Chronically infusing a subpressor dose of angiotensin (Ang) II increases blood pressure via poorly defined mechanisms. We found that this hypertensive response is accompanied by increased oxidant stress and is prevented by blocking endothelin (ET) receptors. Thus, we now tested whether blocking oxidant stress decreases both blood pressure and ET levels. We infused Sprague-Dawley rats (via osmotic pumps) with either vehicle (group 1) or Ang II (5 ng. kg(-1). min(-1); groups 2 to 4) for 15 days. Groups 3 and 4 also received either tempol in the drinking water (1 mmol/L) or vitamin E (5000 IU/kg diet), respectively, for 15 days. We measured systolic blood pressure (SBP) and urinary nitrite excretion every 3 days, and on day 15 we measured systemic and renal venous plasma levels of ET, isoprostanes, and thiobarbituric acid reactive substances (TBARS). SBP in Group 1 did not change throughout the study, whereas Ang II increased SBP (from 132+/-5 to 151+/-7 mm Hg). In addition, Ang II increased the systemic and renal venous levels of isoprostanes, TBARS, and ET and caused a transient decrease in urinary nitrites (that returned to control levels by day 9). Both tempol and vitamin E prevented Ang II-induced hypertension and either prevented or tended to blunt the increase in systemic and renal isoprostanes, TBARS, and ET. Finally, both antioxidants abolished the transient decrease in urinary nitrites. These results together with our previous study suggest that subpressor-dose Ang II increases oxidant stress (and isoprostanes). This in turn increases ET levels, which participate in the hypertensive response to Ang II.

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...

Abstract-There is substantial evidence suggesting that angiotensin II plays an important role in elevating blood pressure of spontaneously hypertensive rats, despite normal plasma renin activity, and that converting enzyme inhibitors (captopril) can effectively normalize blood pressure in the spontaneously hypertensive rats. One mechanism by which angiotensin II induces hypertension is via oxidative stress and endothelin, as seen in subpressor angiotensin II-induced hypertension. In fact, it has been shown that antioxidants lower mean arterial pressure in spontaneously hypertensive rats. However, the relationship between angiotensin II, oxidative stress, and endothelin in the spontaneously hypertensive rats is still relatively undefined. This study examines the relationship between mean arterial pressure, plasma renin activity, angiotensin II, oxidative stress, and endothelin in spontaneously hypertensive rats compared with normotensive Wistar Kyoto rats, and the effects of captopril on this association. Untreated spontaneously hypertensive rats had increased plasma angiotensin II levels despite normal plasma renin activity, oxidative stress, and endothelin. Captopril treatment in spontaneously hypertensive rats lowered mean arterial pressure, angiotensin II, oxidative stress, and endothelin, and increased plasma renin activity. In contrast, captopril increased plasma renin activity (suggesting effective captopril treatment) but did not significantly alter mean arterial pressure, angiotensin II, oxidative stress, or endothelin of Wistar Kyoto rats. These results suggest that in spontaneously hypertensive rats, angiotensin II is a primary instigator of hypertension, and that captopril selectively lowers angiotensin II, oxidant stress, and endothelin, which in turn may contribute to the blood pressure-lowering efficacy of captopril in spontaneously hypertensive rats. Key Words: angiotensin II Ⅲ angiotensin-converting enzyme inhibitors Ⅲ captopril Ⅲ endothelin Ⅲ oxidative stress Ⅲ rats, spontaneously hypertensive N umerous studies have been performed to define the regulatory factors that participate in the pathogenesis of hypertension in spontaneously hypertensive rats (SHR). These studies have demonstrated that despite the presence of normal plasma renin activity (PRA), angiotensin II (Ang II) still appears to play a key role in the pathogenesis of the increased blood pressure. Blood pressure is normalized by administrating renin inhibitors, 1 converting enzyme inhibitors, 2,3 or Ang II receptor blockers. 4 -6 However, despite the efficacy of these agents in lowering blood pressure, the mechanisms that lead to the Ang II-dependent increase in blood pressure in the SHR remain undefined.One mechanism by which Ang II can induce hypertension is via oxidative stress and endothelin (ET). This pathway has been shown to be essential in the maintenance of blood pressure in several models of Ang II-dependent hypertension, including subpressor Ang II-induced hypertension [7][8][9][10][11] and 1-kidney Goldblatt hypertension...

Heme oxygenase-1 (HO-1) is induced in the vasculature in the DOCA-salt model of hypertension in rats. Whereas the HO system and its products may exert vasodilator effects, recent studies have suggested that the HO system may predispose to hypertension. The present study examined the effects of selected components of the HO system, specifically, the HO-1 isozyme and the product bilirubin in the DOCA-salt model of systemic hypertension; the experimental approach employed mutant rodent models, namely, the HO-1(-/-) mouse and the hyperbilirubinemic Gunn rat. DOCA-salt induced HO-1 protein in the aorta in HO-1(+/+) mice and provoked a significant rise in systolic arterial pressure in HO-1(-/-) mice but not in HO-1(+/+) mice; this effect could not be ascribed to impaired urinary sodium excretion or impaired glomerular filtration rate in the DOCA-salt-treated HO-1(-/-) mice. The administration of DOCA salt to uninephrectomized rats significantly increased systolic arterial pressure in wild-type rats, an effect that was attenuated in the mutant Gunn rat; this reduction in systemic hypertension in the DOCA-salt-treated Gunn rat was not due to a greater induction of HO-1 in the vasculature or to a more avid urinary sodium excretion. DOCA-salt impaired endothelium-dependent and endothelium-independent vasorelaxation in wild-type rats but not in Gunn rats; prior exposure to bilirubin repaired the defect in endothelium-dependent vasorelaxation in aortic rings in DOCA-salt-treated rats. DOCA salt stimulated vascular production of superoxide anion in wild-type but not in Gunn rats. We suggest that HO-1 and the product bilirubin may exert a countervailing effect in the DOCA-salt model of systemic hypertension.

