Abstract-Recent studies have indicated that changes in intrarenal nitric oxide (NO) production participate in mediating arterial pressure-induced changes in urinary sodium excretion. Until recently, however, the means to measure changes in intrarenal NO activity in vivo have not been available. For the present study, changes in renal tissue NO activities were assessed directly using an NO-selective microelectrode inserted into the cortical tissue of anesthetized dogs. Control studies demonstrated that the electrode was responsive to intrarenal bolus injections of acetylcholine and to the NO donor S-nitroso-acetylpenicillamine (SNAP). Intrarenal nitro-L-arginine (50 g ⅐ kg Ϫ1 ⅐ min Ϫ1) decreased renal tissue NO concentration by 593Ϯ127 nmol/L (PϽ0.05; nϭ7). Infusions of SNAP (1, 2, and 3 g ⅐ kg Ϫ1 ⅐ min Ϫ1 for 25 minutes) in nitro-L-arginine-treated dogs (nϭ5) resulted in dose-dependent increases in renal tissue NO activity, which showed a positive correlation with changes in urinary excretion rates of NO metabolites, nitrates and nitrites, (rϭ0.62, PϽ0.05) and sodium (rϭ0.78, PϽ0.01). During graded reductions of renal arterial pressure within the autoregulatory range (144Ϯ3 to 73Ϯ2 mm Hg; nϭ10), there were decreases in tissue NO activity that were positively correlated with changes in renal arterial pressure (rϭ0.45; PϽ0.05), urinary nitrate/nitrite excretion (rϭ0.64, PϽ0.005), and urinary sodium excretion (rϭ0.46; PϽ0.05). These data support the hypothesis that acute changes in renal arterial pressure result in alterations in intrarenal NO activity, which may be responsible for the associated changes in sodium excretion. (Hypertension. 1998;32:266-272.) Key Words: nitric oxide electrode Ⅲ sodium excretion Ⅲ nitrate excretion Ⅲ pressure-diuresis N itric oxide is known to play a substantive role in the regulation of renal hemodynamics and renal excretory function.1-3 Previous studies have suggested that renal production of NO is important in the acute and long-term regulation of sodium and water excretion. [4][5][6][7] In particular, the changes in urinary sodium excretion in response to acute alterations in RAP appear to be closely associated with changes in the intrarenal production rate of NO. 4,5,8 -11 In support of this hypothesis, previous studies have demonstrated a positive relationship between RAP and urinary excretion rate of NO metabolites, nitrates and nitrites (NO 3 Ϫ / NO 2 Ϫ ), in anesthetized dogs. 12 However, direct in vivo assessment of changes in intrarenal NO activity during changes in RAP has not yet been performed. To understand further the role of NO in the pressure-natriuresis phenomenon, it is important to determine the dynamic changes in intrarenal NO activity during acute changes in RAP. However, the continuous in vivo assessment of intrarenal NO activity has not been possible until recently. [12][13][14] NO-sensing microelectrodes that provide real-time monitoring of NO concentration in biological tissues during both in vitro and in vivo conditions have been developed recently. [15][1...

