Autoregulatory Efficiency Research Articles

Nitric oxide blunts myogenic autoregulation in rat renal but not skeletal muscle circulation via tubuloglomerular feedback

This rat renal blood flow (RBF) study quantified the impact of nitric oxide synthase (NOS) inhibition on the myogenic response and the balance of autoregulatory mechanisms in the time domain following a 20 mmHg-step increase or decrease in renal arterial pressure (RAP). When RAP was increased, the myogenic component of renal vascular resistance (RVR) rapidly rose within the initial 7-10 s, exhibiting an approximately 5 s time constant and providing approximately 36% of perfect autoregulation. A secondary rise between 10 and 40 s brought RVR to 95% total autoregulatory efficiency, reflecting tubuloglomerular feedback (TGF) and possibly one or two additional mechanisms. The kinetics were similar after the RAP decrease. Inhibition of NOS (by l-NAME) increased RAP, enhanced the strength (79% autoregulation) and doubled the speed of the myogenic response, and promoted the emergence of RVR oscillations ( approximately 0.2 Hz); the strength (52%) was lower at control RAP. An equi-pressor dose of angiotensin II had no effect on myogenic or total autoregulation. Inhibition of TGF (by furosemide) abolished the l-NAME effect on the myogenic response. RVR responses during furosemide treatment, assuming complete inhibition of TGF, suggest a third mechanism that contributes 10-20% and is independent of TGF, slower than the myogenic response, and abolished by NOS inhibition. The hindlimb circulation displayed a solitary myogenic response similar to the kidney (35% autoregulation) that was not enhanced by l-NAME. We conclude that NO normally restrains the strength and speed of the myogenic response in RBF but not hindlimb autoregulation, an action dependent on TGF, thereby allowing more and slow RAP fluctuations to reach glomerular capillaries.

Reduced autoregulatory effectiveness in adenosine 1 receptor-deficient mice

Adjustments of renal vascular resistance in response to changes in blood pressure are mediated by an interplay between the myocyte-inherent myogenic and the kidney-specific tubuloglomerular feedback (TGF) mechanisms. Using mice with deletion of the A(1) adenosine receptor (A1AR) gene, we tested the prediction that the absence of TGF, previously established to result from A1AR deficiency, is associated with a reduction in the efficiency of autoregulation. In anesthetized wild-type (A1AR+/+) and A1AR-deficient mice (A1AR-/-), glomerular filtration rate (GFR) and renal blood flow (RBF) were determined before and after reducing renal perfusion pressure through a suprarenal aortic clamp. In response to a blood pressure reduction by 15.9 +/- 1.34 mmHg in A1AR-/- (n = 9) and by 14.2 +/- 0.9 mmHg in A1AR+/+ mice (n = 8; P = 0.31), GFR fell by 187.9 +/- 37 mul/min and by 72.3 +/- 10 mul/min in A1AR-/- and A1AR+/+ mice, respectively (P = 0.013). Similarly, with pressure reductions of 14.8 +/- 1.1 and 13.3 +/- 1.5 mmHg in A1AR-/- (n = 9) and wild-type mice (n = 8), respectively (P = 0.43), RBF fell by 0.17 +/- 0.02 ml/min in A1AR-/- mice and by only 0.08 +/- 0.02 ml/min in wild-type animals (P = 0.0039). Autoregulatory indexes for both GFR and RBF were significantly higher in A1AR-/- compared with A1AR+/+ mice, indicating reduced regulatory responsiveness in the knockout animals. We conclude that autoregulation of renal vascular resistance is less complete in A1AR-deficient mice, an effect that is presumably related to absence of TGF regulation in these animals.

Cerebral autoregulation during orthostatic stress in healthy controls and in patients with posturally related syncope.

Posturally related syncope (PRS) is a common and distressing problem, which frequently occurs in people with no apparent clinical disorder and is ultimately caused by a reduction in blood supply to the brain. The aim of this study was to compare cerebrovascular responses to orthostatic stress in otherwise healthy patients suffering from PRS, and who were shown to have a poor orthostatic tolerance (n=28), with those in healthy control subjects with good orthostatic tolerance (n=11). Responses of heart rate, arterial blood pressure, end tidal carbon dioxide and middle cerebral artery (MCA) blood flow velocity were determined during a progressive orthostatic stress test of combined head-up tilting and lower body suction, which was continued until presyncope. We assessed the efficiency of autoregulation of cerebral blood flow from the relationship between values of MCA velocity and pressure obtained over the expected range for autoregulation (> 55 mmHg). All patients with PRS had a significant correlation between MCA velocity and pressure, but this was seen in only two of the controls. Furthermore, the values of the correlation coefficients were significantly higher in patients than controls, (p<0.001). We interpret these data as indicating that autoregulation in patients with PRS is less effective than in controls and suggest that this provides evidence for a link between abnormalities of regulation of the cerebral circulation and predisposition to syncope.

