Endothelin-1-receptor-mediated responses in resistance vessels of young and adult spontaneously hypertensive rats

Objective To assess whether primary changes in endothelin-1 (ET-1) receptor responsiveness or secondary vessel functional modifications could characte rize the effects evoked by ET-1 in the mesenteric vascular bed (MVB) of pre hypertensive 5-week-old and 12-week-old spontaneously hypertensive rats (SH Rs). Design and methods We used male 5-week-old and 12-week-old SHRs and sex- an d age-matched Wistar-Kyoto (WKY) rats as controls. ET-1 receptor responsive ness was evaluated by ET-1 (0.04-2 mu mol/l) concentration-response curves and repeated with indomethacin and BO-123 (0.1-0.5 mu mol/l), the latter a selective ETA receptor antagonist. ETB receptor responsiveness was tested b y sarafotoxin S6c (1-100 n-mol/l) and IRL-1620(0.1-10 n-mol/l) concentratio n-response curves, obtained in the noradrenaline-precontracted MVB. Results At 5 weeks of age, ET-1 induced a similar concentration-dependent c ontraction in SHRs and WKY rats, with an overlapping BQ-123 pA2 value (nega tive common logarithm of the antagonist that produces an agonist dose ratio of 2) in the two strains. Indomethacin was ineffective in both groups. Sar afotoxin S6c and IRL-1620 both evoked an ETB-mediated, significant relaxati on, only in WKY rats. In 12-week-old SHRs, ET-1 evoked a markedly increased maximal effect compared with the response in WKY rats (P < 0.01); this was prevented by treatment with indomethacin. The BQ-123 pA2 value was higher in SHRs than in WKY rats (P < 0.01). Both sarafotoxin S6c and IRL-1620 evok ed a significant concentration-dependent relaxation in WKY rats, which was not detected in SHR preparations. Conclusions Our results could suggest that the different responses evoked b y ET-1 in the MVB of SHRs during the onset of hypertension may be related p artially to primary alterations in the ET-1 receptorial pattern and partial ly to the onset of high blood pressure, leading to an impairment in the hae modynamic balance. J Hypertens 2000, 18:893-900 (C) Lippincott Williams & W ilkins.