Am J Physiol Regul Integr Comp Physiol 290: R322-R330, 2006.
First published September 15, 2005; doi:10.1152/ajpregu.00493.2005
0363-6119/06 $8.00
RENAL HEMODYNAMICS AND CARDIORENAL INTEGRATION
Partial renal ischemia elicits heterogeneous control of renal sympathetic nerve activity to ischemic and nonischemic regions of the kidney
Kiyoshi Shimizu,1,2
Kanji Matsukawa,1
Jun Murata,1
Hirotsugu Tsuchimochi,1 and
Ishio Ninomiya2
1Department of Physiology, Graduate School of Health Sciences, Hiroshima University; and 2Department of Clinical Engineering, Faculty of Health Sciences, Hiroshima International University, Hiroshima, Japan
Submitted 7 July 2005
; accepted in final form 13 September 2005
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ABSTRACT
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We tested the hypothesis that renal sympathetic nerve activity (RSNA) to the ischemic and nonischemic regions responded differently during partial ischemia of the kidney in pentobarbital-anesthetized cats. The renal artery divides into two branches at the front of the renal hilus: one branch perfuses predominantly the dorsal half of the kidney, and the other perfuses its ventral half. We identified the innervated area of a renal nerve bundle by supramaximal electrical stimulation and subsequently determined the changes in RSNA in response to occlusion of either renal arterial branch for 3 min. RSNA to the nonischemic region of the kidney gradually decreased by 23 ± 4% during partial renal ischemia, whereas RSNA to the ischemic region of the same kidney showed no significant change. Crushing either all renal nerve bundles or only the renal nerve bundles terminated to the ischemic region abolished the decrease in RSNA to the nonischemic region. Furthermore, intra-arterial administration of a prostaglandin synthesis inhibitor (meclofenamate, 4 mg/kg) abolished the decrease in RSNA to the nonischemic region of the kidney. Following spinal transection at the level of T7, the inhibitory response in RSNA to the nonischemic region disappeared, whereas the RSNA to the ischemic region was markedly augmented by 47 ± 17%. Thus it is likely that renal chemoreceptors activated during renal partial ischemia elicit heterogeneous control of renal sympathetic outflows to the ischemic and nonischemic regions of the same kidney, which may be determined by a net output between the supraspinal inhibitory and spinal excitatory reflexes.
ipsilateral renorenal reflex; supraspinal inhibitory reflex; spinal excitatory reflex; complete renal ischemia; prostaglandins
THE KIDNEYS ARE ONE OF THE target organs that receive abundant innervation of sympathetic efferents. Discharges of renal sympathetic efferent nerves are known to regulate renal blood flow, intrarenal redistribution of blood flow, release of renin, and renal tubular sodium and water reabsorption (5). The kidneys are also able to sense local information by renal sensory receptors and convey it to the central nervous system via renal afferents, which, in turn, exert reflex adjustments on the cardiovascular system and the kidneys themselves. There are two classes of renal sensory receptors: mechanosensitive and chemosensitive (22, 23). Renal mechanoreceptors, which monitor a hydrostatic pressure within the kidneys, are stimulated by an increase in intrarenal pressure, such as ureteral, renal venous, or pelvic pressure (1, 9, 16, 24). On the other hand, renal chemoreceptors, which monitor changes in chemical environment and/or metabolic products released in renal interstitium or pelvic fluid, are activated by backflow of nondiuretic fluid into the renal pelvis (19, 22, 23). When these characteristics of renal afferents are taken into consideration, occlusion of the renal artery reduces activity of renal mechanosensitive afferents (9, 25) but augments activity of renal chemosensitive afferents (2, 19, 20).
