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Am J Physiol Regul Integr Comp Physiol 280: R62-R68, 2001;
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Vol. 280, Issue 1, R62-R68, January 2001

Differential control of intrarenal blood flow during reflex increases in sympathetic nerve activity

Bridget L. Leonard1, Simon C. Malpas1, Kate M. Denton2, Anna C. Madden2, and Roger G. Evans2

1 Circulatory Control Laboratory, Department of Physiology, University of Auckland, Auckland, New Zealand; and 2 Department of Physiology, Monash University, Melbourne, Victoria 3168, Australia


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The role of renal sympathetic nerve activity (RSNA) in the physiological regulation of medullary blood flow (MBF) remains ill defined, yet regulation of MBF may be crucial to long-term arterial pressure regulation. To investigate the effects of reflex increases in RSNA on intrarenal blood flow distribution, we exposed pentobarbital sodium-anesthetized, artificially ventilated rabbits (n = 7) to progressive hypoxia while recording RSNA, cortical blood flow (CBF), and MBF using laser-Doppler flowmetry. Another group of animals with denervated kidneys (n = 6) underwent the same protocol. Progressive hypoxia (from room air to 16, 14, 12, and 10% inspired O2) significantly reduced arterial oxygen partial pressure (from 99 ± 3 to 65 ± 2, 51 ± 2, 41 ± 1, and 39 ± 2 mmHg, respectively) and significantly increased RSNA (by 8 ± 3, 44 ± 25, 62 ± 21, and 76 ± 37%, respectively, compared with room air) without affecting mean arterial pressure. There were significant reductions in CBF (by 2 ± 1, 5 ± 2, 11 ± 3, and 14 ± 2%, respectively) in intact but not denervated rabbits. MBF was unaffected by hypoxia in either group. Thus moderate reflex increases in RSNA cause renal cortical vasoconstriction, but not at vascular sites regulating MBF.

cortical blood flow; hypoxia; medullary blood flow; renal sympathetic nerve activity; anesthetized rabbit


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

IT IS NOW CLEAR THAT BLOOD flow in the renal medulla can be regulated differentially from cortical blood flow (CBF) and that this has profound implications for tubular salt and water handling and blood pressure control (3, 6). Renal sympathetic nerve activity (RSNA) may contribute to this differential regulation, yet whereas RSNA has been shown to be important in the control of total renal blood flow (RBF) (13, 15) its role in the control of regional kidney blood flow remains a matter of considerable controversy. This requires resolution before we can fully understand the impact of RSNA on blood pressure control.

In a previous study investigating the role of renal nerves in the control of regional kidney blood flow, we induced changes in RBF, CBF, and medullary blood flow (MBF) by electrically stimulating the renal nerves. We tested the effects of both graded electrical stimulation of the renal nerves and of electrical stimulation with a sinusoidal pattern of varying frequency (12). Our results indicated that RSNA reduces both CBF and MBF and that these reductions are differentially affected in at least two different ways. First, for any given steady-state frequency or amplitude of nerve stimulation the MBF response is always less than the CBF response. Second, the medullary microvasculature appears to be more able to respond to sinusoidal oscillations in renal nerve stimulation, particularly around frequencies normally observed in the renal vasculature of conscious animals (0.16 and 0.3 Hz) (14). Interpretation of these experiments was limited, however, by the nonphysiological nature of the stimulus. Electrical stimulation recruits nerve fibers in a nonselective way, yet functionally dependent recruitment might occur during reflex stimulation of RSNA (4) that could profoundly affect the relative responses of CBF and MBF. We are not aware of any previous studies that have tested the effects of reflexly activated increases in RSNA while simultaneously measuring RSNA, CBF, and MBF, thus allowing direct analysis of the influence of RSNA on blood flow in these regions. Such a study, as presented here, seems imperative to clarifying the role RSNA may have in the control of regional kidney blood flow.

