Reduction Of Renal Arterial Pressure Research Articles

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.

Fenofibrate Attenuates Malignant Hypertension by Suppression of the Renin-angiotensin System: A Study in Cyp1a1-Ren-2 Transgenic Rats

BackgroundMalignant hypertension is a life-threatening condition, and its pathophysiology is still poorly understood. The present study was designed to evaluate the role of interaction of the renin-angiotensin system with 20-hydroxyeicosatetraenoic acid (20-HETE), a product of cytochrome P450 (CYP)–dependent ω-hydroxylase pathway, in the pathophysiology of angiotensin II (ANG II)–dependent malignant hypertension in Cyp1a1-Ren-2 transgenic rats. MethodsMalignant hypertension was induced by 12 days׳ dietary administration of 0.3 % indole-3-carbinol (I3C), a natural xenobiotic that activates a mouse renin gene. We hypothesized that chronic administration of fenofibrate, 190mg/kg body weight, a lipid-lowering drug, should increase renal production of 20-HETE, a tubular transport inhibitor; an expected increase in sodium excretion would oppose the development of ANG II–dependent malignant hypertension. Blood pressure was monitored by radiotelemetry, and at the end of the experiment rats were prepared for renal functional studies to evaluate in vivo the pressure-natriuresis relationship in response to stepwise reductions in renal arterial pressure (RAP). ResultsIn I3C-induced rats, the treatment with fenofibrate significantly attenuated hypertension and improved the slope of the pressure-natriuresis relationship. Although fenofibrate treatment increased kidney gene and protein expression of CYP4A1, a major isoform responsible for 20-HETE formation, it did not increase renal 20-HETE concentration. On the contrary, fenofibrate treatment significantly suppressed renin gene expression, plasma renin activity and plasma and kidney ANG II levels. ConclusionsFenofibrate treatment significantly attenuated the course of malignant hypertension in I3C-induced CYP1a1-Ren-2 transgenic rats, and the mechanism responsible for antihypertensive action was fenofibrate-induced suppression of renin-angiotensin system activity.

Antihypertensive action of soluble epoxide hydrolase inhibition in Ren‐2 transgenic rats is mediated by suppression of the intrarenal renin–angiotensin system

The aim of the present study was to evaluate the hypothesis that the antihypertensive effects of inhibition of soluble epoxide hydrolase (sEH) are mediated by increased intrarenal availability of epoxyeicosatrienoic acids (EETs), with consequent improvement in renal haemodynamic autoregulatory efficiency and the pressure-natriuresis relationship. Ren-2 transgenic rats (TGR), a model of angiotensin (Ang) II-dependent hypertension, and normotensive transgene-negative Hannover Sprague-Dawley (HanSD) rats were treated with the sEH inhibitor cis-4-(4-(3-adamantan-1-yl-ureido)cyclohexyloxy)benzoic acid (c-AUCB; 26mg/L) for 48h. Then, the effects on blood pressure (BP), autoregulation of renal blood flow (RBF) and glomerular filtration rate (GFR), and on the pressure-natriuresis relationship in response to stepwise reductions in renal arterial pressure (RAP) were determined. Treatment with c-AUCB did not significantly change BP, renal autoregulation or pressure-natriuresis in normotensive HanSD rats. In contrast, c-AUCB treatment significantly reduced BP, increased intrarenal bioavailability of EETs and significantly suppressed AngII levels in TGR. However, treatment with c-AUCB did not significantly improve the autoregulatory efficiency of RBF and GFR in response to reductions of RAP and to restore the blunted pressure-natriuresis relationship in TGR. Together, the data indicate that the antihypertensive actions of sEH inhibition in TGR are predominantly mediated via significant suppression of intrarenal renin-angiotensin system activity.

