rGLP-1 has antihypertensive and cardiac and renoprotective effects in Dahl S rats fed a high salt diet. The antihypertensive effect of rGLP-1 in Dahl S rats is due mainly to its diuretic and natriuretic effects, rather than an effect to improve insulin-resistance.

Abstract-The present study evaluated whether reactive oxygen species-induced alterations in bioavailability of 20-HETE in the kidney contribute to the antihypertensive and renoprotective actions of antioxidant therapy with Tempol in the Dahl salt-sensitive (DS) rat. Superoxide inhibited the synthesis of 20-HETE by renal cortical microsomes and enhanced breakdown of 20-HETE to a more polar product. Addition of Tempol (1 mmol/L) to the drinking water reduced mean arterial pressure from 187Ϯ9 to 160Ϯ3 mm Hg in DS rats fed an 8%-NaCl diet for 2 weeks. 20-HETE excretion rose from 117Ϯ11 to 430Ϯ45 ng/day, and 8-isoprostane excretion fell from 14Ϯ1 to 8Ϯ1 ng/day. Tempol also increased creatinine clearance and reduced the severity of renal damage in DS rats fed a high-salt diet. Key Words: free radicals Ⅲ reactive oxygen species Ⅲ superoxide Ⅲ blood pressure Ⅲ sodium Ⅲ cytochrome P450 I ncreased oxidative stress has been reported in renovascular, 1,2 angiotensin II-induced, 3,4 mineralcorticoid, 5,6 and lead-induced hypertension, 7 as well as in the spontaneously hypertensive rat 8 -12 and Dahl salt-sensitive (DS) 13-15 genetic models of hypertension. Antioxidant therapy with the membrane-permeable superoxide dismutase (SOD) mimetic Tempol 2,3,5,11,12 or with other antioxidants such as vitamin E 16 has been reported to reduce blood pressure and/or end-organ damage in some of these models. Similarly, increased oxidative stress, induced by glutathione depletion 17 or renal medullary infusion of an SOD inhibitor, 18 has been reported to increase blood pressure in normotensive Sprague-Dawley rats. Alterations in redox status and oxidative stress have also been observed in human essential hypertensives 19,20 and in women with preeclampsia. 21 Together, these studies document that there is an association between increased oxidative stress and hypertension in man and experimental animals, but the mechanisms by which oxidative stress contribute to the development and maintenance of hypertension remain to be established.Most investigators have concluded that increased oxidative stress contributes to the development of hypertension by increasing vascular tone and reducing sodium excretion. These actions have been attributed to increased conversion of NO to peroxynitrite by reactive oxygen species (ROS), leading to decreased bioavailability of NO. However, no studies have confirmed that chronic blockade of the formation of NO attenuates the antihypertensive effects of antioxidants, or that NO donors or L-arginine (L-Arg) supplementation blocks the hypertensive actions of elevated production of ROS. Thus, it remains possible that ROS may influence renal and vascular function by some other mechanism, such as altering levels of CYP450 metabolites of arachidonic acid (AA) in the kidney or via direct effects on ion channels. In this regard, epoxyeicosatrienoic acids (EETs) and 20-HETE are the primary CYP450 metabolites of AA produced in the kidney, where they inhibit sodium transport in the proximal tubule and/or thick ascending limb ...

/ajpregu. 00713.2003.-This study examined the effects of chronic blockade of the renal formation of epoxyeicosatrienoic acids and 20-hydroxyeicosatetraenoic acid with 1-aminobenzotriazole (ABT; 50 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ip for 5 days) on pressure natriuresis and the inhibitory effects of elevations in renal perfusion pressure (RPP) on Na ϩ -K ϩ -ATPase activity and the distribution of the sodium/hydrogen exchanger (NHE)-3 in the proximal tubule of rats. In control rats (n ϭ 15), sodium excretion rose from 2.3 Ϯ 0.4 to 19.4 Ϯ 1.8 eq ⅐ min Ϫ1 ⅐ g kidney weight Ϫ1 when RPP was increased from 114 Ϯ 1 to 156 Ϯ 2 mmHg. Fractional excretion of lithium rose from 28 Ϯ 3 to 43 Ϯ 3% of the filtered load. Chronic treatment of the rats with ABT for 5 days (n ϭ 8) blunted the natriuretic response to elevations in RPP by 75% and attenuated the increase in fractional excretion of lithium by 45%. In vehicle-treated rats, renal Na ϩ -K ϩ -ATPase activity fell from 31 Ϯ 5 to 19 Ϯ 2 mol Pi ⅐ mg protein Ϫ1 ⅐ h Ϫ1 and NHE-3 protein was internalized from the brush border of the proximal tubule after an elevation in RPP. In contrast, Na ϩ -K ϩ -ATPase activity and the distribution of NHE-3 protein remained unaltered in rats treated with ABT. These results suggest that cytochrome P-450 metabolites of arachidonic acid contribute to pressure natriuresis by inhibiting Na ϩ -K ϩ -ATPase activity and promoting internalization of NHE-3 protein from the brush border of the proximal tubule. 20-hydroxyeicosatetraenoic acid; epoxyeicosatrienoic acids; sodium/ hydrogen exchanger-3; sodium-potassium-adenosinetriphosphatase; kidney; proximal tubule; renal hemodynamics THE CONCEPT THAT THE KIDNEY plays an important role in the long-term control of arterial pressure is based on the phenomenon of pressure natriuresis (19,21). Despite intensive investigation, many aspects of the mechanism of pressure natriuresis remain unknown. Previous studies have indicated that pressure natriuresis is associated with elevations in renal medullary blood flow (13, 59 -61) and renal interstitial hydrostatic pressure (RIHP) (15,19,31). Na ϩ transport in the proximal tubule (22,32,33,57,76) and the loop of Henle (34, 57) decreases after elevations in renal perfusion pressure (RPP). Increases in RPP have been proposed to inhibit Na ϩ transport in the proximal tubule by increasing backflux of Na ϩ through the paracellular pathway (14,19,36). However, this mechanism seems unlikely because of the lack of an electrochemical gradient for backdiffusion of Na ϩ in the proximal tubule, and the existing Cl Ϫ gradient favors reabsorption rather than backleak. The work of Magyar et al. (37,38) and others (72,74,75,76,78,79), indicating that elevations in RPP are associated with a fall in Na ϩ -K ϩ -ATPase activity and internalization of the sodium/hydrogen exchanger (NHE)-3 from the brush border of the proximal tubule, has led to the suggestion that some signal-transduction pathway probably couples elevations in RPP to inhibition of the active transport of Na ϩ in the proximal tubule. H...

