Role of Endothelin and Isoprostanes in Slow Pressor Responses to Angiotensin II

We tested the hypothesis that angiotensin II (Ang II)–induced stimulations of endothelin (ET) and isoprostanes are implicated in the slow pressor responses to Ang II. We infused either vehicle (group 1) or Ang II (groups 2 to 4) intravenously at 5 ng/kg per minute via osmotic pumps for 15 days into Sprague-Dawley rats. Groups 3 and 4 received 30 mg/kg per day of either losartan (Ang II type 1 receptor blocker) or bosentan (ETA and ETB receptor blocker) in their drinking water. We measured systolic blood pressure (SBP) every 3 days during the infusion. Plasma levels of Ang II, ET, isoprostanes, and urinary nitrites were determined at 15 days. Vehicle infusion did not change SBP (from 138±13 to 136±2 mm Hg at day 15). Circulating Ang II, ET, and isoprostane levels were 35±9, 39±3, and 111±10 pg/mL, respectively, whereas urinary nitrites were 2.3±0.4 μg/d. Ang II increased SBP (from 133±10 to 158±8 mm Hg), plasma Ang II (179±77 pg/mL), and isoprostanes (156±19 pg/mL) without altering ET levels (38±5 pg/mL) or urinary nitrites (1.8±0.5 μg/d). Losartan prevented Ang II–induced increases in SBP and isoprostanes (SBP went from 137±5 to 120±4 mm Hg; isoprostanes were 115±15 pg/mL) while increasing urinary nitrite levels (5.2±1.1 μg/d). Losartan did not alter Ang II (141±57 pg/mL) or ET (40±4 pg/mL) levels. Bosentan also blocked Ang II–induced hypertension (from 135±4 to 139±3 mm Hg) but did not decrease isoprostanes (146±14 pg/mL). Ang II (63±11 pg/mL), ET levels (46±2 pg/mL), and urinary nitrites (2.8±0.4 μg/d) were not altered. In conclusion, our results suggest that low-dose Ang II increases isoprostanes via its Ang II type 1 receptor and causes an ET-dependent hypertension, without altering circulating ET levels.