Inhibition of soluble epoxide hydrolase improves the impaired pressure–natriuresis relationship and attenuates the development of hypertension and hypertension-associated end-organ damage in Cyp1a1-Ren-2 transgenic rats

In the present study, we compared the effects of treatment with the novel soluble epoxide hydrolase (sEH) inhibitor (c-AUCB) with those of the AT1 receptor antagonist losartan on blood pressure (BP), autoregulation of renal blood flow (RBF) and on glomerular filtration rate (GFR) and the pressure-natriuresis relationship in response to stepwise reduction in renal arterial pressure (RAP) in Cyp1a1-Ren-2 transgenic rats. Hypertension was induced in Cyp1a1-Ren-2 rats through dietary administration for 11 days of the natural xenobiotic indole-3-carbinol (I3C) which activates the renin gene. Treatment with c-AUCB and losartan was started 48 h before initiating administration of the diet containing I3C. Rats were prepared for renal functional studies to evaluate in-vivo renal autoregulatory efficiency when RAP was gradually decreased by an aortic clamp. I3C administration resulted in the development of severe hypertension which was associated with markedly lower basal RBF and GFR and substantially impaired autoregulatory efficiency as well as a suppression of the pressure-natriuresis relationship when compared with noninduced rats. Treatment with c-AUCB significantly decreased BP, improved autoregulatory efficiency of RBF and GFR and the slope of pressure-natriuresis relationship. Treatment with losartan completely prevented the impaired autoregulation and pressure-natriuresis relationship as well as the development of hypertension in I3C-induced rats. Our present findings indicate that chronic treatment with the sEH inhibitor c-AUCB substantially attenuates the development of malignant hypertension in I3C-induced rats likely via improvement of the renal autoregulatory efficiency and the pressure-natriuresis relationship.

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.

Effect of renal nerve stimulation on responsiveness of the rat renal vasculature.

When the renal nerves are stimulated with sinusoidal stimuli over the frequency range 0.04-0.8 Hz, low (< or =0.4 Hz)- but not high (> or =0.4 Hz)-frequency oscillations appear in renal blood flow (RBF) and are proposed to increase responsiveness of the renal vasculature to stimuli. This hypothesis was tested in anesthetized rats in which RBF responses to intrarenal injection of norepinephrine and angiotensin and to reductions in renal arterial pressure (RAP) were determined during conventional rectangular pulse and sinusoidal renal nerve stimulation. Conventional rectangular pulse renal nerve stimulation decreased RBF at 2 Hz but not at 0.2 or 1.0 Hz. Sinusoidal renal nerve stimulation elicited low-frequency oscillations (< or =0.4 Hz) in RBF only when the basal carrier signal frequency produced renal vasoconstriction, i.e., at 5 Hz but not at 1 Hz. Regardless of whether renal vasoconstriction occurred, neither conventional rectangular pulse nor sinusoidal renal nerve stimulation altered renal vasoconstrictor responses to norepinephrine and angiotensin. The RBF response to reduction in RAP was altered by both conventional rectangular pulse and sinusoidal renal nerve stimulation only when renal vasoconstriction occurred: the decrease in RBF during reduced RAP was greater. Sinusoidal renal nerve stimulation with a renal vasoconstrictor carrier frequency results in a decrease in RBF with superimposed low-frequency oscillations. However, these low-frequency RBF oscillations do not alter renal vascular responsiveness to vasoconstrictor stimuli.

Nitric oxide and the role of blood pressure variability to the kidney.

Blood pressure variability is buffered by at least two mechanisms: the arterial baroreceptor reflex and nitric oxide (NO). Only recently is the importance of blood pressure variations on cardiovascular control being investigated. Here we report of a study performed in conscious dogs, in which renovascular hypertension was induced. Reduction of renal arterial pressure (RAP) to 85 mmHg for 24 h elicited profound hypertension by 60 mmHg (vs. control: 110 +/- 3 mmHg; P < 0.01). This was accompanied by reduced volume and sodium excretion (-48% of control, P < 0.01 and -80% of control, P < 0.01, respectively) and augmented renin release by more than two-fold (P < 0.01). This intervention was compared with a protocol in which RAP was reduced to the same mean value, however, RAP oscillated by +/-10 mmHg at 0.1 Hz. This manoeuvre led to a transient increase in NO3 excretion in urine (P < 0.01), blunted antidiuresis (-14% of control) as well as antinatriuresis (-40% of control) and attenuated the increased renin release by 30% (P < 0.05). In consequence, the magnitude of blood pressure increase was only half as high as that observed during static reduction of RAP (P < 0.01). It is concluded that blood pressure oscillations to the kidney have a profound influence on water and electrolyte balance and on renin release, which alleviates the onset of Goldblatt hypertension.