Dynamics and contribution of mechanisms mediating renal blood flow autoregulation.

We investigated dynamic characteristics of renal blood flow (RBF) autoregulation and relative contribution of underlying mechanisms within the autoregulatory pressure range in rats. Renal arterial pressure (RAP) was reduced by suprarenal aortic constriction for 60 s and then rapidly released. Changes in renal vascular resistance (RVR) were assessed following rapid step reduction and RAP rise. In response to rise, RVR initially fell 5-10% and subsequently increased approximately 20%, reflecting 93% autoregulatory efficiency (AE). Within the initial 7-9 s, RVR rose to 55% of total response providing 37% AE, reaching maximum speed at 2.2 s. A secondary RVR increase began at 7-9 s and reached maximum speed at 10-15 s. Response times suggest that the initial RVR reflects the myogenic response and the secondary tubuloglomerular feedback (TGF). During TGF inhibition by furosemide, AE was 64%. The initial RVR rise was accelerated and enhanced, providing 49% AE, but it represented only 88% of total. The remaining 12% indicates a third regulatory component. The latter contributed up to 50% when the RAP increase began below the autoregulatory range. TGF augmentation by acetazolamide affected neither AE nor relative myogenic contribution. Diltiazem infusion markedly inhibited AE and the primary and secondary RVR increases but left a slow component. In response to RAP reduction, initial vasodilation constituted 73% of total response but was not affected by furosemide. The third component's contribution was 9%. Therefore, RBF autoregulation is primarily due to myogenic response and TGF, contributing 55% and 33-45% in response to RAP rise and 73% and 18-27% to RAP reduction. The data imply interaction between TGF and myogenic response affecting strength and speed of myogenic response during RAP rises. The data suggest a third regulatory system contributing <12% normally but up to 50% at low RAP; its nature awaits further investigation.

NO dependency of RBF and autoregulation in the spontaneously hypertensive rat.

In the spontaneously hypertensive rat (SHR), renal blood flow (RBF) has been reported to be very dependent on nitric oxide (NO); however, autoregulation is normal, albeit shifted to higher perfusion pressures. To test the hypothesis that in the SHR NO dependency of RBF autoregulation is diminished, we investigated RBF autoregulation in anesthetized young male SHR and normotensive Wistar-Kyoto (WKY) rats before and during acute intravenous NO synthase (NOS) inhibition with N(omega)-nitro-L-arginine (L-NNA) and urinary excretion of nitrate plus nitrite (U(NOx)V) at different renal perfusion pressures (RPP). Under baseline conditions, SHR had higher mean arterial pressure (147 +/- 4 mmHg) and renal vascular resistance (16 +/- 1 U) than WKY (105 +/- 4 mmHg and 10 +/- 0.5 U, respectively, P < 0.05). RBF was similar (9.4 +/- 0.5 vs. 10.3 +/- 0.1 ml x min(-1)x g kidney wt(-1)). Acute NOS blockade increased mean arterial pressure similarly, but there was significantly more reduction in RBF and hence an enhanced increase in renal vascular resistance in SHR (to 36 +/- 3 vs. 17 +/- 1 U in WKY, P < 0.001). The renal vasculature of SHR is thus strongly dependent on NO in maintaining basal RBF. The lower limit of autoregulation was higher in SHR than WKY in the baseline situation (85 +/- 3 vs. 71 +/- 2 mmHg, P < 0.05). Acute L-NNA administration did not decrease the lower limit in the SHR (to 81 +/- 3 mmHg, not significant) and decreased the lower limit to 63 +/- 2 mmHg (P < 0.05) in the WKY. The degree of compensation as a measure of autoregulatory efficiency attained at spontaneous perfusion pressures was comparable in SHR vs. WKY but with a shift of the curve toward higher perfusion pressures in SHR. Acute NOS blockade only increased the degree of compensation in WKY. Remarkably, U(NOx)V was significantly lower at spontaneous RPP in SHR. After reduction of RPP, the observed decrease in U(NOx)V was significantly more pronounced in WKY than in SHR. In conclusion, the renal circulation in SHR is dependent on high levels of NO; however, the capacity to modulate NO in response to RPP-induced changes in shear stress seems to be limited.

