Changes In Renal Arterial Pressure Research Articles

Renal sympathetic denervation improves pressure-natriuresis relationship in cardiorenal syndrome: insight from studies with Ren-2 transgenic hypertensive rats with volume overload induced using aorto-caval fistula

The aim was to evaluate the effects of renal denervation (RDN) on autoregulation of renal hemodynamics and the pressure-natriuresis relationship in Ren-2 transgenic rats (TGR) with aorto-caval fistula (ACF)-induced heart failure (HF). RDN was performed one week after creation of ACF or sham-operation. Animals were prepared for evaluation of autoregulatory capacity of renal blood flow (RBF) and glomerular filtration rate (GFR), and of the pressure-natriuresis characteristics after stepwise changes in renal arterial pressure (RAP) induced by aortic clamping. Their basal values of blood pressure and renal function were significantly lower than with innervated sham-operated TGR (p < 0.05 in all cases): mean arterial pressure (MAP) (115 ± 2 vs. 160 ± 3 mmHg), RBF (6.91 ± 0.33 vs. 10.87 ± 0.38 ml.min–1.g–1), urine flow (UF) (11.3 ± 1.79 vs. 43.17 ± 3.24 µl.min–1.g–1) and absolute sodium excretion (UNaV) (1.08 ± 0.27 vs, 6.38 ± 0.76 µmol.min–1.g–1). After denervation ACF TGR showed improved autoregulation of RBF: at lowest RAP level (80 mmHg) the value was higher than in innervated ACF TGR (6.92 ± 0.26 vs. 4.54 ± 0.22 ml.min–1.g–1, p < 0.05). Also, the pressure-natriuresis relationship was markedly improved after RDN: at the RAP of 80 mmHg UF equaled 4.31 ± 0.99 vs. 0.26 ± 0.09 µl.min–1.g–1 recorded in innervated ACF TGR, UNaV was 0.31 ± 0.05 vs. 0.04 ± 0.01 µmol min–1.g–1 (p < 0.05 in all cases). In conclusion, in our model of hypertensive rat with ACF-induced HF, RDN improved autoregulatory capacity of RBF and the pressure-natriuresis relationship when measured at the stage of HF decompensation.

Impaired renal autoregulation and pressure-natriuresis: any role in the development of heart failure in normotensive and angiotensin II-dependent hypertensive rats?

The aim of the present study was to assess the autoregulatory capacity of renal blood flow (RBF) and of the pressure-natriuresis characteristics in the early phase of heart failure (HF) in rats, normotensive and with angiotensin II (ANG II)-dependent hypertension. Ren-2 transgenic rats (TGR) were employed as a model of ANG II-dependent hypertension. HF was induced by creating the aorto-caval fistula (ACF). One week after ACF creation or sham-operation, the animals were prepared for studies evaluating in vivo RBF autoregulatory capacity and the pressure-natriuresis characteristics after stepwise changes in renal arterial pressure (RAP) induced by aortic clamping. In ACF TGR the basal mean arterial pressure, RBF, urine flow (UF), and absolute sodium excretion (UNaV) were all significantly lower tha n in sham-operated TGR. In the latter, reductions in renal arterial pressure (RAP) significantly decreased RBF whereas in ACF TGR they did not change. Stepwise reductions in RAP resulted in marked decreases in UF and UNaV in sham-operated as well as in ACF TGR, however, these decreases were significantly greater in the former. Our data show that compared with sham-operated TGR, ACF TGR displayed well-maintained RBF autoregulatory capacity and improved slope of the pressure-natriuresis relationship. Thus, even though in the very early HF stage renal dysfunction was demonstrable, in the HF model of ANG II-dependent hypertensive rat such dysfunction and the subsequent HF decompensation cannot be simply ascribed to impaired renal autoregulation and pressure-natriuresis relationship.