In this study we induced progressive increases in RSNA by exposing pentobarbital sodium-anesthetized rabbits to graded hypoxia. We simultaneously measured RSNA, CBF, and MBF (determined by laser-Doppler flowmetry) and used standard renal clearance techniques to measure effective RBF (ERBF), glomerular filtration rate (GFR), urine flow (UV), and urinary sodium excretion (UNaV). A renal denervated group of animals (control group) allowed us to determine the contribution RSNA made to the observed changes in intrarenal blood flow. Our results show that moderate physiological activation of RSNA reduces CBF but has little impact on MBF.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Experiments were performed on rabbits of a multicolored English strain or the New Zealand White strain (n = 13, mean weight 3.02 ± 0.13 kg). Animals were randomly assigned to the two experimental groups (intact or denervated), meal fed, and allowed water ad libitum until experimental procedures began. All procedures were performed in accordance with the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes and were approved in advance by the Animal Ethics Committee of the Department of Physiology, Monash University.

Surgical procedures. Induction of anesthesia was by intravenous administration of pentobarbital sodium (90-150 mg Nembutal; Boehringer Ingelheim, New South Wales, Australia) and was immediately followed by endotracheal intubation and artificial ventilation. Anesthesia was maintained throughout the surgery and experiment by intravenous pentobarbital infusion (30-50 mg/h). During surgery and throughout the experiment, a solution of compound sodium lactate (Hartmann's, Baxter Healthcare, Toongabbie, New South Wales, Australia) was infused intravenously at a rate of 0.18 ml · min-1 · kg-1 to replace fluid losses. A heated table and infrared light were used to maintain body temperature at 36-38°C (5).

A catheter was inserted into the central ear artery for monitoring arterial pressure. The left kidney was approached via a retroperitoneal incision, freed from the peritoneal lining and surrounding fat, and placed in a stable cup. A Silastic catheter was inserted into the left ureter for urine collection. In six of the seven rabbits in the intact group, the renal nerves were then identified using a surgical microscope, freed from surrounding tissue, and carefully placed across a pair of hooked silver recording electrodes. The nerve and electrode were insulated from the surrounding tissue using Wacker Sil-Gel (Wacker-Chemie, Munich, Germany). In one of the rabbits in the intact group, the renal nerves were left undisturbed, so that RSNA was only recorded in six of the seven rabbits. In the six rabbits in the denervated group, the left renal nerves were sectioned and the area was painted with 10% phenol in alcohol. In all rabbits, MBF was monitored using a 26-gauge needle-type laser-Doppler flow probe (DP4s, Moor Instruments, Millwey, Devon, UK) inserted into the kidney using a micromanipulator (Narashige, Tokyo, Japan), so that its tip lay 10 mm below the midregion of the lateral surface of the kidney within the "white" inner medulla. For monitoring CBF, a straight plastic probe (DP2b, Moor Instruments) was placed on the dorsal surface of the kidney and secured in place with gauze packing.

After completion of the surgery, bolus doses of [3H]inulin (4 µCi; NEN Research Products, Sydney, Australia) and [14C]para-aminohippurate [(PAH); 1 µCi; NEN Research Products] were administered. The infusion of Hartmann's solution (0.18 ml · min-1 · kg-1) was supplemented with 300 nCi/ml [3H]inulin and 83 nCi/ml [14C]PAH. After 75 min of initial loading this protocol maintains stable plasma levels of [3H]inulin and [14C]PAH throughout the experiment.

Experimental protocol. The experiment was started 90 min after the completion of surgery. Animals were artificially ventilated (tidal volume = 14-18 ml, rate = 30-50 breaths/min) so that during the control periods (room air) arterial oxygen partial pressure (PaO2) was 90-110 mmHg. Each of the gas mixtures (10%, 12%, 14%, 16%, room air, ~21%, and 100% O2) were administered for 15 min. Each gas was preceded by a 15-min control period and followed by a 15-min recovery period, which also served as the control period for the subsequent gas mixture. Gas mixtures were administered in random order. Urine samples (for clearance measurements) were collected over the final 5 min of each 15-min period. Arterial blood samples (0.7 ml total, for clearance and blood gas measurements) were collected in the midpoint of each of these 5-min periods. At the conclusion of the experiment each animal was killed with an intravenous overdose of pentobarbital sodium(300 mg).