The reflex effect of renal afferent stimulation on renal sympathetic nerve activity (RSNA) to the contralateral kidney, termed a contralateral renorenal reflex, has been extensively studied in anesthetized animals. A mechanical stimulus, such as an increase in renal venous, ureteral, or pelvic pressure, decreased contralateral RSNA in rats (12, 13). A chemical stimulus, such as renal venous occlusion or pelvic perfusion of hypertonic NaCl, reduced the contralateral RSNA in rats and dogs (12, 13, 14), although the similar intervention (such as renal artery or ureteral occlusion or the backflow of concentrated urine or KCl into the renal pelvis) increased the contralateral RSNA in rats and dogs (7, 18). Furthermore, renal denervation increased the contralateral RSNA in rats and cats (4, 6, 10), suggesting that the ongoing activity of renal afferents inhibits sympathetic outflow to the other kidney. Taken together, it is most likely that activation of renal mechanoreceptors and chemoreceptors results in reflex inhibition of renal sympathetic outflow to the contralateral kidney, which may, in turn, decrease renal vascular resistance and increase urine flow rate and urinary sodium excretion.
On the other hand, the reflex effect of renal afferent stimulation on RSNA to the same kidney, termed an ipsilateral renorenal reflex, has been much more controversial. When elevating renal venous, ureteral, or pelvic pressure, ipsilateral RSNA decreased in rats (12) but increased in spinalized cats (3). The backflow of concentrated urine or occlusion of the renal artery or ureter increased ipsilateral RSNA in rats (18, 21), whereas renal venous occlusion decreased the RSNA in rats and dogs (12, 25). Renal denervation increased the ipsilateral RSNA in cats (8). Why the similar kind of renal intervention caused the variant responses in the ipsilateral RSNA remains unexplained, although species difference cannot be neglected. As one reason responsible for the controversy about the ipsilateral renorenal reflex, we hypothesized that when renal receptors in a localized area of the kidney are stimulated, the ipsilateral renorenal reflex may evoke heterogeneous responses of RSNA within the same kidney, depending on the innervating area of a renal nerve bundle. For example, the ipsilateral renorenal reflex during partial ischemia of the kidney may cause an increase in renal sympathetic outflow to the ischemic region and a decrease in renal sympathetic outflow to the nonischemic region of the same kidney. As a matter of fact, Rogenes (21) reported, using single-unit analysis of renal efferent activity, that stimulation of renal chemoreceptors, induced by backflow of concentrated urine into the renal pelvis, increased the firing frequency of the majority (65%) of ipsilateral renal efferent fibers, but the firing frequency of the remaining units (35%) was decreased or unaffected by that intervention. The cat renal artery usually divides into two branches at the front of the renal hilus. One branch perfuses predominantly the dorsal half of the kidney, and the other branch perfuses predominantly its ventral half. To test our hypothesis, we identified the innervated area of a renal nerve bundle by supramaximal electrical stimulation and subsequently examined the reflex change in RSNA in response to occlusion of either renal arterial branch in the anesthetized cat.
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METHODS
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The experiments were performed on 26 anesthetized cats weighing between 1.6 and 3.8 kg, in accordance with the "Guiding Principles for the Care and Use of Animals in the Fields of Physiological Sciences," approved by the Physiological Society of Japan. The present study was approved by the Committee of Research Facilities for Laboratory Animal Science, Natural Science Center for Basic Research and Development, Hiroshima University.
Preparation of animals.
