Objective-We sought to evaluate the influence of streptozotocin (STZ)-induced diabetes on renal outer medullary pO 2 and blood flow by invasive microprobes and to demonstrate feasibility that blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) can monitor these changes.Materials and Methods-A total of 60 Wistar-Furth rats were used. Diabetes was induced by STZ in 48. Animals were divided into OxyLite group (n = 30) and BOLD MRI groups (n = 30) each with a 5 subgroups of 6 animals: control and 2, 5, 14, and 28 days after induction of diabetes. Outer renal medullary oxygen tension and blood flow were measured by the combined OxyLite/OxyFlo probes. Results-BothOxyLite and BOLD MRI showed a significant increase in the renal hypoxia levels after STZ at all time points. However, no changes were observed in the outer renal medullary oxygen tension and blood flow between diabetic and control groups.Conclusions-These preliminary results suggest that hypoxic changes can be detected as early as 2 days in rat kidneys with diabetes by BOLD MRI and that these early changes are not dependent on blood flow.

Abstract-Recent studies have demonstrated that inhibition of renal medullary heme oxygenase (HO) activity and carbon monoxide (CO) significantly decreases renal medullary blood flow and sodium excretion. Given the crucial role of renal medullary blood flow in the control of pressure natriuresis, the present study was designed to determine whether renal medullary HO activity and resulting CO production participate in the regulation of pressure natriuresis and thereby the long-term control of arterial blood pressure. In anesthetized Sprague-Dawley rats, increases in renal perfusion pressure induced significant elevations of CO concentrations in the renal medulla. Renal medullary infusion of chromium mesoporphyrin (CrMP), an inhibitor of HO activity, remarkably inhibited HO activity and the renal perfusion pressure-dependent increases in CO levels in the renal medulla and significantly blunted pressure natriuresis. In conscious Sprague-Dawley rats, continuous infusion of CrMP into the renal medulla significantly increased mean arterial pressure (129Ϯ2.5 mm Hg in CrMP group versus 118Ϯ1.6 mm Hg in vehicle group) when animals were fed a normal salt diet (1% NaCl). After rats were switched to a high-salt diet (8% NaCl) for 10 days, CrMP-treated animals exhibited further increases in mean arterial pressure compared with CrMP-treated animals that were kept on normal salt diet (152Ϯ4.1 versus 130Ϯ4.2 mm Hg). These results suggest that renal medullary HO activity plays a crucial role in the control of pressure natriuresis and arterial blood pressure and that impairment of this HO/CO-mediated antihypertensive mechanism in the renal medulla may result in the development of hypertension. Key Words: carbon monoxide Ⅲ sodium excretion Ⅲ bilirubin Ⅲ chromium mesoporphyrin Ⅲ nitric oxide Ⅲ high salt T he heme oxygenase (HO) catalyzes the rate-limiting step in heme degradation, producing equimolar quantities of biliverdin (BV), iron, and carbon monoxide (CO). BV is subsequently converted to bilirubin (BR) by BV reductase. 1-3 It has been shown that the products of HO are involved in the regulation of cardiovascular-renal function 3 and that induction of HO-1 by pharmacological/genetic interventions improves vascular function and ameliorates both genetic and experimental forms of hypertension. [3][4][5] However, most studies showing the contribution of HO to the regulation of blood pressure are systemic interventions and focused on the vasculature. Given the crucial role of the kidneys in the long-term control of arterial blood pressure, it is imperative to determine whether local HOs in the kidneys participate in the regulation of the renal function and arterial blood pressure and how HOs and their products work to alter the blood pressure.The 2 major functional isoforms of HO are the inducible (HO-1) and the constitutive (HO-2) forms. Numerous tissues, 1 including the kidneys, 6 express HOs. Previous studies have reported that both HO-1 and HO-2 are more abundantly expressed in the renal medulla than in the renal cortex. 6,7 It...

/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...