Data acquisition. The ear artery catheter was connected to a pressure transducer (Cobe, Arvarda, CO) and the laser-Doppler flow probes were connected to a laser-Doppler flowmeter (DRT4, Moor Instruments). Sympathetic nerve activity was amplified, filtered between 50 and 5,000 Hz, full-wave rectified, and integrated using a low-pass filter with a time constant of 20 ms. The average voltage from the sympathetic neurogram over 2-s periods was defined as total RSNA. Changes in voltage of the nerve signal above a defined threshold were classified as RSNA discharges. Total RSNA, mean arterial pressure (MAP), CBF, MBF, and heart rate (HR, calculated from triggering of the systolic blood pressure wave) were all continuously recorded throughout the experiment and were sampled using an analog-to-digital data acquisition card (Lab-PC+, National Instruments). Calibrated signals were displayed on the screen and saved to a disk as 2-s averages of each variable using a program written in the LabVIEW graphical programming language (National Instruments). CBF and MBF were recorded in the 60 s after the animal was humanely killed (but still being artificially ventilated) and averaged 14 ± 2 and 35 ± 5 perfusion units, respectively. Before analysis, these offset values were subtracted from the values obtained throughout the experiment.

Analysis of urine and blood samples. [3H]inulin clearance was used to estimate GFR, whereas the clearance of [14C]PAH was used to calculate effective renal plasma flow, which was corrected for hematocrit to provide ERBF (5). Sodium concentrations in plasma and urine were measured by flame photometry (943; Instrumentation Laboratory, Milan, Italy). At the completion of experiments the kidneys were removed, desiccated, and the dry weight was determined, thus ERBF, GFR, and renal excretory variables are expressed per gram of kidney dry weight. Blood gas analysis was performed on 0.2-ml blood samples (ABL510; Radiometer, Copenhagen, Denmark).

Data analysis. MAP, HR, RSNA, CBF, and MBF were calculated from the files of 2-s averages. Comparisons were made between the average value for the final 5 min of the control period prior to each gas exposure and the average value for the final 5 min during gas exposure. The final 5-min period of gas exposure was used because this allowed sufficient time for blood gases to stabilize. The 5-min period also allowed sufficient time for urine volume collection for later analysis of both UV rates and estimation of GRF and ERBF. Because total RSNA voltages vary between animals and because ERBF was measured in milliliters per minute per gram and CBF and MBF were measured in perfusion units, changes in these variables were normalized as percent change from the final 5 min of the control period before each gas exposure (with the control period equal to 0%). This allowed comparison of responses to different levels of nerve inhibition between the different vascular beds. GFR, UV, and UNaV are also expressed as percent change from control levels.

Statistical analysis. All values are expressed as means ± SE and P <=  0.05 was considered statistically significant. Student's unpaired t-test was used to test for differences between the intact and renal-denervated groups during the control periods. For comparison of responses during gas exposure, statistical analyses were performed using split-plot ANOVA, the factors comprising rabbit, gas (i.e., percentage O2 of the inspired gas), and state (i.e., intact or renal denervated). The main effect of gas (Pgas) tested whether, across the two groups of rabbits, progressive hypoxia altered the levels of the measured variables. The main effect of state (Pstate) tested whether the levels of each variable differed between intact and denervated rabbits in a manner independent of the inspired gas mixture. The interaction term (Pgas*state) tested whether the responses to graded hypoxia differed in intact compared with denervated rabbits.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Baseline cardiovascular variables and renal hemodynamics (Table 1). Baseline levels of MAP, HR, hematocrit, PaO2, arterial carbon dioxide partial pressure PaCO2, pH, CBF, MBF, ERBF, GFR, and filtration fraction measured during the 5-min control period immediately before each gas administration were similar in innervated and denervated rabbits (Table 1). Baseline levels of UV, UNaV, and fractional excretions of urine and sodium were all significantly greater in denervated than innervated rabbits (Table 1).