S-12-5: IMPAIRMENT OF RENAL BLOOD FLOW AUTOREGULATION AND PRESSURE-NATRIURESIS: ROLE IN THE DEVELOPMENT OF HEART FAILURE IN REN-2 TRANSGENIC HYPERTENSIVE RATS

Objective: The prognosis of patients with heart failure (HF), particularly those who were hypertensive before the onset of HF, remains poor and new therapeutic strategies are needed, based on understanding the pathophysiology of the progression of HF. We hypothesized that the kidney is here not simply a victim but also a culprit of the progression. Specifically, we hypothesized that the impairment of renal blood flow (RBF) autoregulation and pressure-natriuresis relationship is present in the very early HF phase, and precedes HF decompensation. Design and method: In Ren-2 transgenic rats (TGR), a model of hypertension with increased endogenous activity of the renin-angiotensin system (RAS), HF was induced by volume overload achieved by creation of the aorto-caval fistula (ACF). One week after ACF creation or sham-operation animals were prepared for studies evaluating in vivo RBF autoregulatory capacity and pressure-natriuresis relationship after stepwise changes in renal arterial pressure (RAP) that were induced by aortic clamps. Sham-operated TGR were evaluated at physiological level of RAP, then at RAP reduced to 125, 100, 90 and 80 mmHg. In ACF TGR RAP was reduced to 100, 90 and 80 mmHg, followed by period of RAP increased to 125 mmHg. Results: In sham-operated TGR as compared with ACF TGR the basal mean arterial pressure (156 ± 3 vs. 98 ± 3 mmHg), RBF (11.45 ± 0.6 vs. 8.13 ± 0.3 ml.min-1.g-1), urine flow (UF) (38.3 ± 3.1 vs. 8.7 ± 1.0 μl.min-1.g-1) and absolute sodium excretion (UNaV) (4.77 ± 0.54 vs. 0.46 ± 0.11 μmol.min-1.g-1) were all significantly lower. In sham-operated TGR reductions in RAP resulted in significant decreases in RBF whereas in ACF TGR it did not change in response to RAP alterations. Stepwise reductions in RAP resulted in marked decreases in UF and UNaV in sham-operated as well as in ACF TGR, however, these decreases were significantly greater in the former. Conclusions: Our data show that at the physiological RAP level ACF TGR displayed marked reduction in RBF, UF and UNaV as compared with sham-operated TGR. However, in contrast to sham-operated TGR, ACF TGR displayed well-maintained RBF autoregulatory capacity and better slope of pressure-natriuresis relationship. Thus, even in the very early HF stage the renal dysfunction is demonstrable but such dysfunction and the subsequent onset of HF decompensation cannot be simply ascribed to impaired RBF autoregulation and pressure-natriuresis relationship, at least not in the high-output HF model of originally RAS-dependent hypertensive rat.

Altered Vascular Resistance Properties and Acute Pressure-Natriuresis Mechanism in Neonatal and Weaning Spontaneously Hypertensive Rats

Although it has been extensively scrutinized, the factor(s) involved in the initiation and development of hypertension in spontaneously hypertensive rats (SHRs) remains unresolved. The objective of the present study was to determine whether, early in development, the causal mechanism(s) for the development of hypertension in young SHRs involves an integration of 2 processes, specifically an upregulation of structurally based vascular resistance properties and a rightward shift in the hemodynamic component of pressure-natriuresis. Mean arterial pressure was determined in conscious 4-week-old SHRs and Wistar-Kyoto rats via previously implanted aortic catheters. Structurally based hindlimb vascular resistance properties were assessed in 2- and 4-week-old SHRs and Wistar-Kyoto rats. Renal interstitial hydrostatic pressure was measured after short-term manipulations of renal arterial pressure (RAP) in 4-week-old, anesthetized rats. Although mean arterial pressure in conscious SHRs (113±5 mm Hg) and Wistar-Kyoto rats (110±6 mm Hg) was not significantly different at 4 weeks of age, SHRs at 2 and 4 weeks of age already had increases in structurally based vascular resistance properties of ≈30% above age- and weight-matched Wistar-Kyoto rats. Furthermore, the acute RAP-renal interstitial hydrostatic pressure relationship was found to be linear in both strains, and the temporal coupling of the stimulus to response was rapid; that is, renal interstitial hydrostatic pressure responses to changes in RAP were <2 s. Although the slope of the RAP-renal interstitial hydrostatic pressure relationship was not significantly different between strains, the relationship was significantly shifted (18%) to higher RAPs in SHRs. These results suggest that alterations in both vascular structure and renal function in young SHRs occur before elevations in mean arterial pressure.

