Cross-desensitization between angiotensin II and endothelin-1 in the pithed rat

It has been shown that in vitro angiotensin II (Ang II) potently downregulates endothelin-1 (ET-1) binding sites. In this study, we investigated in vivo the interactions between the renin-angiotensin system and ET-1. Sprague-Dawley rats were pithed, ventilated, and diastolic blood pressure (DBP) was recorded. ET-1 (1 nmol/kg) induced a biphasic response: a transient hypotension followed by a sustained increase of DBP. Captopril (5 mg/kg, i.v.) or Sar1-Ile8-Ang II (10 ng/kg/min) did not affect ET-1 responses. In other experiments, DBP was increased by infusion of methoxamine (MTX: 10, 20, 25, 32.5 micrograms/kg/min) or Ang II (50, 100, 150, 200 ng/kg/min). ET-1-induced hypotension correlated with the level of DBP (r = 0.94) for both agonists. The elevation of DBP in response to ET-1 was also related to the vascular tone but was dose-dependently attenuated by Ang II infusion when compared with MTX. Conversely, infusion of ET-1 (0.1 nmol/kg/min) blunted the pressor response to Ang II (0.1 micrograms/kg) but not to MTX (50 micrograms/kg). These doses induced the same increase of DBP in pithed control rats. Similarly, increased plasma renin activity induced by chronic salt depletion (0% NaCl) in pithed rats provoked a shift to the right of the dose-response curves to Ang II and ET-1 but not to MTX. These results suggest an in vivo cross-desensitization between ET-1 and Ang II.