                              
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  		Table 1.   Resting cardiovascular and renal hemodynamic variables for innervated and denervated rabbits

Arterial blood gas during gas exposure. Progressive hypoxia caused PaO2 to fall similarly in innervated and denervated rabbits (Fig. 1). PaCO2 and pH remained unchanged from baseline levels during hypoxia (data not shown).


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  		Fig. 1.   Levels of arterial oxygen partial pressure (PaO2) during progressive hypoxia in innervated (, n = 7) and denervated (open circle , n = 6) rabbits. P values refer to the outcomes of split-plot ANOVA testing the effects of %inspired O2 (Pgas) and the effects of state (renal innervated or denervated) independent of (Pstate) and dependent on (Pgas*state) inspired O2.

RSNA and intrarenal blood flow responses to progressive hypoxia. As blood flow measurements were taken during the final 5 min of gas exposure, the effects of RSNA on CBF that we describe are actually underestimated relative to the effect seen in the initial 5 min of gas exposure. An increase in RSNA and decrease in CBF were seen in response to hypoxia in innervated animals (Figs. 2-4). As the percentage O2 of the inspired gas decreased, RSNA progressively increased. The CBF response was a mirror image of the RSNA response (Figs. 2-4) with a progressive decrease seen as percentage O2 of the inspired gas progressively decreased. For example, 10% O2 caused an average 76 ± 37% increase in RSNA and 14 ± 1% decrease in CBF by the final 5 min of gas exposure. These responses were significantly different from denervated animals where CBF did not decrease in response to progressive hypoxia [e.g., 1 ± 2% decrease in response to 10% O2 (Figs. 3 and 4)]. MBF responses in both innervated and denervated groups of animals were more variable than CBF responses (Fig. 4). Although MBF increased in response to progressive hypoxia in some animals, overall there was no significant effect on MBF and responses were indistinguishable between innervated and denervated rabbits.


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  		Fig. 2.   Responses from one innervated rabbit showing changes in renal sympathetic nerve activity (RSNA), cortical blood flow (CBF), and medullary blood flow (MBF) during exposure to 10% O2. PaO2 = 34 mmHg during the final 5 min of gas exposure. Heart rate (HR) increased from 245 beats/min during control to 267 beats/min during exposure to 10% O2. Mean arterial pressure (MAP) during exposure to 10% O2 was unchanged from the control period (88 mmHg).



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  		Fig. 3.   Mean responses in RSNA, CBF, and MBF during exposure to 10% O2 in innervated () and denervated (open circle ) rabbits. Innervated rabbits: n = 6 for RSNA, n = 7 for CBF and MBF; denervated rabbits: n = 6. Mean PaO2 during the final 5 min of gas exposure was 39 ± 2 and 44 ± 2 mmHg for innervated and denervated rabbits, respectively. HR in innervated animals increased from a control level of 223 ± 4 to 246 ± 5 beats/min during exposure to 10% O2. In denervated rabbits, HR increased from a control level of 242 ± 3 to 249 ± 3 beats/min during exposure to 10% O2. MAP was maintained at 78 ± 2 mmHg in innervated rabbits and changed from 74 ± 1 mmHg (control) to 79 ± 2 mmHg during the final 5 min of exposure to 10% O2 in denervated animals. Error bars show SE.



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  		Fig. 4.   Mean responses of RSNA, CBF, and MBF during changes in percentage inspired O2 in innervated () and denervated (open circle ) rabbits. Values shown are percentage changes during the final 5 min of each gas exposure compared with the final 5 min of the preceding control period. Innervated rabbits: n = 6 for RSNA, n = 7 for CBF and MBF; denervated rabbits: n = 6. Error bars show SE. P values are same as described in legend for Fig. 1.

Cardiovascular variables and renal function during gas exposure. MAP remained stable throughout the experiment in both innervated and denervated animals; however, a significant increase in HR occurred in response to hypoxia in both groups [e.g., 230 ± 9 to 244 ± 11 beats/min and 237 ± 5 to 247 ± 6 beats/min in response to 10% O2 in innervated and denervated rabbits, respectively (Fig. 5)].