Moment-to-Moment Characteristics of the Relationship Between Arterial Pressure and Renal Interstitial Hydrostatic Pressure

The kidney is a key controller of the long-term level of arterial pressure, in part through pressure-natriuresis. Although direct coupling of changes in renal arterial pressure to renal interstitial hydrostatic pressure (RIHP) and consequent sodium excretion is well established, few studies have characterized the moment-to-moment aspects of this process. These studies characterized the short-term hemodynamic component of pressure-natriuresis in vivo before and after autonomic nervous system and renin-angiotensin system inhibition. Changes in RIHP were determined over a range of renal arterial pressures in Wistar rats receiving no treatment, a ganglionic blocker (hexamethonium; 20 mg/kg per hour IV), or an angiotensin II type 1 receptor blocker (losartan; 10 mg/kg per hour IV). After a series of changes in renal arterial pressure, a delay of only ≈1 second was found for the onset of RIHP responses that was independent of the stimulus magnitude and neurohumoral manipulation; however, completion of the full RIHP response was within ≈15 seconds for renal arterial pressure changes of ≤30 mm Hg. The overall slope of the renal arterial pressure- RIHP relationship (0.09±0.01) was also not affected by autonomic nervous system and renin-angiotensin system inhibition despite decreasing renal arterial pressure (↓40% and ↓28%, respectively). Separate assessment of this relationship above and below the prevailing arterial pressure revealed that the pressor versus the depressor portion was blunted (P<0.001), a difference that was abolished after autonomic nervous system and renin-angiotensin system inhibition. The results suggest that spontaneous changes in arterial pressure are coupled to moment-to-moment changes in RIHP over a wide range of pressures, emphasizing a likely role for the dynamic component of the renal arterial pressure-RIHP relationship in the modulation of sodium excretion and, hence, arterial pressure.

SUPEROXIDE ACTIVITY DOES NOT PLAY A ROLE IN THE MEDIATION OF PRESSURE NATRIURESIS.

Nitric oxide (NO) synthase inhibition enhances superoxide (O2−) activity and attenuates arterial pressure induced natriuretic responses in the kidney. To examine whether an alteration in O2− activity involved in the mediation of pressure natriuresis, we evaluated the renal responses to acute changes in renal arterial pressure (RAP), before and during intra-arterial administration NO synthase inhibitor, nitro-L-arginine (NLA, 50 μg/kg/min) followed by co-infusion of NLA and a O2− scavenger, tempol (0.5 mg/kg/min) in the denervated kidneys of 5 anesthetized sodium replete dogs. As reported earlier, NLA infusion alone decreased renal blood flow (4.9 ± 0.8 to 3.3 0.5 mL/min/g), sodium excretion (UNaV; 0.93 ± 0.16 to 0.23 ± 0.06 μmol/min/g) without an appreciable change in glomerular filtration rate (0.71 ± 0.03 to 0.67 ± 0.10 mL/min/g). UNaV responses to stepwise reductions in RAP (140 to 90 mmHg) were attenuated during NLA infusion (RAP vs UNaV slope decreased from 0.05 ± 0.002 to 0.02 ± 0.002 μmol/min/g/mmHg; P<0.003). Co-infusion of tempol with NLA increased sodium excretion (0.42 ± 0.1 μmol/min/g) but failed to reverse the attenuated slope of the relation between RAP and UNaV (0.02 ± 0.003 μmol/min/g/mmHg). These data do not indicate any involvement of intrarenal O2− activity in RAP induced changes in sodium excretion and further support a mediatory role of NO in the phenomenon of pressure natriuresis.

Renal interstitial fluid ATP responses to arterial pressure and tubuloglomerular feedback activation during calcium channel blockade

