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

Abstract

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...

Inhibition of Na-K-ATPase in thick ascending limbs by NO depends on O2−and is diminished by a high-salt diet

“…The fact that O 2 Ϫ production in the thick ascending limb falls when rats are placed on a high-salt diet is consistent with the finding that oxidative stress is increased in renovascular hypertension (14) and in ANG II-induced hypertension (26,27,37). Given that Sprague-Dawley rats do not develop hypertension when placed on a high-salt diet, it is also consistent with findings in the Dahl salt-resistant rat.…”

Endothelin, Angiotensin, and Oxidative Stress in Hypertension

“…9 These effects could be prevented with bosentan, suggesting a role for ET in mediating the increase in oxidative stress in this model. They went on to demonstrate that antioxidant treatment with the superoxide dismutase mimetic, tempol, or the combination of vitamins C and E reduced Ang II-induced changes in ET expression.…”

“…4,5 Furthermore, the hypertension and changes in endothelial function associated with chronic Ang II infusion can be attenuated by selective ET A receptor antagonists 7,8 and nonselective antagonists. 9 Whereas these studies suggest a relation between Ang II and ET in the long-term regulation of arterial pressure, Riggleman et al have also shown that ET A receptor blockade prevents the renal vasoconstrictor actions of low doses of acutely administered Ang II and the natriuretic and diuretic actions of higher doses of Ang II in the rat. 10 More recently, Montanari et al had reported that an ET A selective antagonist inhibits the acute renal hemodynamic response to Ang II in humans.…”

Angiotensin II and Catecholamines Increase Plasma Levels of 8-Epi-Prostaglandin F 2α With Different Pressor Dependencies in Rats

“…Because the nonpressor dose of Ang II readily increased plasma 8-epi-PGF 2␣ levels, plasma 8-epi-PGF 2␣ does not seem to mediate the pressor properties of Ang II; this notion has also been suggested in a recent article. 23 In contrast to Ang II-infused rats, hypertension per se seemed to account for the increase in plasma 8-epi-PGF 2␣ in NE-infused rats, because all 3 antihypertensive drugs tested-prazosin, losartan, and hydralazine-were effective in blocking the increase. Increased production of ROS caused by hemodynamic alterations not linked to changes in circulating hormones may be supported by the in vitro observation that stretching vascular endothelial and smooth muscle cells results in an increased production of superoxide.…”