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.

The use of microcomputed tomography to study microvasculature in small rodents. Am J Physiol Regulatory Integrative Comp Physiol 282: R1267-R1279, 2002 10.1152/ajpregu.00560.2001.-Appropriate nephron function is dependent on the intrarenal arrangement of blood vessels. The preferred and primary means to study the architecture of intrarenal circulation has been by filling it with opaque substances such as india ink, radio-opaque contrast material, or various polymers for study by light or scanning electron microscopy. With such methodologies, superficial vessels may obscure deep vessels and little quantitative information may be obtained. Serial-section microtomy has not been practical because of problems relating to alignment and registration of adjacent sections, lost sections, and preparation time and effort. Microcomputed tomography (micro-CT) overcomes such limitations and provides a means to study the three-dimensional architecture of filled vessels within an intact rodent kidney and to obtain more quantitative information. As an example of micro-CT's capabilities, we review the use of micro-CT to study the alterations in renal microvasculature caused by the development of liver cirrhosis after chronic bile duct ligation. In this example, micro-CT evidence shows a selective decrease in cortical vascular filling in the kidney, with a maintenance of medullary vascular filling. These changes may contribute to the salt and water retention that accompanies cirrhosis. These results indicate that micro-CT is a promising method to evaluate renal vascular architecture in the intact rodent kidney relative to physiological and pathological function. kidney; imaging; microcirculation; vasculature APPROPRIATE NEPHRON FUNCTION appears to be dependent on the detailed three-dimensional interrelationship of blood vessels with the tubular components. Many techniques and/or methods have been developed to examine the microanatomic arrangement of pre-and postglomerular vasculature (4,29,36,40,54,55,59,71,98). In this respect, such efforts were prompted by early studies showing that urinary excretion varied in relation to the intrarenal environment and was dependent on the coupling of renal microcirculation and tubular components. In 1947, Trueta and colleagues (96), studying the crush syndrome in rabbits, observed that there was a shift of blood flow from the renal cortex to the medulla during hemorrhage. They suggested this shift to be the major explanation for the lack of urine flow, despite a preservation of renal blood flow (RBF). The shift of blood flow within the renal cortex from superficial short nephrons to deep long nephrons was later observed in sodium-retaining states such as cardiac insufficiency, hepatic cirrhosis, or hypovolemia (1,18,53,104). showed that changes in renal perfusion pressure, within a range (75-130 mmHg) in which RBF remains unchanged (RBF autoregulation), were followed by dramatic changes in sodium excretion. This situation is comparable to that seen in the early stages Address for reprint requ...