A close relationship between changes in renal interstitial fluid (RIF) ATP concentrations and renal autoregulatory or tubuloglomerular feedback (TGF)-dependent changes in renal vascular resistance (RVR) has been demonstrated, but it has not been determined whether the changes in RIF ATP are a consequence or the cause of the changes in RVR. The present study was performed in anesthetized dogs to assess the changes in RIF ATP following changes in renal arterial pressure (RAP) or stimulation of the TGF mechanism under conditions where changes in RVR were prevented by nifedipine, a calcium channel blocker. RIF ATP levels were measured by using microdialysis probes. Intra-arterial infusion of nifedipine (0.36 microg x kg(-1) x min(-1)) increased renal blood flow (RBF: from 4.49 +/- 0.27 to 5.34 +/- 0.39 ml x min(-1) x g(-1)) and glomerular filtration rate (GFR: from 0.84 +/- 0.07 to 1.09 +/- 0.11 ml x min(-1) x g(-1)). Under conditions of nifedipine infusion, autoregulatory adjustments in RBF, GFR, and RVR were not observed during stepwise reductions in RAP within the autoregulatory range (from 135 +/- 7 to 76 +/- 1 mmHg, n = 7). Furthermore, stimulation of the TGF mechanism with intra-arterial infusion of acetazolamide (100 microg x kg(-1) x min(-1)) did not alter RBF, GFR, and RVR (n = 7). During treatment with nifedipine, RIF ATP levels were significantly decreased in response to reductions in RAP (10.7 +/- 0.7, 5.8 +/- 0.7 and 2.8 +/- 0.3 nmol/l at 135 +/- 7, 101 +/- 4, and 76 +/- 1 mmHg, n = 7) and increased by acetazolamide infusion (from 8.8 +/- 0.8 to 17.0 +/- 1.8 nmol/l, n = 7). These results are similar to those that occurred in dogs not treated with nifedipine and thus demonstrate that the changes in RIF ATP can occur in the absence of autoregulatory or TGF-mediated changes in RVR. The data provide further support to the hypothesis that RIF ATP contributes to adjustments in RVR associated with renal autoregulation and changes in activity of the TGF mechanism.

Response to J. Schnermann: Adenosine mediates tubuloglomerular feedback

schnermann makes several strong points in his article “Adenosine mediates tubuloglomerular feedback responses” ([19][1]). We completely agree that the data provided by two independent laboratories demonstrating that tubuloglomerular feedback (TGF) responses to increases in distal perfusion rate

Nitric oxide dependency of arterial pressure-induced changes in renal interstitial hydrostatic pressure in dogs.

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 4.7+/-1.1 mm Hg with a slope of 0.04+/-0.026 mm Hg. mm Hg(-)(1) 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 (r=0.743; P:<0.001) with the changes in U(NOx)V but not with cortical or medullary blood flow. NLA infusion decreased RIHP to 1.9+/-0.5 mm Hg and also reduced U(NOx)V from 1.8+/-0.2 to 0.9+/-0.01 nmol. min(-)(1). g(-)(1). Infusion of NO donors restored RIHP (4.3+/-0.9 mm Hg) and U(NOx)V (1.5+/-0.2 nmol. min(-)(1). g(-)(1)). During 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.

Renal Interstitial ATP Responses to Changes in Arterial Pressure During Alterations in Tubuloglomerular Feedback Activity

P90 We have recently demonstrated a direct relationship between autoregulatory related changes in renal vascular resistance (RVR) and changes in renal interstitial ATP levels. To examine further the possible role for extracellular ATP in the regulation of tubuloglomerular feedback (TGF)-mediated autoregulatory adjustments in RVR, experiments were performed in 8 anesthetized dogs to assess interstitial ATP concentrations in response to changes in renal arterial pressure (RAP) during augmented and diminished activity of the TGF mechanism. Using a microdialysis method, interstitial ATP levels were assessed at different levels of RAP before and during intra-arterial administration of acetazolamide (ACZ; 100 μg/kg/min, n=4) which increases solute delivery to the macula densa thus augmenting TGF activity, and after furosemide treatment (10 μg/kg/min, n=4) which inactivates the TGF mechanism. During the control period, stepwise reductions in RAP within the autoregulatory range from ambient pressure (126±4 mmHg) to 100±2 mmHg (step-1: S1) and 76±2 mmHg (step-2: S2) resulted in significant decreases in ATP concentrations from 8.9±0.7 to 6.3±0.6 nM (S1) and 4.0±0.5 nM (S2). ACZ decreased renal blood flow (RBF; -22±6%) and glomerular filtration rate (GFR; -28±4%), and increased RVR (22±2%) and ATP concentrations (7.9±0.9 to 14.3±1.8 nM). During ACZ infusion, the autoregulatory efficiency of RBF and GFR were maintained, and ATP levels were significantly decreased in responses to reductions in RAP (8.8±0.8 nM in S1 and 6.5±0.7 nM in S2). Inhibition of the TGF mechanism by furosemide increased RBF (32±9%) and GFR (17±2%), and decreased RVR (25±6%); ATP levels concentrations decreased from 8.7±1.1 to 5.4±0.9 nM. Furosemide caused marked impairment of RBF and GFR autoregulatory efficiency (by -17±3 and -16±6% in S1 and by -31±5 and -23±7% in S2, respectively). In addition, pressure-induced changes in ATP levels were completely prevented by furosemide (5.3±0.4 nM in S1 and 5.5±0.5 nM in S2). These data support the hypothesis that extracellular ATP contributes to the RVR adjustments that are elicited by changes in activity of the TGF mechanism.