Role of angiotensin II in dynamic renal blood flow autoregulation of the conscious dog.

The influence of angiotensin II (ANGII) on the dynamic characteristics of renal blood flow (RBF) was studied in conscious dogs by testing the response to a step increase in renal artery pressure (RAP) after a 60 s period of pressure reduction (to 50 mmHg) and by calculating the transfer function between physiological fluctuations in RAP and RBF. During the RAP reduction, renal vascular resistance (RVR) decreased and upon rapid restoration of RAP, RVR returned to baseline with a characteristic time course: within the first 10 s, RVR rose rapidly by 40 % of the initial change (first response, myogenic response). A second rise began after 20-30 s and reached baseline after an overshoot at 40 s (second response, tubuloglomerular feedback (TGF)). Between both responses, RVR rose very slowly (plateau). The transfer function had a low gain below 0.01 Hz (high autoregulatory efficiency) and two corner frequencies at 0.026 Hz (TGF) and at 0.12 Hz (myogenic response). Inhibition of angiotensin converting enzyme (ACE) lowered baseline RVR, but not the minimum RVR at the end of the RAP reduction (autoregulation-independent RVR). Both the first and second response were reduced, but the normalised level of the plateau (balance between myogenic response, TGF and possible slower mechanisms) and the transfer gain below 0.01 Hz were not affected. Infusion of ANGII after ramipril raised baseline RVR above the control condition. The first and second response and the transfer gain at both corner frequencies were slightly augmented, but the normalised level of the plateau was not affected. It is concluded that alterations of plasma ANGII within a physiological range do not modulate the relative contribution of the myogenic response to the overall short-term autoregulation of RBF. Consequently, it appears that ANGII augments not only TGF, but also the myogenic response.

Interaction between nitric oxide and renal myogenic autoregulation in normotensive and hypertensive rats

Blood pressure fluctuates continuously throughout life and autoregulation is the primary mechanism that isolates the kidney from this fluctuation. Compared with Wistar rats, Brown Norway (B-N) rats display impaired renal myogenic autoregulation when blood pressure fluctuation is increased. They also are very susceptible to hypertension-induced renal injury. Because blockade of nitric oxide augments myogenic autoregulation in Wistar rats, we compared the response of the myogenic system in B-N rats to nitric oxide blockade with that of other strains [Wistar, Sprague-Dawley, Long-Evans, spontaneously hypertensive (SHR)]. Renal blood flow dynamics were assessed in isoflurane anesthetized rats before and after inhibition of nitric oxide synthase by Lomega-nitro-arginine methyl-ester (L-NAME, 10 mg/kg, iv). Under control conditions, myogenic autoregulation in the B-N rats was weaker than in the other strains. Myogenic autoregulation was not augmented after L-NAME administration in the SHR, but was augmented in all the normotensive rats. The enhancement was significantly greater in B-N rats so that after L-NAME the efficiency of autoregulation did not differ among the strains. The data suggest that nitric oxide is involved in the impaired myogenic autoregulation seen in B-N rats. Furthermore, the similarity of response in Wistar, Long-Evans, and Sprague-Dawley rats suggests that modulation by nitric oxide is a fundamental property of renal myogenic autoregulation.

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.