Abstract-Subpressor doses of angiotensin II (SP-Ang II) cause a slow increase in blood pressure in rats as assessed by tail cuff plethysmography (TCP), reflecting either sustained hypertension or an exaggerated pressor response to diverse stimuli. We examined whether subpressor doses of Ang II enhance blood pressure responses to simple stress (handling of trained rats for TCP). We implanted telemetry in Sprague-Dawley rats. After 10 days of recovery and TCP training, we implanted osmotic minipumps with either SP-Ang II (50 ng/kg per minute) or vehicle, and then measured systolic blood pressure continuously in unrestrained rats for 13 days. We also recorded telemetry readings while obtaining TCP measurements every 2 days. SP-Ang II increased blood pressure from 134Ϯ19 to 159Ϯ22 mm Hg by TCP, which matched the simultaneous telemetry readings of 131Ϯ20 to 154Ϯ25 mm Hg. In contrast, SP-Ang II did not change the blood pressure in the unrestrained rats (measured with continuous telemetry: 124Ϯ2 versus 127Ϯ1 mm Hg). The blood pressure in the control rats did not change in the unrestrained state (125Ϯ3 versus 128Ϯ5 mm Hg on days 0 and 12, respectively), and only slightly increased during TCP (11Ϯ5 and 6Ϯ4 mm Hg by TCP and simultaneous telemetry, respectively; PϭNS). In summary, SP-Ang II, although unable to provoke sustained hypertension, nonetheless magnifies the pressor response to otherwise trivial stimuli. We speculate that even modestly elevated Ang II levels may contribute to hypertensive complications because such levels promote the punctuation of an apparent normotensive state by episodic hypertension occasioned by seemingly innocuous stimuli. Key Words: angiotensin II, Ⅲ hypertension, experimental Ⅲ blood pressure Ⅲ vasculature C hronically infusing a subpressor dose of angiotensin II (SP-Ang II) increases blood pressure after several days. 1-2 This hypertensive response, known as the slow pressor response to Ang II, has been shown by many laboratories including our own. 3 Most have studied this phenomenon using tail cuff plethysmography (TCP) to measure blood pressure in the conscious animals. 1,2,3 Although this technique is very valuable, it does have certain limitations. For instance, it does not allow for continuous monitoring of blood pressure. In addition, the procedure is somewhat cumbersome and involves warming the rats, placing them in restraining cages, and then inflating the tail cuff; all of these steps have been shown to induce a stress response in trained normotensive animals, which consequently may alter the blood pressure. 4,5 Recently, a radiotelemetric recording system has been developed, which permits long-term continuous monitoring of blood pressure in animals without the stress of heating, handling, or restraining. 6,7 Thus, we incorporated this new technology in our laboratory to enhance our blood pressure monitoring during SP-Ang II-induced hypertension (HTN). Using this methodology, we initially attempted to reproduce our previous findings. However, we were surprised to find that 5 ng/k...

Vitamin E improves MAP and renal function in CBDL rats, and selectively decreases renal levels of oxidative stress and ET, suggesting that local redox balance is implicated in CBDL-induced renal dysfunction.

44 Chronic infusion of subpressor doses of Ang II causes blood pressure to increase progressively over several days. The mechanisms underlying this response are unknown but may involve Ang II-induced generation of additional vasoconstrictor processes. In this study, we tested whether endothelin and/or oxidative stress are implicated in the slow pressor responses to Ang II. We infused either vehicle (group 1; n=6) or Ang II (group 2; n=5) intravenously at 5 ng/kg/min via osmotic pumps for 15 days into Sprague Dawley rats. In addition to the Ang II infusion, groups 3 and 4 (n=6 each) received 30 mg/kg/day of either losartan (an angiotensin AT 1 receptor blocker) or bosentan (a blocker of both endothelin receptors, ET A and ET B ) in their drinking water. We measured systolic blood pressure (SBP) during the infusion, and the levels of circulating Ang II and isoprostanes (a marker of oxidative stress) at the conclusion of the experiments. Rats infused with vehicle had no change in SBP (from 138±13 to 138±2 mmHg) and normal levels of Ang II (34.5±9 pg/ml) and isoprostanes (111±10 pg/ml). Ang II infusion increased SBP from 133±10 to 158±8 mmHg, as well as circulating levels of Ang II (144±65 pg/ml) and isoprostanes (156±19 pg/ml). Losartan treatment abolished Ang II induced increases in SBP (SBP went from 137±5 to 120±4 mmHg), and isoprostanes (115±15 pg/ml), without altering Ang II levels (101±30 pg/ml). Bosentan also blocked Ang II-induced increases in SBP (from 135±4 to 139±3) but did not alter the increased isoprostane levels (146±14 pg/ml). Surprisingly, bosentan blunted the increase in Ang II levels (51±10 pg/ml). In conclusion, low dose Ang II-induced increases in SBP and oxidant stress depend on the AT 1 receptor. Endothelin receptor blockade also reduces SBP, but it does so independently of reducing oxidative stress (as measured by isoprostanes).