ROLE FOR ENDOTHELIN-1 IN ANGIOTENSIN II-MEDIATED HYPERTENSION

Experiments in cultured vascular smooth muscle cells have shown that a ngiotensin II (Ang II) stimulates expression of endothelin-l. We sough t to examine role of endothelin-l in the effects of Ang II in vivo. An g II infusion in rats (0.7 mg/kg per day for 5 days) was associated wi th marked increases in vascular smooth muscle endothelin-l levels, as assessed by immunostaining. Administration of the selective endothelin type A (ETA) receptor antagonist PD 155080 (50 mg/kg per day) abrogat ed the hypertensive response to a 5-day infusion of Ang II (0.7 mg/kg per day), as did losartan (25 mg/kg per day). ETA receptor blockade du ring Ang II-mediated hypertension was associated with marked elevation s of plasma endothelin-l levels. Ang II-mediated hypertension was asso ciated with heightened vascular responsiveness to a variety of vasocon strictor agents except endothelin-l. Blockade of ETA receptor invariab ly corrected this vasoconstrictor hyperresponsiveness. We conclude tha t some of the vascular effects of Ang II thought to be unique to this hormone are likely mediated by endothelin-1.