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  		Fig. 5.   Cardiovascular and renal function variables during changes in percentage inspired O2 in innervated (, n = 7) and denervated (open circle , n = 6) rabbits. Values shown are percentage changes during the final 5 min of each gas exposure compared with the final 5 min of the preceding control period. ERBF, effective renal blood flow; UV, urine flow; GFR, glomerular filtration rate; UNaV, urinary sodium excretion. Error bars show SE. P values are same as described in legend for Fig. 1.

In innervated rabbits, ERBF, GFR, UV, and UNaV fell progressively with graded hypoxia, so that during 10% O2 they averaged, respectively, 37 ± 16, 40 ± 14, 60 ± 14, and 60 ± 11% less than control. This response was not observed in denervated rabbits, in which these variables remained fairly stable as inspired O2 was reduced, and during 10% O2 averaged, respectively, 3 ± 6, 3 ± 8, 15 ± 13, and 11 ± 14% less than control. However, because of the variability in these data in both groups of rabbits, a significant gas-state interaction was found only for UV (Fig. 5).


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

In the present study we tested whether reflex increases in RSNA differentially affect CBF and MBF. Our major finding was that moderate increases in RSNA reduced CBF but not MBF. We have previously shown that electrical stimulation of the renal nerves produces larger steady-state changes in CBF than in MBF, indicating that RSNA differentially regulates blood flow in these regions (12). Both of these results support the hypothesis that CBF and MBF are differentially regulated by RSNA. Whereas previous studies have examined the effects of electrical stimulation of the renal nerves on CBF and MBF (1, 2, 9, 17) or have tested the effects on CBF and MBF of stimuli that were presumed to reflexly increase RSNA (11, 18), we are aware of no previous studies in which RSNA, CBF, and MBF have been monitored during stimuli that influence renal hemodynamics exclusively by reflex activation of RSNA.

Our results clearly show that hypoxia-induced increases in RSNA reduce CBF but not MBF. The blood supply to the renal medulla arises from the efferent arterioles of juxtamedullary glomeruli, which comprise only about 10% of the total glomerular number. Thus it is possible for MBF to change dramatically, even when total RBF and CBF do not change appreciably. It might be hypothesized that hypoxia selectively activates a subpopulation of cortically directed nerve fibers and that other stimuli, which reflexly increase RSNA, may produce a different pattern of response. However, our previous study shows that when renal nerves are recruited in a functionally nonspecific manner (i.e., by electrical stimulation), MBF is insensitive to the very low levels of stimulation that still reduce CBF (12). Furthermore, we attribute the effects of hypoxia on renal hemodynamics and excretory function solely to the increase in RSNA as in a separate group of renal-denervated rabbits hypoxia did not significantly alter MAP, renal hemodynamics, or excretory function. Thus we would expect other stimuli, which similarly increase RSNA, to have similar effects on CBF and MBF.

Our results should not be interpreted as indicating that the medullary vasculature is unaffected by increases in RSNA, rather that the level of sympathetic activation we induced was not sufficient to cause a reduction in MBF. Previously we found that MBF was only reduced at levels of electrical stimulation that reduced CBF by more than 20%, yet in the present study the maximal stimulus (10% hypoxia; 76 ± 37% increase in RSNA) reduced CBF by only 14 ± 1%. A reduction in MBF is not confined to artificial nerve stimulation as we have also found that when RSNA was increased by around 135% with nasopharyngeal stimulation in conscious rabbits, an ~30% reduction occurred in both MBF and CBF (6).

Thus taken together with the results of previous experiments (11, 12, 17), our present findings provide strong evidence that the medullary microcirculation is less sensitive to the vasoconstrictor influence of RSNA than is the cortical microcirculation. The mechanisms responsible for this remain to be precisely determined, but may include differences in vascular elements controlling MBF and CBF; in vascular structure or innervation density, in sensitivity to norepinephrine, or even in locally acting counter-regulatory mechanisms. This insensitivity occurs despite juxtamedullary efferent arterioles having more layers of smooth muscle cells (10, 16) and denser innervation (7) than superficial or outer cortical efferent arterioles. Conversely, as we have discussed in detail previously (12), Poiseuille's relationship predicts that the greater diameters of juxtamedullary efferent arterioles relative to those in other regions of the cortex should render blood flow less sensitive to equivalent degrees of smooth muscle contraction in these vessels, consistent with our present observations.

