Abstract-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 (ET A and ET B 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 138Ϯ13 to 136Ϯ2 mm Hg at day 15). Circulating Ang II, ET, and isoprostane levels were 35Ϯ9, 39Ϯ3, and 111Ϯ10 pg/mL, respectively, whereas urinary nitrites were 2.3Ϯ0.4 g/d. Ang II increased SBP (from 133Ϯ10 to 158Ϯ8 mm Hg), plasma Ang II (179Ϯ77 pg/mL), and isoprostanes (156Ϯ19 pg/mL) without altering ET levels (38Ϯ5 pg/mL) or urinary nitrites (1.8Ϯ0.5 g/d). Losartan prevented Ang II-induced increases in SBP and isoprostanes (SBP went from 137Ϯ5 to 120Ϯ4 mm Hg; isoprostanes were 115Ϯ15 pg/mL) while increasing urinary nitrite levels (5.2Ϯ1.1 g/d). Losartan did not alter Ang II (141Ϯ57 pg/mL) or ET (40Ϯ4 pg/mL) levels. Bosentan also blocked Ang II-induced hypertension (from 135Ϯ4 to 139Ϯ3 mm Hg) but did not decrease isoprostanes (146Ϯ14 pg/mL). Ang II (63Ϯ11 pg/mL), ET levels (46Ϯ2 pg/mL), and urinary nitrites (2.8Ϯ0.4 g/d) were not altered. Key Words: blood pressure Ⅲ free radicals Ⅲ hypertension, arterial Ⅲ kidney Ⅲ losartan T he renin-angiotensin system plays an important role in the regulation of blood pressure and may be implicated in the pathogenesis of essential hypertension. [1][2][3] Drugs that block this system (ie, ACE inhibitors and angiotensin receptor blockers) are effective in reducing blood pressure. 4 -6 Interestingly, these agents can lower blood pressure even when plasma levels of angiotensin II (Ang II) are normal or just slightly elevated. This observation has raised questions regarding the mechanisms by which Ang II participates in the maintenance of hypertension. One observation that may help explain this is that if a small nonpressor dose of Ang II is infused chronically, blood pressure gradually increases. This response, known as the slow pressor response to Ang II, 6 -8 occurs without plasma concentrations of Ang II reaching pressor levels, suggesting that blood pressure is increasing via mechanisms other than the direct vasoconstrictor action of Ang II. Yet the nature of these mechanisms remains obscure. Indeed, Ang II is known to have many other actions, which may help to explain the slow pressor responses. For instance, recent studies have shown that Ang II can stimulate the formation of other factors, such as superoxide (thus increasing oxidative stress 9 ) and endothelin (ET). 10 -12 Both of these factors are capable of increasing blood pressure and have been implicated in several models of h...

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