Responses to acute changes in arterial pressure on renal medullary nitric oxide activity in dogs.

A direct relationship between renal arterial pressure (RAP) and cortical tissue nitric oxide (NO) activity in the canine kidney was reported earlier. We have conducted further experiments to evaluate medullary NO responses to alterations in RAP with the use of a NO-selective microelectrode inserted into the renal medulla of 6 anesthetized, sodium-replete dogs. Graded reductions in RAP (from 140 to 80 mm Hg) elicited decreases in medullary tissue NO concentration, with a slope of 10.2+/-4.5 nmol x L(-1) x mm Hg(-1). These changes in NO levels were associated with decreases in urinary excretion rate of nitrate and nitrite (U(NOx)V; control value, 1.7+/-0.03 nmol x min(-1) x g(-1); slope, 0.02+/-0.004 nmol x min(-1) x g(-1) x mm Hg(-1)) and sodium excretion (U(Na)V; control, 3.2+/-0.7 micromol x min(-1) x g(-1); slope, 0.06+/-0.02 micromol x min(-1) x g(-1) x mm Hg(-1)) without changes in glomerular filtration rate control (0.84+/-0.06 mL x min(-1) x g(-1)). Intra-arterial administration of the NO synthase inhibitor N(omega)-nitro-L-arginine (NLA; 50 microg x kg(-1) x min(-1)) decreased medullary NO concentration by 218+/-55 nmol x L(-1) (n=5) and attenuated the relationship between RAP and NO concentration (slope, 2.7+/-2.2 nmol x L(-1) x mm Hg(-1)). NLA infusion decreased U(NOx)V (0.8+/-0.06 nmol x min(-1) x g(-1)) and U(Na)V (1.1+/-0.2 micromol x min(-1) x g(-1)) 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.

Intrarenal Nitric Oxide Activity and Pressure Natriuresis in Anesthetized Dogs

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 microg x kg(-1) x min(-1)) decreased renal tissue NO concentration by 593+/-127 nmol/L (P<0.05; n=7). Infusions of SNAP (1, 2, and 3 microg x kg(-1) x min(-1) for 25 minutes) in nitro-L-arginine-treated dogs (n=5) 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, (r=0.62, P<0.05) and sodium (r=0.78, P<0.01). During graded reductions of renal arterial pressure within the autoregulatory range (144+/-3 to 73+/-2 mm Hg; n=10), there were decreases in tissue NO activity that were positively correlated with changes in renal arterial pressure (r=0.45; P<0.05), urinary nitrate/nitrite excretion (r=0.64, P<0.005), and urinary sodium excretion (r=0.46; P<0.05). 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.

Pressure natriuresis and autoregulation of inner medullary blood flow in canine kidney.

We have evaluated the responses to changes in arterial pressure on regional blood flows in the renal medulla and sodium excretion simultaneously in denervated kidneys of six anesthetized sodium-replete dogs. Renal regional blood flow responses were determined using laser-Doppler needle flow probes and whole-kidney blood flow was assessed using an electromagnetic flow probe. The responses to stepwise reductions in renal arterial pressure (140 to 70 mm Hg) were examined first with a laser-Doppler needle probe inserted in the outer medulla and then repeated after advancing the same probe in the inner medulla. There were no differences in the control values of total renal blood flow (4.4 +/- 0.7 to 4.5 +/- 0.5 mL.min-1.g-1), glomerular filtration rate (0.89 +/- 0.7 to 0.94 +/- 0.9 mL.min-1.g-1), sodium excretion (3.6 +/- 0.6 to 3.4 +/- 0.5 mumol.min-1.g-1), and urinary excretion rate of nitric oxide metabolites (nitrate/nitrite, 1.6 +/- 0.2 to 1.5 +/- 0.2 nmol.min-1.g-1) at the start of both experimental periods. During changes in renal arterial pressure, inner medullary blood flow exhibited efficient autoregulation similar to that in outer medullary blood flow. Usual excretory responses to reductions in renal arterial pressure as well as autoregulation of cortical and whole-kidney blood flows and glomerular filtration rate were observed in these dogs. The slopes of the relationship between arterial pressure and sodium excretion (0.046 +/- 0.007 to 0.044 +/- 0.009 mumol.min-1.g-1.mm Hg-1) or nitrate/nitrite excretion (0.014 +/- 0.003 to 0.013 +/- 0.003 nmol.min-1.g-1.mm Hg-1) were similar in both experimental periods. These data indicate that blood flow to the inner medulla is efficiently autoregulated as in outer medulla and cortex of the kidney in anesthetized dogs and demonstrate further that the arterial pressure-induced natriuretic responses do not require associated changes in medullary blood flow.