We recently demonstrated a direct relationship between autoregulation-related changes in renal vascular resistance (RVR) and renal interstitial ATP concentrations. To assess the possible role for extracellular ATP in the regulation of tubuloglomerular feedback (TGF)-mediated autoregulatory adjustments in RVR, renal interstitial ATP concentrations were measured with microdialysis probes in anesthetized dogs at different renal arterial pressures (RAPs) within the autoregulatory range during augmented and diminished activity of the TGF mechanism. Stepwise reductions in RAP from ambient pressure (129+/-3 mm Hg) to 102+/-2 mm Hg (step 1) and 75+/-1 mm Hg (step 2) resulted in significant decreases in ATP concentrations from 9.0+/-0.8 to 6.3+/-0.6 nmol/L in step 1 and to 4.2+/-0.5 nmol/L in step 2. Changes in RVR were highly correlated with changes in ATP concentrations (r=0.86, P<0.001, n=12). Acetazolamide (100 microgram. kg(-1). min(-1), n=6), which increases solute delivery to the macula densa, thus augmenting TGF activity, significantly decreased renal blood flow (RBF) by -16+/-2% and glomerular filtration rate (GFR) by -22+/-4% and increased ATP concentrations from 8.4+/-0.7 to 15.5+/-1.4 nmol/L. Although basal RBF and GFR levels were reduced by the acetazolamide infusion, autoregulation efficiency was maintained, and interstitial ATP concentrations were significantly decreased in response to reductions in RAP by -36+/-4% in step 1 and by -54+/-2% in step 2. The relationship between changes in RVR and interstitial ATP concentrations was preserved during acetazolamide treatment (r=0.80, P<0.01). Inhibition of the TGF mechanism by furosemide significantly increased RBF by 33+/-6% and GFR by 13+/-2% and decreased ATP concentrations from 8.9+/-1.4 to 5.0+/-0.8 nmol/L (n=6). Furosemide caused marked impairment of RBF and GFR autoregulatory efficiency (by -14+/-3% and -11+/-3% in step 1 and by -26+/-2% and -18+/-4% in step 2, respectively). In the furosemide-treated kidneys, interstitial ATP levels remained low and were not altered during reductions in RAP (4.7+/-0.7 nmol/L in step 1 and 4.7+/-0.8 nmol/L in step 2), and changes in RVR did not exhibit a correlation with changes in ATP concentrations (r=0.22, P=0.30). These data support the hypothesis that extracellular ATP contributes to autoregulatory adjustments in RVR that are mediated by changes in activity of the TGF mechanism.

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.

Impaired autoregulation of cerebral blood flow in an experimental model of traumatic brain injury.

In order to study the pathophysiology and the intracranial hemodynamics of traumatic brain injury, we have developed a modified closed-head injury model of impact-acceleration that expresses several features of severe head injury in humans, including acute and long-lasting intracranial hypertension, diffuse axonal injury, neuronal necrosis, bleeding, and edema. In view of the clinical relevance of impaired autoregulation of cerebral blood flow after traumatic brain injury, and aiming at further characterization of the model, we investigated the autoregulation efficiency 24 h after experimental closed-head injury. Cortical blood flow was continuously monitored with a laser-Doppler flowmeter, and the mean arterial blood pressure was progressively decreased by controlled hemorrhage. Relative laser-Doppler flow was plotted against the corresponding mean arterial blood pressure, and a two-line segmented model was applied to determine the break point and slopes of the autoregulation curves. The slope of the curve at the right hand of the break point was significantly increased in the closed head injury group (0.751 +/- 0.966%/mm Hg versus -0.104 +/- 0.425%/mm Hg,p = 0.028). The break point tended towards higher values in the closed head injury group (62.2 +/- 20.8 mm Hg versus 46.9 +/- 12.7 mm Hg; mean +/- SD, p = 0.198). It is concluded that cerebral autoregulation in this modified closed head injury model is impaired 24 h after traumatic brain injury. This finding, in addition to other characteristic features of severe head injury established earlier in this model, significantly contributes to its clinical relevance.

Effects of Ca(2+) channel activity on renal hemodynamics during acute attenuation of NO synthesis in the rat.

In cultured vascular muscle cells, nitric oxide (NO) has been shown to inhibit voltage-dependent Ca(2+) channels, which are involved in renal blood flow (RBF) autoregulation. Therefore, our purpose was to specify in vivo the effects of this interaction on RBF autoregulation. To do so, hemodynamics were investigated in anesthetized rats during Ca(2+) channel blockade before or after acute NO synthesis inhibition. Rats were treated intravenously with vehicle (n = 10), 0.3 mg/kg body wt N(G)-nitro-L-arginine-methyl ester (L-NAME; n = 7), 4.5 microg. kg body wt(-1). min(-1) nifedipine (n = 8) alone, or with nifedipine infused before (n = 8), after (n = 8), or coadministered with L-NAME (n = 10). Baseline renal vascular resistance (RVR) averaged 14.0 +/- 1.2 resistance units and did not change after vehicle. RVR increased or decreased significantly by 27 and 29% after L-NAME or nifedipine, respectively. Nifedipine reversed, but did not prevent, RVR increase after or coadministered with L-NAME. RBF autoregulation was maintained after L-NAME, but the autoregulatory pressure limit (P(A)) was significantly lowered by 15 mmHg. Nifedipine pretreatment or coadministration with L-NAME limited P(A) resetting or suppressed autoregulation at higher doses. Results were similar with verapamil. Intrarenal blockade of Ca(2+)-activated K(+) channels also prevented autoregulatory resetting by L-NAME (n = 8). These findings suggest NO inhibits voltage-dependent Ca(2+) channels and thereby modulates RBF autoregulatory efficiency.

