in SHR (P < 0.05). Sarafotoxin S6c produced an ETB-dependent endothelium-mediated relaxant effect in WKY rats, which w as not observed in SHR. Conclusions The higher vasoconstriction induced by endothelin-1 in SHR may be related to a greater number of available ETA receptors, due to the prese nce of an ETA receptor subtype. This mechanism may be linked to the product ion of prostanoids that add to the direct endothelin-1-evoked vasoconstrict ion. These results, together with the lack of relaxation in response to sar afotoxin S6c in SHR, suggest that an imbalance in the endothelin-1 ability to induce both contraction and relaxation is present in SHR with sustained hypertension, manifesting as a greater contractile effect evoked in this st rain. J Hypertens 1999; 17:45-52 (C) Lippincott Williams & Wilkins.