Medullary blood flow responses to changes in arterial pressure in canine kidney.

Although it is well recognized that whole kidney and cortical blood flow exhibit efficient autoregulation in response to alterations in renal arterial pressure (RAP), the autoregulatory behavior of medullary blood flow (MBF) has remained uncertain. We have evaluated MBF responses to stepwise reductions in RAP for both short-term (2 min, n = 6) and longer periods (15 min, n = 7) using single-fiber laser-Doppler flowmetry with needle probes inserted into the mid-medullary region in denervated kidneys of 13 anesthetized dogs. The changes in cortical blood flow (CBF) were assessed with either a surface probe or a needle probe inserted into the cortex. Control total renal blood flow (RBF), assessed by electromagnetic flow probe in these dogs, was 5.2 +/- 0.3 ml.min-1.g-1, and glomerular filtration rate was 0.97 +/- 0.05 ml.min-1.g-1 (n = 7). RBF, MBF, and CBF all exhibited efficient autoregulatory behavior during changes in RAP from 150 to 75 mmHg. The slopes of RAP vs. RBF, CBF, as well as MBF, were not significantly different from zero within this range of RAP. Below RAP of 75 mmHg, all indexes of blood flow showed linear decreases with reductions in pressure. The data indicate that blood flow in the renal medulla of dogs exhibits efficient autoregulatory behavior, similar to that in the cortex.

Relation between pressure natriuresis and urinary excretion of nitrate/nitrite in anesthetized dogs.

Alterations in intrarenal nitric oxide (NO) formation during changes in renal arterial pressure (RAP) have been suggested as a mechanism mediating pressure natriuresis. To test this hypothesis further, we examined the relation between RAP and the urinary excretion rate of nitrate/nitrite (NO3-/NO2-; NO metabolites) in anesthetized sodium-replete dogs before (n = 9) and during (n = 6) intrarenal infusion of the NO synthesis inhibitor nitro-L-arginine (NLA; 50 micrograms.kg-1.min-1). Urinary NO3-/NO2- concentrations were measured with the Griess reaction and spectrophotometry methods after enzymatic reduction of NO3- to NO2- in the samples. During control conditions, there were decreases in the urinary NO3-/NO2- excretion rate in response to reductions in RAP (150 to 75 mm Hg; slope, 0.04 +/- 0.01 nmol.min-1.g-1.mm Hg-1) in association with decreases in urinary sodium excretion (UNaV). There was a positive correlation between changes in NO3-/NO2- excretion rate and changes in RAP (r = .48; P < .005) or UNaV (r = .59; P < .001). NLA infusion resulted in decreases in NO3-/NO2- excretion rate (4.8 +/- 1.4 to 1.0 +/- 0.3 nmol.min-1.g-1) in association with reductions in UNaV (4.3 +/- 0.3 to 0.7 +/- 0.2 microL.min-1.g-1), fractional excretion of sodium (2.9 +/- 0.2% to 0.5 +/- 0.1%), and renal blood flow (4.8 +/- 0.3 to 3.3 +/- 0.2 mL.min-1.g-1), without changes in glomerular filtration rate. Furthermore, there was a marked attenuation of the NO3-/NO2- and sodium excretory responses to alterations in RAP during NO synthesis inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Impaired renal autoregulatory ability in dogs with reduced renal mass.