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.

Buffering of blood pressure variability by the renin-angiotensin system in the conscious dog.

1. The renin-angiotensin system (RAS) participates in the compensation of major blood pressure disturbances such as haemorrhage and is involved in the tonic long-term (> 1 day) maintenance of mean arterial blood pressure (MABP). Since its contribution to the short-term (< 1 h) buffering of normal blood pressure variability is not known, this was investigated in resting conscious dogs. 2. The regulatory efficiency and the response time of the RAS were studied by an acute step reduction of renal artery pressure to 70 mmHg for 1 h using a suprarenal aortic cuff. After a delay of at least 100 s, MABP rose exponentially by 22 +/- 5 mmHg in normal dogs (n = 4), by 6 +/- 3 mmHg after angiotensin converting enzyme (ACE) inhibition (n = 4), and by 25 +/- 5 mmHg after ganglionic blockade (n = 4). MABP returned to control after release of the cuff with similar time courses. The time constants of the MABP responses were in the range of 20 min. Thus, possible feedback oscillations of the RAS would be expected around 0.0025 Hz (1/(4 x 100 s)); a buffering effect would be possible below this frequency. 3. Blood pressure variability was investigated by spectral analysis of MABP from 3.75 h recordings in the frequency ranges of 0.002-0.003 Hz (feedback oscillations) and below 0.002 Hz (buffering effect). 4. ACE inhibition (n = 7) decreased MABP by 11 +/- 2 mmHg (P < 0.05), but in both frequency ranges integrated spectral density was not affected. ACE inhibition also failed to significantly change spectral density in either of the two frequency ranges under the following conditions: (1) during ganglionic blockade (n = 7), (2) during a low-sodium diet (except for a very slight elevation below 0.002 Hz) (n = 7), and (3) when the fall of MABP induced by ACE inhibition was compensated by an angiotensin II infusion (n = 7). 5. It is concluded that in spite of its high regulatory efficiency with an adequate response time the RAS does not directly contribute to the short-term buffering of blood pressure variability, nor does it give rise to feedback oscillations under normal resting conditions. Even if the RAS is stimulated by sodium restriction its contribution to short-term blood pressure buffering is only marginal.

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.

Resetting of renal blood autoregulation during acute blood pressure reduction in hypertensive rats.

Decrease in systemic blood pressure, duration of pressure decrease, and change in the activity of the renin or the sympathetic nervous system may represent mechanisms involved in resetting the renal blood flow (RBF) autoregulation found in hypertensive rats. Autoregulation of RBF, plasma renin concentration (PRC), and the time needed for resetting to take place were studied in the nonclipped kidney before and after removal of the clipped kidney of two- kidney, one-clip (2K1C) hypertensive rats and before and after mechanical reduction of the renal arterial pressure (RAP) for 10 min in the spontaneously hypertensive rat (SHR) and in the nonclipped kidney of 2K1C hypertensive rats with and without renal denervation. Mean arterial pressure (MAP) fell from 147 to 107 mmHg 30 min after removal of the clipped kidney, and the lower pressure limit of RBF autoregulation decreased from 113 to 90 mmHg (P < 0.01); PRC fell. Mechanical reductions of RAP from 161 to 120 mmHg in the nonclipped kidney for 10 min did not change RBF, but at 120 mmHg, the lower pressure limit of RBF autoregulation was reduced from 115 mmHg before pressure reduction to 96 mmHg afterwards (P < 0.02). In SHR, similar pressure reduction for 10 min decreased the lower pressure limit of RBF autoregulation from 106 to 86 mmHg (P < 0.01). PRC was unchanged in both models, and denervation did not change RBF autoregulation. When RAP was reduced below the lower pressure limit of RBF autoregulation, RBF decreased approximately 20%; the lower pressure limit of RBF autoregulation remained unchanged. In normotensive Wistar-Kyoto rats, pressure reduction did not change the range of RBF autoregulation. These results indicate that acute normalization of the pressure range of RBF autoregulation in hypertensive rats is dependent on the degree of pressure reduction of RAP, whereas renal innervation and PRC do not play a major role. We propose that the mechanism of resetting is due to afterstretch of noncontractile elements of the vessel wall or is caused by pure myogenic mechanisms. An effect of intrarenal angiotensin cannot be excluded.