Abstract-This study examined whether chronic blockade of epoxyeicosatrienoic acids (EETs) and/or 20-hydroxyeicosatetraenoic acid (20-HETE) formation promotes development of salt-sensitive hypertension. Changes in blood pressure, renal cytochrome P450 metabolism of arachidonic acid, and 20-HETE excretion in response to a high salt diet were measured in rats chronically treated with 1-aminobenzotriazole (ABT, 50 mg/kg per day) to block EETs and 20-HETE formation or N-hydroxy-NЈ-(4-butyl-2 methylphenyl) formamidine (HET0016, 10 mg/kg per day) that selectively reduces 20-HETE formation. ABT reduced blood pressure in rats fed a low salt (0.4% NaCl) diet, but blood pressure rose by 20 mm Hg after these rats were switched to a high salt (8% NaCl) diet for 10 days. HET0016 had no effect on blood pressure in rats fed a low salt diet; however, blood pressure rose by 18 mm Hg after the rats were fed a high salt diet. 20-HETE formation in kidney homogenates rose by 30% and epoxygenase activity doubled when rats were fed a high salt diet. Chronic treatment with ABT and HET0016 inhibited the renal formation of 20-HETE by Ϸ90%. Renal epoxygenase activity decreased by 76% in ABT-treated rats and was not significantly altered in rats treated with HET0016. 20-HETE excretion rose from 470Ϯ21 to 570Ϯ41 ng/d when the rats were switched from the low to the high salt diet. 20-HETE excretion fell by 68% and 85% in rats that were chronically treated with ABT and HET0016. These results suggest that chronic blockade of the formation of 20-HETE promotes the development of salt-sensitive hypertension in rats. Key Words: rats, Dahl Ⅲ metabolism Ⅲ arachidonic acids Ⅲ blood pressure Ⅲ hypertension, sodium-dependent T he role of the cytochrome P450 (P450) metabolites of arachidonic acid (AA) in the development and maintenance of hypertension remains uncertain in part because this pathway has both prohypertensive and antihypertensive actions. 1 20-Hydroxyeicosatetraenoic acid (20-HETE) inhibits Na ϩ transport in the proximal tubule and thick ascending limb of the loop of Henle (TALH), 2-5 and compounds that induce the renal formation of 20-HETE lower blood pressure in Dahl salt-sensitive (DS) rats. 1 Similarly, epoxyeicosatrienoic acids (EETs) inhibit Na ϩ transport in the proximal tubule and collecting duct, 6,7 and increasing the renal levels of EETs with inhibitors of soluble epoxide hydrolase (sEH) reduces blood pressure in spontaneously hypertensive rats (SHRs) 8 and angiotensin II-induced hypertensive rats. 9 However, 20-HETE is also a potent vasoconstrictor, 1 and many investigators have reported that blocking the vascular effects of 20-HETE may contribute to its antihypertensive effect in SHR and other experimental models of hypertension. 10,11 Part of the problem in defining the role of the P450 metabolites of AA in the control of blood pressure has been the lack of selective inhibitors of the pathway that chronically block the formation of 20-HETE and EETs in vivo. Inhibitors that are commonly used to inhibit the formation of EETs and ...

This study examined the role of transforming growth factor-␤ (TGF-␤) in the development of hypertension and renal disease in 9-wk-old male Dahl salt-sensitive (Dahl S) rats fed an 8% NaCl diet for 3 wk. The rats received an intraperitoneal injection of a control or an anti-TGF-␤ antibody (anti-TGF-␤ Ab) every other day for 2 wk. Mean arterial pressure was significantly lower in Dahl S rats treated with anti-TGF-␤ Ab (177 Ϯ 3 mmHg, n ϭ 12) than in control rats (190 Ϯ 4 mmHg, n ϭ 17). Anti-TGF-␤ Ab therapy also reduced proteinuria from 226 Ϯ 20 to 154 Ϯ 16 mg/day. Renal blood flow, cortical blood flow, and creatinine clearance were not significantly different in control and treated rats; however, medullary blood flow was threefold higher in the treated rats than in the controls. Despite the reduction in proteinuria, the degree of glomerulosclerosis and renal hypertrophy was similar in control and anti-TGF-␤ Ab-treated rats. Renal levels of TGF-␤1 and -␤2, ␣-actin, type III collagen, and fibronectin mRNA decreased in rats treated with anti-TGF-␤ Ab. To examine whether an earlier intervention with anti-TGF-␤ Ab would confer additional renoprotection, these studies were repeated in a group of 6-wk-old Dahl S rats. Anti-TGF-␤ Ab therapy significantly reduced blood pressure, proteinuria, and the degree of glomerulosclerosis and renal medullary fibrosis in this group of rats. The results indicate that anti-TGF-␤ Ab therapy reduces blood pressure, proteinuria, and the renal injury associated with hypertension.