Limitations. Our experimental design did not include direct blockade of the renin-angiotensin system. However, we believe that we are still justified in attributing the responses seen to the direct vasoconstrictor effects of RSNA rather than indirect effects mediated by increased circulating ANG II for the following reasons. First, the temporal nature of the CBF response when the test gas is removed and the animal returns to breathing room air is too rapid to be attributed to ANG II (see Fig. 2). Second, the denervated preparation was a unilateral denervation only, so any neurally mediated renin release would have still occurred in the contralateral kidney. This renin release would lead to increased circulating ANG II and therefore renal vasoconstriction. Because we saw no change in CBF in response to hypoxia in the denervated preparation, hypoxia-induced reductions in CBF in the innervated rabbits likely resulted chiefly from the direct effects of increased RSNA

Our use of an anesthetized and surgically stressed animal may also be interpreted as influencing our results because surgery and stress are known to result in high circulatory levels of epinephrine, renin-angiotensin, and vasopressin, all of which reduce levels and possible responsiveness of MBF. However, our results are consistent with those seen in conscious instrumented rats in response to chemoreceptor stimulation (11).

Perspectives

If MBF is not affected when RSNA is moderately increased, and in fact only responds when RSNA is increased to levels that cause CBF to fall by more than 20%, can we consider it to be outside the regulatory range of RSNA under physiological and even pathophysiological conditions? This question remains unanswered but we can at least draw some tentative conclusions from studies in which total RBF and RSNA have been measured under a range of experimental conditions. In conscious rabbits, stimuli such as noise stress, air-jet stress, and hypoxia increase RSNA by only 10-30% and reduce RBF by only about 10% (13), so these stimuli are unlikely to also reduce MBF. In comparison, it may be expected that during severe hemorrhage (14) and during the nasopharyngeal reflex when RSNA more than doubles it is likely that MBF also falls (6). It seems reasonable to hypothesize therefore that chronic increases in RSNA such as occur in heart failure, (19) where norepinephrine spillover increases by over 200% and RBF decreases to 65% of control levels (8), could also be associated with decreases in MBF. This is likely to have important consequences for the control of fluid balance in these subjects.


    ACKNOWLEDGEMENTS

This research was supported by grants from the Auckland Medical Research Foundation and Marsden Fund (awarded to S. C. Malpas), and the National Heart Foundation of Australia (G 98M 0125) and Ramaciotti Foundations (awarded to R. G. Evans and K. M. Denton). B. L. Leonard is a postgraduate student supported by the Health Research Council of New Zealand. R. G. Evans is an R. Douglas Wright Research Fellow of the National Health and Medical Research Council of Australia (977713).


    FOOTNOTES

Address for reprint requests and other correspondence: B. L. Leonard, Dept. of Physiology, Univ. of Auckland Medical School, Private Bag 92019, Auckland, New Zealand (E-mail: b.leonard{at}auckland.ac.nz).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 5 June 2000; accepted in final form 21 August 2000.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

1.   Aukland, K. Effect of adrenaline, noradrenaline, angiotensin and renal nerve stimulation on intrarenal distribution of blood flow in dogs. Acta Physiol Scand 72: 498-509, 1968[ISI][Medline].

2.   Chapman, BJ, Horn NM, and Robertson MJ. Renal blood-flow changes during renal nerve stimulation in rats treated with alpha-adrenergic and dopaminergic blockers. J Physiol (Lond) 325: 67-77, 1982[Abstract/Free Full Text].

3.   Cowley, AW, Jr. Role of the renal medulla in volume and arterial pressure regulation. Am J Physiol Regulatory Integrative Comp Physiol 273: R1-R15, 1997[Abstract/Free Full Text].

4.   DiBona, GF, Sawin LL, and Jones SY. Differentiated sympathetic neural control of the kidney. Am J Physiol Regulatory Integrative Comp Physiol 271: R84-R90, 1996[Abstract/Free Full Text].