Abstract-A direct relationship between renal arterial pressure (RAP) and renal interstitial hydrostatic pressure (RIHP) has been shown under conditions of efficient renal blood flow autoregulation. Experiments were performed in six anesthetized dogs to evaluate whether these RIHP responses to changes in RAP were modified during nitric oxide (NO) inhibition with nitro-L-arginine (NLA) or after administration of NO donor agents. A microtip catheter transducer was placed underneath the renal capsule to measure RIHP. Stepwise reductions in RAP (140 to 80 mm Hg) during control conditions resulted in decreases in RIHP from its basal value of 4.7Ϯ1.1 mm Hg with a slope of 0.04Ϯ0.026 mm Hg ⅐ mm Hg Ϫ1 along with decreases in urinary nitrate/nitrite excretion rate (U NOx V). Renal cortical and medullary blood flows, measured by laser-Doppler flowmetry, exhibited high autoregulatory efficiency over this RAP range. The changes in RIHP during alterations in RAP were positively correlated (rϭ0.743; PϽ0.001) with the changes in U NOx V but not with cortical or medullary blood flow. NLA infusion decreased RIHP to 1.9Ϯ0.5 mm Hg and also reduced U NOx V from 1.8Ϯ0.2 to 0.9Ϯ0.01 nmol ⅐ min Ϫ1 ⅐ g Ϫ1 . Infusion of NO donors restored RIHP (4.3Ϯ0.9 mm Hg) andDuring NLA infusion, the RIHP responses to reductions in RAP were markedly attenuated and were not restored even during constant-rate infusion of NO donors. The results suggest that changes in RIHP in response to alterations in RAP are associated with changes in intrarenal NO, suggesting a direct effect of NO to regulate RIHP. Key Words: renal regional blood flow Ⅲ laser-Doppler flowmetry Ⅲ nitrate/nitrite excretion P revious studies in dogs and rats have shown that changes in renal arterial pressure (RAP), within the autoregulatory range, are associated with changes in renal interstitial hydrostatic pressure (RIHP), and it has been suggested that these changes in RIHP contribute to the control of tubular reabsorptive function via alterations in the renal interstitial environment. [1][2][3][4][5] The mechanism responsible for RAP-induced changes in RIHP has remained difficult to explain, because renal blood flow (RBF) and peritubular capillary pressure are efficiently autoregulated during alterations in RAP over a wide range. 6 -8 Findings in volume-expanded rats that the renal medullary blood flow (MBF) is more sensitive to changes in RAP than the cortical blood flow (CBF) 9 have led to the suggestion that impaired autoregulatory efficiency of MBF may be linked to the changes in RIHP. 1,10 However, direct associations between changes in RIHP and changes in regional blood flows in the kidney during alterations in RAP have not been established. In addition, studies in dogs as well as in euvolumic rats have failed to demonstrate reduced autoregulatory efficiency of MBF. 6,9,11,12 Inhibition of nitric oxide (NO) synthesis in rats was shown to decrease RIHP and attenuate RIHP responses to changes in renal perfusion pressure. 3 Moreover, selective inhibition of NO in the rat renal med...

The relative roles of ANG II and bradykinin (BK) in the regulation of renal medullary circulation have remained unclear. We compared the contributions of ANG II and BK to the renal medullary blood flow (MBF) responses to angiotensin-converting enzyme (ACE) inhibition (enalaprilat, 33 μg ⋅ kg−1 ⋅ min−1) in dogs maintained on a normal-salt diet (0.63%, 3 days, n = 14; group 1) with those fed a low-salt diet (0.01%, 5 days, n = 14; group 2), which upregulates both the kallikrein-kinin and the renin-angiotensin systems. MBF responses to ACE inhibition were evaluated either before ( n = 7) or after ( n = 7) treatment with the BK B2 receptor blocker icatibant (100–300 μg) in both groups. Laser-Doppler needle flow probes were used to determine relative changes in MBF and cortical blood flow (CBF). ACE inhibition increased MBF ( group 1, 33 ± 9%, P ≤ 0.01; group 2, 24 ± 9%, P ≤ 0.005) as well as CBF ( group 1, 23 ± 2%, P ≤ 0.006; group 2, 28 ± 10%, P ≤ 0.05). These responses were prevented by prior blockade of B2receptors in group 2, but not in group 1. These data indicate that under normal sodium intake, increases in MBF and CBF caused by ACE inhibition are primarily due to reduced intrarenal ANG II levels. In contrast, the renal vasodilatory responses to ACE inhibition in dogs on low salt intake were markedly dependent on the activation of BK B2 receptors.