In normal dogs, the renal autoregulatory mechanism limits the effect of changes in renal arterial pressure (RAP) on RBF, renal outer cortical blood flow (OCBF), and GFR by adjusting the vascular tone of the preglomerular arterioles. To determine the extent to which autoregulatory ability was impaired in remnant renal tissue in dogs, the effects of variations in RAP on RBF, OCBF, and GFR were studied after sham-operation (Group 1; N = 5), 3/4 nephrectomy (Group 2; N = 5), or 7/8 nephrectomy (Group 3; N = 5). In Group 1, the RBF, OCBF, and GFR were not significantly affected by variations in RAP between 75 and 125 mm Hg, indicating intact renal autoregulatory ability. In contrast, both groups of partially nephrectomized dogs exhibited a loss of renal autoregulatory ability below 100 mm Hg (P < 0.05). As RAP rose above 100 mm Hg, dogs with 7/8 nephrectomy exhibited a greater increase than control dogs in RBF (0.586 +/- 0.211 versus -0.080 +/- 0.030 percent change in RBF/mm Hg change in RAP; P < 0.05), OCBF (0.408 +/- 0.157 versus -0.059 +/- 0.054 percent change in RBF/mm Hg change in RAP; P < 0.05), and GFR (0.784 +/- 0.230 versus 0.134 +/- 0.049 percent change in RBF/mm Hg change in RAP; P < 0.05). The ability of the renal vasculature to maintain renal function stable above 100 mm Hg was intermediate in Group 2 and not significantly different from corresponding values for Group 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Nitric oxide in the kidney: synthesis, localization, and function.

The characterization and cloning of constitutive and inducible nitric oxide (NO)-synthesizing enzymes and the development of specific inhibitors of the L-arginine NO pathway have provided powerful tools to define the role of NO in renal physiology and pathophysiology. There is increasing evidence that endothelium-derived NO is tonically synthesized within the kidney and that NO plays a crucial role in the regulation of renal hemodynamics and excretory function. Bradykinin and acetylcholine induce renal vasodilation by increasing NO synthesis, which in turn leads to enhancement of diuresis and natriuresis. The blockade of basal NO synthesis has been shown to result in decreases of renal blood flow and sodium excretion. These effects are partly mediated by an interaction between NO and the renin angiotensin system. Intrarenal inhibition of NO synthesis leads to reduction of sodium excretory responses to changes in renal arterial pressure without an effect on renal autoregulation, suggesting that NO exerts a permissive or a mediatory role in pressure natriuresis. Nitric oxide released from the macula densa may modulate tubuloglomerular feedback response by affecting afferent arteriolar constriction. Nitric oxide produced in the proximal tubule possibly mediates the effects of angiotensin on tubular reabsorption. In the collecting duct, an NO-dependent inhibition of solute transport is suggested. The L-arginine NO pathway is also active in the glomerulus. Under pathologic conditions such as glomerulonephritis, NO generation is markedly enhanced due to the induction of NO synthase, which is mainly derived from infiltrating macrophages. An implication of NO in the mechanism of proteinuria, thrombosis mesangial proliferation, and leukocyte infiltration is considered. In summary, the data presented on NO and renal function have an obvious clinical implication. A role for NO in glomerular pathology has been established. Nitric oxide is the only vasodilator that closely corresponds to the characteristics of essential hypertension. Using chronic NO blockade, models of systemic hypertension will provide new insights into mechanisms of the development of high blood pressure.

Blockade of distal nephron sodium transport attenuates pressure natriuresis in dogs.