Anesthesia was introduced by inhalation of a gas mixture of halothane (4%), N2O, and O2. Pentobarbital sodium (30–40 mg/kg) was intraperitoneally administered, and an endotracheal tube was inserted. The animals breathed spontaneously throughout the experiments. Rectal temperature was maintained at 37.0–37.5°C by an external heating pad and a lamp. Surgery was conducted to isolate renal nerve bundles and the renal artery near the renal pelvis. Polyvinyl catheters were inserted into the right femoral vein and artery for administering drugs and measuring arterial blood pressure (AP). AP was continuously monitored with a pressure transducer (DPT III, Baxter, Tokyo, Japan). To maintain the level of surgical anesthesia, supplemental pentobarbital sodium (2–3 mg/kg) was intravenously injected if increases in heart rate (HR), AP, and/or respiration were observed and/or if withdrawal of the limb in response to noxious pinch of the paw and/or the surgical procedure were observed. The left kidney was retroperitoneally exposed in the lateral position. The renal artery usually divides into two branches at the front of the renal hilus. The perfusing area of each branch of the renal artery was identified by a brief occlusion of the vessel. During the occlusion, a surface area of the kidney with decreased blood flow became pale. One branch of the renal artery perfused predominantly the dorsal half of the kidney, and the other branch perfused predominantly the ventral half of the kidney. The perfused area of each branch was confirmed by injecting an Evans blue dye after the end of the experiments. The renal nerve bundles were carefully isolated as many as possible from the renal plexus and surrounding connective tissue near the renal artery and vein with use of an operating microscope (OME, Olympus Optical, Tokyo, Japan). To identify an area innervated by each nerve bundle, the nerve bundle was supramaximally stimulated with electrical pulses at a frequency of 10 Hz for 30 s (pulse voltage, 10 V; duration, 0.5–1.0 ms). If electrical stimulation of the renal nerve bundle evoked vasoconstriction of blood vessels in the innervated area, a surface area with decreased blood flow became pale. We judged the surface area as that innervated by the nerve bundle, which was contained in either the dorsal or ventral half of the kidney. By observing the renal surface area during the nerve stimulation, we identified 17 renal nerve bundles that innervated an area in the dorsal half of the kidney (n = 16 cats) and 5 renal nerve bundles that innervated an area in the ventral half of the kidney (n = 5 cats).
Recording of data.
We recorded multifiber activity from an intact nerve bundle with a pair of silver electrodes. The nerve bundle and electrodes were bathed in a pool of liquid paraffin surrounded by tissue and skin. RSNA was amplified by a differential preamplifier (S-0476, Nihon Kohden, Tokyo, Japan) with a band-pass filter of 50–3,000 Hz. The amplified output was converted into standard pulse trains by using a digital technique that detected the peaks of the original signal (15, 17). A resistance-capacitance integrator with a time constant of 20 ms integrated the pulse trains, and the integrated signal was used as a monitor of RSNA. The afferent and efferent components of renal nerve discharge could not be differentiated in this study. To examine to what extent our multiunit recordings of the renal nerve bundles contained renal afferent activity, we attempted to tie the renal nerve bundles at the proximal side of the recording site at the end of the experiments. As soon as the renal nerve bundles were tied, the baseline RSNA discharges disappeared, and no significant changes in RSNA were evoked during the partial renal ischemia. We also observed that, following spinal cord transection, tying the nerve bundle at the proximal side of the recording site abolished the response in RSNA to the ischemic region. Taken together, it is likely that the afferent component contained in the present neural recordings was negligible and the most renal nerve discharges to the ischemic and nonischemic regions of the kidney reflected renal sympathetic efferent activity.
HR was derived from AP pulse by a tachometer (1321, NEC San-ei Instruments, Tokyo, Japan). Timings at the start and the end of occlusion of one renal arterial branch were manually marked with an electric switch. RSNA, mean AP (MAP), HR, and the marking signal were continuously recorded on an eight-channel pen-writing recorder (Recti-8K, NEC San-ei Instruments) and were sampled at 400 Hz in a computer. The beat-to-beat calculated parameters of RSNA, MAP, and HR and their corresponding mean values over 1 s were stored on a hard disk by using a customized software program (Cordat II, Data Integrated Scientific Systems, Pinckney, MI) for off-line analysis.
Experimental protocols.
After identifying the innervated area of each renal nerve bundle, we examined the responses in RSNA during occlusion of each renal arterial branch (Fig. 1). If a renal nerve bundle innervated an area in the dorsal part of the kidney, we examined the response in RSNA to occlusion of either the dorsal arterial branch (the RSNA response to the ischemic region) or the ventral arterial branch (the RSNA response to the nonischemic region). If a renal nerve bundle innervated an area in the ventral part of the kidney, we examined the response in RSNA to occlusion of either the ventral arterial branch (the RSNA response to the ischemic region) or the dorsal arterial branch (the RSNA response to the nonischemic region). Each arterial branch was occluded for 3 min with a small vessel clip. The order of the two kinds of occlusion was randomized for every nerve bundle. The partial renal ischemia was confirmed by visually observing the color of the renal surface area. In addition, we performed occlusion of the renal artery in six cats, to examine the change in RSNA in response to whole ischemia of the kidney.