Influence of hemodilution on the renal blood flow autoregulation during acute expansion in rats.

Autoregulation of renal blood flow (RBF) was studied in rats that underwent equivalent blood volume expansion with saline (Sal; 5% body wt), 7% BSA solution (1.4% body wt), and reconstituted whole blood from donor rats (WBL; 1.4% body wt). Renal perfusion pressure (RPP) and renal neural reflexes were prevented by clamping RPP and sectioning the vagus, baro/chemoreceptor, and renal nerves. Sal and BSA expansion increased RBF by approximately 60%, whereas no effect was observed with WBL. RBF autoregulation was markedly attenuated after expansion with cell-free solutions, but no change occurred in WBL-expanded rats. Correction of the fall in hematocrit in Sal- and BSA-expanded rats restored RBF and its autoregulation to control levels. Expansion with Sal or BSA after inhibition of renal vascular tone with intrarenal infusion of papaverine still increased RBF and further changed the RBF-RPP relationship. These findings suggest that the hemodilution plays a central role in the reduction of renal vascular resistance and in the attenuation of the autoregulatory efficiency of renal circulation that accompany expansion with cell-free solutions.

Integrating multiple paracrine regulators of renal microvascular dynamics.

There has been tremendous growth in our knowledge about the multiple interacting mechanisms that regulate renal microvascular function. Paracrine signals originating from endothelial and epithelial cells exert profound influences on the basal tone and reactivity of the pre- and postglomerular arterioles. Selective responsiveness of these arterioles to various stimuli is possible because of differential activating mechanisms in vascular smooth muscle cells of afferent and efferent arterioles. Afferent arterioles rely predominantly on voltage-dependent calcium channels, while efferent arterioles utilize other mechanisms for calcium entry as well as intracellular calcium mobilization. The autoregulatory responses of preglomerular arterioles exemplify the selectivity of these complex control mechanisms. The myogenic mechanism responds to increases in renal perfusion pressure through "stretch-activated" cation channels that lead to depolarization, calcium entry, and vascular contraction. Autoregulatory efficiency is enhanced by the tubuloglomerular feedback (TGF) mechanism which responds to flow-dependent changes in tubular fluid composition at the level of the macula densa and transmits signals to the afferent arterioles to alter the activation state of voltage-dependent calcium channels. Recent studies have implicated extracellular ATP as one paracrine factor mediating TGF and autoregulatory related signals to the afferent arterioles. Other paracrine agents including nitric oxide, angiotensin II, adenosine, and arachidonic acid metabolites modulate vascular responsiveness in order to maintain an optimal balance between the metabolically determined reabsorptive capabilities of the tubules and the hemodynamically dependent filtered load.

Renal hemodynamics and blood flow autoregulation during acute cyclooxygenase inhibition in male rats

After the acute inhibition of prostanoid synthesis, adjustments of renal hemodynamics may not be characterized immediately. Therefore, time-related effects of indomethacin on hemodynamics and renal blood flow (RBF) autoregulation were studied in anesthetized euvolemic male rats injected intravenously with vehicle, indomethacin (3, 4, or 5 mg/kg body wt), or meclofenamate (4 or 5 mg/kg body wt). Hemodynamics and RBF autoregulation were not influenced by vehicle injection, nor by time (n = 6). In contrast, mean arterial pressure (MAP) decreased significantly from 117 +/- 4 to 103 +/- 3 mmHg, and RBF progressively and significantly increased from 8.00 +/- 0.34 to 9.17 +/- 0.50 ml/min in the 3 mg/kg body wt indomethacin group (n = 8). Treatment with the higher doses of indomethacin (n = 9) or meclofenamate (n = 6) did not change RBF, while MAP decreased by 15 mmHg. A time-dependent significant enhancement of RBF autoregulatory efficiency was found in the drug-treated rats. Changes in renal function and reductions of prostanoid excretion in urine, of plasma renin activity, or serum aldosterone were similar in the nonsteroidal antiinflammatory drug groups. In conclusion, our findings demonstrate important time-related adjustments of renal hemodynamics in male rats treated with indomethacin, especially with the lower dose (3 mg/kg body wt iv). The factor(s) responsible for the hemodynamic changes remains unknown.