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.

Acute Effects of Angiotensin II Receptor Antagonist on Autoregulation of Zonal Glomerular Filtration Rate in Renovascular Hypertensive Rats

This study was designed to assess the renal capability to autoregulate total blood flow, glomerular filtration rate (GFR) and local GFR in outer, middle and inner cortical layers (OC, MC, IC) in the two-kidney, one-clip (2K-1C) renovascular hypertensive rat, with or without acute infusion of the angiotensin II receptor antagonist losartan (5 mg/kg, i.v.). Age-matched, sham-operated Wistar rats were used as controls. The hemodynamic study in all animals was performed 4 weeks after clipping. The clipping increased blood pressure significantly, whereas losartan reduced the renal arterial pressure (RAP) from 165+/-8 to 125+/-6 mm Hg (p < 0.01) in 2K-1C hypertensive rats and reduced the RAP from 107+/-2 to 101+/-1 mm Hg (p < 0.05) in normotensive animals. Renal blood flow (RBF), total and local GFR were decreased in the nonclipped kidney of 2K-1C hypertensive rats compared with sham-operated rats, but losartan significantly increased the RBF and GFR. RBF was well maintained in response to reduction in RAP in the nonclipped kidneys with and without losartan treatment. The capability of total GFR autoregulation was impaired in untreated 2K-1C hypertensive rats and losartan-treated sham-operated rats, whereas losartan completely abolished GFR autoregulation in the nonclipped kidney of 2K-1C hypertensive rats. Losartan impaired autoregulation of zonal GFR to the same extent in all three cortical layers of sham-operated rats, whereas in the nonclipped kidney of 2K-1C hypertensive rats losartan had a more pronounced effect on the superficial GFR autoregulation than in middle and inner cortex, indicating that angiotensin II plays a major role in regulating the GFR response to the acute changes of renal arterial pressure.

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.

ANG II dependence of tubuloglomerular feedback responsiveness in hypertensive ren-2 transgenic rats.

The present study was performed to determine the angiotensin II (ANG II) dependence of stop-flow pressure (SFP) tubuloglomerular feedback responses in hypertensive transgenic rats [strain name: TGR(mRen2)27] harboring the mouse ren-2 renin gene. SFP feedback responses to increases in late proximal perfusion rate were assessed in pentobarbital-anesthetized male ren-2 transgenic rats during control conditions and after administration of the AT1 receptor antagonist, L-158,809 (1 mg/kg iv). During control conditions, increases in late proximal perfusion rate elicited flow-dependent decreases in SFP. The magnitude of the maximal SFP feedback response to a late proximal perfusion rate of 40 nl/min averaged 16.1 +/- 1.4 mmHg (n = 7), a value higher than that normally observed in normotensive rats. Administration of L-158,809 decreased mean arterial blood pressure (174 +/- 6 vs. 117 +/- mmHg, P < 0.01, n = 10) and attenuated the magnitude of the maximal SFP feedback response by 84 +/- 4% (16.1 +/- 1.4 vs. 2.6 +/- 0.5 mmHg, P < 0.01, n = 7). In contrast, mechanical reduction of renal arterial pressure from 179 +/- 5 to 113 +/- 1 mmHg (P < 0.01, n = 7) attenuated the magnitude of the maximal SFP feedback response by only 43 +/- 5% (14.4 +/- 1.9 vs. 7.9 +/- 0.7 mmHg, P < 0.01, n = 7), indicating that approximately one-half of the attenuation of SFP feed-back responses elicited by AT1 receptor blockade was due to removal of the stimulatory effect of ANG II on the sensitivity of the tubuloglomerular feedback mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

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)