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Fig. 1. An experimental setup. The cat renal artery usually divides into two branches at the front of the renal hilus. One branch perfuses predominantly the dorsal half of the kidney, and the other branch perfuses predominantly its ventral half. We identified 17 renal nerve bundles that innervated an area in the dorsal half of the kidney (A) and 5 renal nerve bundles that innervated an area in the ventral half of the kidney (B). Subsequently, each renal arterial branch was occluded for 3 min. The responses in renal sympathetic nerve activity (RSNA) of a given renal nerve bundle to the partial renal ischemia were classified into the response in RSNA to the ischemic region (in the case that the ischemic region involved the innervated area of the nerve bundle) and the response in RSNA to the nonischemic region (in the case that the ischemic region did not involve the innervated area of the nerve bundle).
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To identify whether the RSNA response during occlusion of either renal arterial branch was evoked by a reflex arising from the same kidney, we examined the effect on the RSNA response of crushing either all renal nerve bundles that we were able to isolate (n = 4 cats) or only the renal nerve bundles innervating the ischemic region (n = 2 cats) at the distal side of the recording site. To examine whether prostaglandins released during partial renal ischemia mediated the ipsilateral renorenal reflex, we compared the RSNA response to partial renal ischemia before and after intra-arterial injection of a prostaglandin synthesis inhibitor (meclofenamate, 4 mg/kg) in four cats. Furthermore, to determine a supraspinal influence on the ipsilateral renorenal reflex responses during the partial ischemia, we examined the responses in RSNA to occlusion of either arterial branch before and 1 h after the spinal cord was transected at the level of T7 (n = 4 cats).
Data treatment and statistical analysis.
The average values of RSNA, MAP, and HR over a period of 10 s were sequentially calculated. In each occlusion trial, the RSNA during the preocclusion control period for 1 min was defined as the 100% control value. The response in RSNA during occlusion was expressed as the percent change (%) from the control value, as well as the absolute change (impulses/s). The responses in MAP and HR were expressed as the absolute changes (mmHg and beats/min) from their control values. The effect of partial renal occlusion on RSNA, MAP, and HR was compared by using a two-way ANOVA with repeated measures. If the main effect of time or renal region (ischemic vs. nonischemic) was significant, a Tukey test was performed as a post hoc analysis for multiple comparisons among the mean values. Some comparisons in the average values before and after an intervention were performed by a paired or unpaired t-test. The level of statistical significance was defined as P < 0.05. The data in the text and Figs. 4–6 are expressed as means ± SE.
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RESULTS
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There was no significant difference in the discharge frequency and pattern of RSNA between renal nerve bundles innervating the dorsal part of the kidney and the ventral part of the kidney; the baseline frequency of the RSNA to the dorsal part was 138 ± 14 impulses/s and that of the RSNA to the ventral part was 127 ± 21 impulses/s. Baseline MAP and HR were 123 ± 6 mmHg and 194 ± 6 beats/min, respectively.
Differential responses in RSNA to the ischemic and nonischemic regions of the kidney.
A typical example of the changes in RSNA and MAP during occlusion of either renal arterial branch is shown in Fig. 2. The recorded renal nerve bundle innervated an area in the dorsal half of the kidney. RSNA was inhibited during ischemia of the ventral half of the kidney (Fig. 2). This decrease was developed gradually and peaked 2.8 min after the onset of renal occlusion. After release of the occlusion, RSNA gradually recovered to the preocclusion level. Crushing all renal nerve bundles isolated at the distal side of the recording site abolished the reduction in RSNA to the nonischemic area, as shown in Fig. 3. The decrease in RSNA (18 ± 11%) to the nonischemic region during partial renal occlusion was markedly reduced to 2 ± 2% by crushing the nerve bundles. Especially, crushing only the renal nerve bundles that innervated the ischemic region was enough to abolish the reflex reduction in RSNA, suggesting that a reflex arising from the kidney, especially from the ischemic region, caused the decrease in RSNA to the nonischemic region. On the contrary, RSNA was slightly increased during ischemia of the dorsal half of the kidney (Fig. 2). MAP did not change significantly during occlusion of either renal arterial branch.