Pathophysiology of Altered Renal Function in Renal Vascular Hypertension

It is now clear that specific angiotensin-dependent mechanisms contribute importantly to the pathophysiology of hypertension (HT) and altered renal function in models of two-kidney, one-clip (2-K,1-C) HT in rats. The discovery of specific antagonists for angiotensin-converting enzyme and the newer angiotensin receptor and kinin receptor antagonists have allowed delineation of the contributions of these hormones to altered renal function in these models. The focus of interest in most of these studies has been the nonclipped kidney, which would be expected to ameliorate elevated blood pressure by exhibiting a pressure diuresis and natriuresis in the environment of systemic HT. Antagonism of the renin-angiotensin system in rat models of renal vascular HT indicates that the effects of angiotensin attenuate renal hemodynamic and excretory behavior, particularly in the nonclipped kidney. Furthermore, angiotensin attenuates the efficiency of autoregulation of renal hemodynamics in the nonclipped kidney. Function of the clipped kidney appears to be both angiotensin and perfusion pressure dependent. Evidence that inhibition of angiotensin reverses or improves these altered hemodynamic and excretory functions indicates that angiotensin may contribute importantly to the pathophysiology of HT in these models by altering or impairing the ability of the nonclipped or “normal” kidney to excrete sodium and volume. The precise roles of altered activity of vasodilator hormones to contribute to these alterations of renal function remains to be defined.

Direct measurement of renal medullary blood flow in the dog.

We studied the responses of total renal blood flow (RBF) and renal medullary blood flow (RMBF) to changes in renal perfusion pressure (RPP) within and below the range of renal autoregulation in the anesthetized dog (n = 7). To measure RMBF, we developed a technique in which the medulla is exposed by excising a section of infarcted cortex and a multiple optical fiber flow probe, connected to a laser-Doppler flowmeter, is placed on the medulla. At the baseline RPP of 120 +/- 1 mmHg, RBF was 2.58 +/- 0.33 ml.min-1.g perfused kidney wt-1, and RMBF was 222 +/- 45 perfusion units. RPP was then decreased in consecutive 20-mmHg steps to 39 +/- 1 mmHg. At 80 +/- 1 mmHg, RBF remained at 89 +/- 4% of the baseline value; however, RMBF had decreased significantly (P < 0.05) to 73 +/- 4% of its baseline value. The efficiency of autoregulation of RBF and of RMBF within the RPP range of 120 to 80 mmHg was determined by calculating an autoregulatory index (AI) for each parameter using the formula AI = (%delta blood flow)/(%delta RPP). An AI of 0 indicates perfect autoregulation, and an index of 1 indicates a system with a fixed resistance. The AI for RBF averaged 0.33 +/- 0.12 over this pressure range and showed a significantly greater (P < 0.05) autoregulatory ability than did the RMBF (0.82 +/- 0.13). Decreasing perfusion pressure < 80 mmHg produced significant decreases in both RBF and RMBF.(ABSTRACT TRUNCATED AT 250 WORDS)

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)

Effect of l-NG-Nitro-Arginine, Inhibitor of Nitric Oxide Synthesis, on Autoregulation of Renal Blood Flow in Dogs

The present experiments were designed to evaluate the importance of nitric oxide in the regulation of renal hemodynamics and the autoregulation of renal blood flow (RBF) in anesthetized dogs. RBF was measured by an electromagnetic flowmeter, and renal arterial pressure (RAP) was varied by an adjustable aortic clamp. The RAP-RBF relations were examined during the intrarenal infusion of saline or agents. The intrarenal infusion of l-NG-nitro-arginine (l-NNA, 40μg/kg-min) at normal Rap decreased RBF and urine flow (UF), while the infusion of larginine-HCI(1 mg/kg.min) increased RBF and UF. Both agents did not affect the glomerular filteration rate and mean arterial pressure. The autoregulation of RBF was impaired during the l-NNA infusion. The L-arginine infusion did not affect autoregulatory efficiency. When l-NNA (40 μg/kg-min) and l-arginine were infused simulataneously into the renal artery, the autoregulation of RBF was maintained. However, a higher dose of l-NNA (200 μg/kg-min) impaired the autoregulation of RBF. These results suggest that the basal production and/or the release of nitric oxide contributes to the regulation of renal hemodynamics and urine formation. During the reduction of RAP, nitric oxide may play an important role in the autoregulation of RBF.