The sodium excretory responses (UNaV) to acute changes in renal arterial pressure (RAP) during blockade of distal nephron sodium transport were evaluated in seven sodium-replete anesthetized dogs. The major distal sodium entry pathways were blocked by intrarenal infusion of amiloride (AM, 10(-5) mol/L) and bendroflumethiazide (BZ, 10(-6) mol/L). Infusion of AM plus BZ caused slight increases in renal blood flow (RBF, 4.1 +/- 0.5 to 4.6 +/- 0.4 mL.min-1.g-1; P < .001) but no changes in glomerular filtration rate (GFR, 0.96 +/- 0.05 to 1.01 +/- 0.07 mL.min-1.g-1; P = NS) or autoregulatory efficiency of RBF and GFR. There were significant increases in UNaV (2.7 +/- 0.7 to 5.2 +/- 0.6 mumol.min-1.g-1) and fractional excretion of sodium (FENa, 1.8 +/- 0.4% to 3.5 +/- 0.3%) and decreases in potassium excretion (0.59 +/- 0.10 to 0.35 +/- 0.06 mumol.min-1.g-1) during AM plus BZ infusion. During the control period and during repeat measurements in time control studies, decreases in RAP (150 to 100 mm Hg) elicited the usual decreases in UNaV (slope, 0.022 +/- 0.007 mumol.min-1.g-1.mm Hg-1; P < .01). After administration of AM plus BZ, there was a marked attenuation of the pressure-natriuretic responses, and the slopes of the RAP versus UNaV and RAP versus FENa relations at RAP levels above 100 mm Hg were not significantly different from zero. However, the pressure-natriuresis response was maintained at arterial pressure between 75 and 100 mm Hg.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal responses to intra-arterial administration of nitric oxide donor in dogs.

Inhibition of nitric oxide synthesis by intra-arterial administration of nitro-L-arginine (NLA) leads to attenuation of the slope of the relation between renal arterial pressure (RAP) and sodium excretion without an alteration in renal autoregulatory efficiency. In the present study, we examined whether only the presence of nitric oxide or, alternatively, changes in nitric oxide production during changes in RAP are required for pressure natriuresis to occur. Anesthetized sodium-replete dogs (n = 8) were treated with NLA (50 micrograms.kg-1 x min-1) to inhibit endogenous nitric oxide formation, and S-nitroso-n-acetylpenicillamine (SNAP) was infused intra-arterially at a constant rate (2 micrograms.kg-1 x min-1) to replenish intrarenal nitric oxide levels. Renal responses to reductions in RAP within the autoregulatory range were assessed before and during NLA infusion followed by SNAP+NLA infusion. As reported previously, NLA infusion alone increased renal vascular resistance and decreased renal blood flow, urine flow, sodium excretion, and fractional excretion of sodium, with no change in glomerular filtration rate. Autoregulatory efficiency remained intact, whereas the pressure-induced natriuretic responses were attenuated. During SNAP+NLA infusion, renal blood flow increased from 2.8 +/- 0.3 to 3.5 +/- 0.3 mL.min-1 x g-1 (P < .001), without significant changes in glomerular filtration rate (0.75 +/- 0.07 to 0.81 +/- 0.05 mL.min-1 x g-1); the autoregulatory efficiency of renal blood flow and glomerular filtration rate remained intact. SNAP increased urine flow (4.8 +/- 1.8 to 10.0 +/- 2.5 microL.min-1 x g-1), sodium excretion (0.63 +/- 0.26 to 1.70 +/- 0.37 mumol.min-1 x g-1), and fractional excretion of sodium (0.55 +/- 0.20% to 1.38 +/- 0.27%).(ABSTRACT TRUNCATED AT 250 WORDS)

Spontaneous pressure-flow relationships in renal circulation of conscious dogs.

Renal pressure-flow (P-F) relationships are usually evaluated by measuring effects of mechanically induced changes in renal arterial pressure (AP) on renal blood flow (RBF). We devised a method allowing evaluation of renal P-F relationships during normal changes in AP occurring spontaneously in a conscious animal rather than during artificially induced changes in AP. In 18 trials in 6 dogs standing at rest, we measured average AP and RBF for each cardiac cycle over periods of approximately 35 min (approximately 3,100 cardiac cycles/trial). AP and RBF values for each cardiac cycle were expressed as percent change (%delta) from the 35-min average (beat-to-beat changes). Slope and angle of each consecutive beat-to-beat P-F change were calculated and collated into one of eight zones representing the possible physiological mechanisms responsible for concurrent, spontaneous changes in RBF and AP. In a predominance of the cardiac cycles (approximately 43%), the spontaneous AP-RBF relationship was consistent with being mediated by arterial baroreflexes (i.e., increases in AP were accompanied by proportionately greater increases in RBF during 44.4% of cardiac cycles in which AP increased, and decreases in AP were accompanied by proportionately greater decreases in RBF during 41.4% of cardiac cycles in which AP decreased). Blockade of autonomic ganglionic transmission with hexamethonium markedly attenuated this pattern. Our results indicate that renal circulation participates in moment-to-moment control of AP via a predominant baroreflex-like pattern.