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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were only small nonsignificant changes in SO animals. ThereRecent work indicates that nitric oxide (NO) plays an imfore, these results indicate that the expression, activity and portant role in the systemic and renal alterations of cirrhosis.production of NO in kidneys, glomeruli, and mononuclear In the present study, we have evaluated whether the inducible lymphocyte cells is elevated in BDL rats, and this is partly NO synthase (iNOS) isoform participates in the enhanced because of a plasma-derived substance(s), which stimulates renal and systemic NO production of a rat model of cirrhosis.iNOS formation. The amelioration of the arterial hypotension In vitro and in vivo experiments were performed in rats suband the associated reduced excretory levels of these cirrhotic jected to chronic bile duct ligation (BDL) and in sham-operanimals by aminoguanidine further support the involvement ated (SO) animals. Plasma nitrite (3.1 { 0.1 mmol/L in SO of the inducible NO synthase isoform in the renal alterations and 6.6 { 0.2 mmol/L in BDL), glomerular nitrite production observed in BDL animals. (HEPATOLOGY 1997;26:268-276.) (6.4 { 0.1 vs. 9.8 { 0.1 nmol/24h/7,000 glomeruli, respectively), and mononuclear lymphocyte cells nitrite production During the last years, it has become increasingly clear that (0.3 { 0.04 vs. 0.6 { 0.12 nmol/10 6 cells, respectively) nitric oxide (NO) plays an important role as a mediator of were all significantly higher in BDL than in SO. Moreover, the systemic and renal alterations of liver cirrhosis. 1 Recent mononuclear lymphocytes and glomeruli from BDL rats studies have revealed that rats with experimentally induced showed an increased expression of macrophage-type iNOS, cirrhosis show an increased endothelium-dependent renal detected by Western blot. Kidneys from BDL animals also vasodilation, 2 as well as an increased renal sensitivity to NO showed an increased calcium-independent NO synthase activinhibition. [3][4][5] Moreover, NO inhibition results in a reduction ity, compared with those from SO rats. Constitutive endotheof the hyperdynamic circulation 3,6-7 and produces beneficial lial-type NO synthase expression in glomeruli or the activity effects on renal excretory function. 4,5,8 However, to the best of calcium-dependent NO synthase in whole kidney did not of our knowledge, no direct demonstration of increased renal show differences between BDL and SO rats. In cultured mesproduction of NO in experimental or clinical cirrhosis has angial cells from normal rats, the addition of plasma from been published. Moreover, the type of NO synthase (NOS) BDL but not of plasma from SO significantly stimulated (35%) isoforms involved and the mechanisms responsible for their nitrite production and increased the expression of macroactivation are not completely established. 9-13phage-type iNOS. In addition, administration of aminoguaIn the present study, we have evaluated whether the inducnidine (AG), a preferential iNOS inhibitor, elevated dose-deible NOS isoform participates in the enhanced renal a...

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Nitric oxide (NO) is a vasodilator substance controlling renal papillary blood flow (PBF) in the rat. In this study we have evaluated the role of AT1 angiotensin II receptors as modulators of the whole kidney and papillary vasoconstrictor effects induced by the acute or chronic inhibition of NO synthesis. Experiments have been performed in anesthetized, euvolemic Munich-Wistar rats prepared for the study of renal blood flow (RBF) and PBF. In normal rats, acute administration of the NO synthesis inhibitor N ω-nitro-l-arginine methyl ester (l-NAME) increased mean arterial pressure (MAP) and decreased RBF and PBF. Either acute or chronic treatment with the AT1 receptor blocker losartan did not modify the decreases in RBF or PBF secondary to l-NAME. In animals made hypertensive by chronic inhibition of NO, basal MAP was higher, whereas RBF and PBF were lower than in the controls. In these animals, acute or chronic administration of losartan decreased MAP and increased both RBF and PBF significantly. These results indicate that, under normal conditions, the decreases in RBF or PBF induced by the acute inhibition of NO synthesis are not modulated by AT1-receptor stimulation. However, the arterial hypertension, renal vasoconstriction, and reduced PBF present in chronic NO-deficient hypertensive rats is partially due to the effects of angiotensin II, via stimulation of AT1-receptors.

Background: we have evaluated the antihypertensive effect of several flavonoid extracts in a rat model of arterial hypertension caused by chronic administration (6 weeks) of the nitric oxide synthesis inhibitor, L-NAME. Methods: Sprague Dawley rats received L-NAME alone or L-NAME plus flavonoid-rich vegetal extracts (Lemon, Grapefruit + Bitter Orange, and Cocoa) or purified flavonoids (Apigenin and Diosmin) for 6 weeks. Results: L-NAME treatment resulted in a marked elevation of blood pressure, and treatment with Apigenin, Lemon Extract, and Grapefruit + Bitter Orange extracts significantly reduced the elevated blood pressure of these animals. Apigenin and some of these flavonoids also ameliorated nitric oxide-dependent and -independent aortic vasodilation and elevated nitrite urinary excretion. End-organ abnormalities such as cardiac infarcts, hyaline arteriopathy and fibrinoid necrosis in coronary arteries and aorta were improved by these treatments, reducing the end-organ vascular damage. Conclusions: the flavonoids included in this study, specially apigenin, may be used as functional food ingredients with potential therapeutic benefit in arterial hypertension.