5.   Evans, RG, Bergström G, and Lawrence AJ. Effects of the vasopressin V1 agonist [Phe2,Ile3,Orn8]vasopressin on regional kidney perfusion and renal excretory function in anesthetized rabbits. J Cardiovasc Pharmacol 32: 571-581, 1998[ISI][Medline].

6.   Evans, RG, Madden AC, and Denton KM. Diversity of responses of renal cortical and medullary blood flow to vasoconstrictors in conscious rabbits. Acta Physiol Scand 169: 297-308, 2000[ISI][Medline].

7.   Gorgas, K. Innervation of the juxtaglomerular apparatus. In: Peripheral Neuroendocrine Interaction, edited by Coupland RE, and Forssmann WG.. New York: Springer-Verlag, 1978, p. 144-152.

8.   Hasking, GJ, Esler MD, Jennings GL, Burton D, Johns JA, and Korner PI. Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity. Circulation 73: 615-621, 1986[Abstract/Free Full Text].

9.   Hermansson, K, Ojteg G, and Wolgast M. The cortical and medullary blood flow at different levels of renal nerve activity. Acta Physiol Scand 120: 161-169, 1984[ISI][Medline].

10.   Kriz, W. Structural organization of the renal medulla: comparative and functional aspects. Am J Physiol Regulatory Integrative Comp Physiol 241: R3-R16, 1981[Abstract/Free Full Text].

11.   Ledderhos, C, Gross V, and Cowley AW, Jr. Pharmacological stimulation of arterial chemoreceptors in conscious rats produces differential responses in renal cortical and medullary blood flow. Clin Exp Pharmacol Physiol 25: 536-540, 1998[ISI][Medline].

12.   Leonard, BL, Evans RG, Navakatikyan MA, and Malpas SC. Differential neural control of intrarenal blood flow. Am J Physiol Regulatory Integrative Comp Physiol 279: R907-R916, 2000[Abstract/Free Full Text].

13.   Malpas, SC, and Evans RG. Do different levels and patterns of sympathetic activation all provoke renal vasoconstriction? J Auton Nerv Syst 69: 72-82, 1998[ISI][Medline].

14.   Malpas, SC, Evans RG, Head GA, and Lukoshkova EV. Contribution of renal nerves to renal blood flow variability during hemorrhage. Am J Physiol Regulatory Integrative Comp Physiol 274: R1283-R1294, 1998[Abstract/Free Full Text].

15.   Malpas, SC, Shweta A, Anderson WP, and Head GA. Functional response to graded increases in renal nerve activity during hypoxia in conscious rabbits. Am J Physiol Regulatory Integrative Comp Physiol 271: R1489-R1499, 1996[Abstract/Free Full Text].

16.   Pallone, TL, Silldorff EP, and Turner MR. Intrarenal blood flow: microvascular anatomy and the regulation of medullary perfusion. Clin Exp Pharmacol Physiol 25: 383-392, 1998[ISI][Medline].

17.   Rudenstam, J, Bergström G, Taghipour K, Göthberg G, and Karlström G. Efferent renal sympathetic nerve stimulation in vivo. Effects on regional renal haemodynamics in the Wistar rat, studied by laser-Doppler technique. Acta Physiol Scand 154: 387-394, 1995[ISI][Medline].

18.   Zillig, B, Schuler G, and Truniger B. Renal function and intrarenal hemodynamics in acutely hypoxic and hypercapnic rats. Kidney Int 14: 58-67, 1978[ISI][Medline].

19.   Zucker, IH, Wang W, Brandle M, Schultz HD, and Patel KP. Neural regulation of sympathetic nerve activity in heart failure. Prog Cardiovasc Dis 37: 397-414, 1995[ISI][Medline].

Am J Physiol Regul Integr Comp Physiol 280(1):R62-R68
0363-6119/01 $5.00 Copyright © 2001 the American Physiological Society


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The kidney and hypertension
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Differential control of sympathetic outflow
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Sympathetic modulation of renal blood flow by rilmenidine and captopril: central vs. peripheral effects
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