Abstract-A direct relationship between renal arterial pressure (RAP) and cortical tissue nitric oxide (NO) without changes in glomerular filtration rate and attenuated RAP versus U Nox V and U Na V relationships. Total and regional blood flows, as measured by electromagnetic and laser Doppler needle flow probes, respectively, remained autoregulated both before and during NLA infusion. These data support the hypothesis that acute changes in RAP elicit changes in intrarenal NO production, which may participate in the mediation of pressure natriuresis. Key Words: natriuresis Ⅲ nitric oxide Ⅲ selective electrode Ⅲ laser Doppler flowmetry I t is well appreciated that endogenous nitric oxide (NO) is an important regulator of renal hemodynamics and renal function. [1][2][3][4][5] Evidence accumulated during recent years indicates that NO exerts a substantive role in regulating tubular sodium reabsorption and in mediating renal arterial pressure (RAP)-induced changes in urinary sodium excretion (U Na V). [1][2][3][4][5][6][7][8][9][10][11][12] Changes in U Na V during acute alterations in RAP within autoregulatory range have been demonstrated to be associated with parallel changes in the urinary excretion rate of NO metabolites nitrate and nitrite (U NOx V). 6 More recently, we have also demonstrated a direct relationship between RAP and cortical tissue NO activity with a NO-selective microelectrode in the canine kidney. 12 However, studies have suggested that the deeper nephrons rather than the superficial cortical nephrons are primarily involved in pressure-induced natriuretic responses. [13][14][15] Thus, it is possible that medullary rather than cortical tissue NO activity is of more direct interest in relation to the mechanism of pressure natriuresis.In the present study, we evaluated the responses to alterations in RAP on tissue NO activity in the renal medulla of anesthetized dogs. An NO-selective microelectrode was used to assess the changes in renal tissue NO activity in vivo as shown previously. 12,16 MethodsExperiments were performed in 6 mongrel dogs (17 to 21 kg body wt) of either sex supplied by an accredited dealer (Martin Creek Kennels, Williford, Ark). All procedures that involved animals were reviewed and approved by the Animal Care and Use Committee of Tulane University, New Orleans, La. To achieve a positive sodiumreplete state, dogs received supplemental amounts of sodium chloride (1.5 g/kg body wt per day for 3 days) in the normal laboratory diet. On the morning of the experiment, the dogs were anesthetized with pentobarbital sodium (30 mg/kg body wt IV); surgical anesthesia was maintained throughout the experiments by additional doses of pentobarbital sodium as needed. A cuffed endotracheal tube was inserted into the trachea to allow positive pressure ventilation with an artificial respirator at a breath rate of 18 per minute and a stroke volume of Ϸ15 mL/kg body wt. Body temperature was measured continuously by a telethermometer placed in the rectum of the dog and was maintained within normal r...

The relative contributions of ANG II and bradykinin (BK) to the renal regional blood flow responses during angiotensin-converting enzyme (ACE) inhibition remain unclear. This study was performed to evaluate renal cortical (CBF) and medullary blood flow (MBF) responses to intrarterial administration of enalaprilat (33 microg. kg(-1). min (-1)) after blockade of the ANG II AT(1 )receptors with candesartan (100 microg) in 7 dogs fed a low-salt diet (0.01%) for 5 days. Laser-Doppler flowmetry was used to measure relative changes in CBF and MBF. Candesartan alone increased CBF (+20 +/- 2%) and MBF (+22 +/- 7%). Enalaprilat infusion after candesartan administration resulted in further increases in both CBF (+21 +/- 5%) and MBF (+41 +/- 8%). However, the relative changes in MBF were significantly greater (P < 0.01) than those in CBF. Administration of the BK B(2) receptor blocker icatibant (300 microg) after enalaprilat returned CBF and MBF to values seen with candesartan alone. These data support a substantive role for BK potentiation during ACE inhibitor-induced renal vasodilation in dogs maintained on a low-sodium diet, with a relatively greater effect on MBF compared to CBF.