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Fig. 2. A typical example of the responses in RSNA and mean arterial blood pressure (MAP) during partial renal ischemia. RSNA was measured from a renal nerve bundle that innervated an area in the dorsal half of the kidney. RSNA gradually decreased during ischemia of the ventral half of the kidney (A), whereas RSNA slightly increased during ischemia of the dorsal half of the kidney (B). After release of the occlusion, RSNA gradually returned to the preocclusion level. MAP did not change significantly during occlusion of either renal arterial branch.
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Fig. 3. Identification of a reflex arising from the kidney. RSNA was measured from a nerve bundle that innervated an area in the dorsal half of the kidney. The response in RSNA during partial ischemia of the ventral half of the kidney (RSNA response to nonischemic region) is shown before (A) and after (B) crushing all isolated renal nerve bundles at the distal side of the recording site. The decrease in RSNA to the nonischemic region was abolished by the crush.
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Figure 4 shows the time courses of the average responses of RSNA, MAP, and HR during occlusion of either renal arterial branch. When RSNA was measured from the renal nerve bundles that innervated an area in the dorsal half of the kidney (Fig. 4A), RSNA was slowly decreased during occlusion of the ventral half of the kidney. The decrease in RSNA peaked to 23 ± 4% (32 ± 7 impulses/s) at 2 min during occlusion. Subsequently, it was attenuated during the last 1-min period of occlusion, and, simultaneously, the surface color of the ischemic region tended to become ruddy. After the occlusion was released, it took 
2 min for RSNA to return to the preocclusion level. In contrast, the RSNA did not change significantly during occlusion of the dorsal half of the kidney. On the other hand, when RSNA was measured from the renal nerve bundles that innervated an area in the ventral half of the kidney (Fig. 4B), RSNA decreased by 20 ± 6% (23 ± 9 impulses/s) during occlusion of the dorsal half of the kidney, whereas it did not change significantly during occlusion of the ventral half of the kidney. The greater SE values of the changes in the RSNA were probably due to a smaller sample size. MAP and HR were not significantly altered during occlusion of either renal arterial branch. Obviously, it was irrespective of the innervated area of the individual nerve bundles that RSNA to the nonischemic region was reduced during partial renal ischemia, while the RSNA to the ischemic region of the same kidney showed no significant changes. Furthermore, to confirm the reproducibility of the RSNA response to the nonischemic region during partial renal occlusion, we conducted a pair of partial renal artery occlusion trials in three cats. Indeed, we repeatedly observed the same inhibitory response in the RSNA, which was peaked at 2.5 min during partial renal ischemia; the decrease in RSNA was 39 ± 15% for the first trial and 32 ± 9% for the second trial.
Effect of a prostaglandin synthesis inhibitor on the RSNA responses to partial renal ischemia.
To examine whether prostaglandins released during partial renal ischemia mediated the reflex responses in RSNA, we investigated the effect of an intra-arterial injection of a prostaglandin synthesis inhibitor (meclofenamate) on the responses in RSNA (Fig. 5). Meclofenamate did not affect significantly the baseline levels of RSNA, MAP, and HR. However, the decrease in RSNA to the nonischemic area, which peaked to 25 ± 10% in the absence of meclofenamate, was abolished by administration of meclofenamate. On the other hand, RSNA to the ischemic region showed no significant change, even in the presence of meclofenamate.
RSNA response to the whole ischemia of the kidney.
RSNA did not change significantly (1 ± 5%) during whole renal ischemia, although the significant decrease of 22 ± 5% in RSNA to the nonischemic region was induced during partial renal ischemia in the same nerve bundles. MAP increased and HR decreased slightly, although these changes were not significant.
Effect of spinal cord transection on the RSNA responses to partial renal ischemia.
After the spinal cord was transected at the level of T7, the baseline value of RSNA decreased from 132 ± 27 to 69 ± 12 impulses/s. MAP also decreased from 130 ± 2 to 81 ± 10 mmHg, but HR increased from 211 ± 8 to 256 ± 42 beats/min. The responses in RSNA due to partial renal ischemia were greatly modified by the spinal cord transection (Fig. 6). Following the spinal cord transection, the RSNA to the ischemic region was largely increased by 47 ± 17% (26 ± 8 impulses/s) during partial ischemia, whereas the RSNA to the nonischemic region of the kidney was unaffected (Fig. 6). It was noted that this increase in RSNA (76%) to the ischemic region was greatly reduced to 10% by a subsequent injection of meclofenamate in one cat.
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DISCUSSION
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We have investigated for the first time the differential responses in ipsilateral RSNA during partial ischemia of the kidney in anesthetized cats, which has not been attempted before. The major new finding of this study was that RSNA to the nonischemic region of the kidney was reduced during partial renal ischemia, whereas RSNA to the ischemic region showed no significant changes, irrespective of the innervated area of an individual nerve bundle. Such heterogeneous responses in the ipsilateral RSNA cannot be explained by a secondary influence of arterial baroreflex and/or a change in systemic hemodynamics, because MAP and HR did not alter during the partial renal ischemia. Crushing the nerve bundles terminated to the ischemic region abolished the reduction in RSNA to the nonischemic region. The decrease in RSNA was attenuated during the last period of the renal arterial occlusion when the surface color of the ischemic region turned ruddy, probably due to development of collateral blood flow. Taken together, these findings indicate that an ipsilateral renorenal reflex, which is initiated via renal afferents from the ischemic region, in turn induces an inhibitory response in the RSNA to the nonischemic region alone. Thus it is likely that partial renal ischemia causes heterogeneous control of renal sympathetic outflows within the same kidney.
Ipsilateral renorenal reflex.
The effect of renal afferent stimulation on RSNA to the same kidney has been controversial. For example, whole renal ischemia induced an increase in the ipsilateral RSNA in the rat (18) and a slight increase or no change in the dog (25). In this study, occlusion of the whole renal artery did not alter the ipsilateral RSNA in the cat. In addition, when elevating renal venous, ureteral, or pelvic pressure, ipsilateral RSNA decreased in the rat (12) but increased in the spinalized cat (3). The backflow of concentrated urine into the renal pelvis increased the RSNA in the rat (18, 21). We hypothesized that, if renal receptors in a localized area of the kidney are stimulated, the ipsilateral renorenal reflex may evoke heterogeneous reflex responses of RSNA within the same kidney. We found that the ipsilateral renorenal reflex during partial ischemia of the kidney caused a decrease in renal sympathetic outflow to the nonischemic region, whereas renal sympathetic outflow to the ischemic region of the same kidney did not change significantly. Such differential reflex responses of RSNA, depending on the innervating area of a given nerve bundle, may explain, at least partly, the controversy about the ipsilateral renorenal reflex, although species difference cannot be neglected. Interestingly, following spinal cord transection at the level of T7, the RSNA to the ischemic region was markedly increased by the partial renal ischemia, whereas the RSNA to the nonischemic region did not change significantly. It was important to determine whether this increase in RSNA to the ischemic region might be either the result of stimulation of afferent fibers at the site of ischemia or the results of the increase in renal sympathetic efferent discharge, because the afferent and efferent components of renal nerve discharge could not be differentiated in this study. To examine this, we tied the renal nerve bundles at the proximal side of the recording site. Tying the nerve bundle at the proximal side of the recording site abolished the baseline discharges and the responses in RSNA to the ischemic and nonischemic regions during the partial renal ischemia in either the intact or spinalized condition. It is likely that the afferent component contained in the present neural recordings was negligible, and the most renal nerve discharges to the ischemic and nonischemic regions of the kidney reflected renal sympathetic efferent activity. If so, the present new findings suggest the existence of a spinal excitatory component of the ipsilateral renorenal reflex as well as its supraspinal inhibitory component. From these reasons, we can speculate that the same kind of renal intervention causes the variant responses in the ipsilateral RSNA, depending on the innervating area of the renal nerve bundle recorded and depending on an interaction between the two components of the ipsilateral renorenal reflex.
Activation of renal chemosensitive afferents.
Mechanosensitive and chemosensitive receptors in the kidney are widely distributed in the renal pelvis and interstitium of the kidney (22, 23). To evoke localized activation of renal sensory receptors, we used partial renal ischemia by occluding one renal arterial branch. This intervention may cause a decrease in pressures of renal blood vessels, ureteral, and pelvis, which may, in turn, reduce activity of renal mechanosensitive afferents. Indeed, spontaneous discharge of renal mechanoreceptors is inhibited by occlusion of the renal artery (9, 25), whereas it is enhanced by elevating renal arterial, venous, or ureteropelvic pressure (1, 16, 24). On the other hand, partial renal occlusion is considered to activate renal chemosensitive receptors due to changes in chemical environment and/or metabolic byproducts released in the ischemic area. There are two types of renal chemosensitive afferents, called R1 and R2 chemoreceptors (22, 23). R1 chemoreceptors are silent at rest and do not respond to any changes in intrarenal pressure. R2 chemoreceptors show a pulse-asynchronous spontaneous firing at rest and are markedly activated by backflow into the pelvis of concentrated urine and suitable KCl and NaCl solutions, even in the absence of any change in intrapelvic pressure (19). With respect to renal artery occlusion, R1 chemoreceptors are activated with a delay of 30 s, whereas R2 chemoreceptors are promptly stimulated by renal artery occlusion (19, 20). This increased activity of R2 chemoreceptors is blocked by pretreatment with either indomethacin or meclofenamate (2), suggesting that intrarenal prostaglandins are involved in the response of R2 chemoreceptors during renal artery occlusion. The reduction of RSNA to the nonischemic region of the kidney observed in this study cannot be explained by a blunted activity of renal mechanoreceptors during the renal partial ischemia, because stimulation of renal mechanoreceptors by increasing venous pressure reduced the ipsilateral RSNA (12). On the other hand, the slow time course of the renal nerve response is in favor of the assumption that R1 chemosensitive afferents are stimulated during the partial renal ischemia and contribute to an ipsilateral renorenal reflex. However, the finding that the decrease in RSNA to the nonischemic region during partial renal ischemia was abolished by administration of meclofenamate suggests that the stimulation of renal R2 chemoreceptors may play an important role in initiating the renorenal reflex response. Taken together, both types of renal chemosensitive afferents in the ischemic region are stimulated during renal partial ischemia, which, in turn, may elicit the ipsilateral inhibitory reflex response on RSNA to the nonischemic region of the kidney. It is interesting that, following spinal cord transection, the onset and recovery of the RSNA response to the ischemic region during partial renal ischemia seemed much faster than those of the RSNA response to the nonischemic region in the intact condition (Fig. 6). Thus it is possible that R2 renal chemosensitive afferents are more stimulated by renal ischemia in the spinalized condition. This possibility is further supported by the finding in one cat that this increase in RSNA to the ischemic region was inhibited by meclofenamate.
The effects of spinal transection on the differential RSNA responses.
It has been reported that spinal transection modifies the ipsi- and contralateral renorenal reflexes (7, 12, 18, 21). The ipsilateral excitatory renorenal reflex evoked by backflow of concentrated urine into the renal pelvis or by whole ischemia of the kidney was augmented following spinal transection at the level of C3 or T6 (18, 21). On the other hand, the contralateral inhibitory renorenal reflex was abolished by spinal transection at the level of T6 (12). In this study, we examined the effects of spinal transection at the level of T7 on the differential RSNA responses during partial renal ischemia, to clarify a supraspinal influence on the differential responses in the ipsilateral RSNA. We found that the RSNA to the ischemic region became markedly increased following the spinal transection, whereas the RSNA to the nonischemic region did not change significantly. Thus an excitatory reflex from the ischemic region may play a role under the spinalized condition. It should be emphasized that the spinal excitatory reflex may operate on the ipsilateral RSNA only to the ischemic region, but not to the nonischemic region, within the same kidney. The excitatory ipsilateral reflex, which has a spinal origin, may act on the renal sympathetic preganglionic neurons to the ischemic region. These data are in agreement with the previous studies (18, 21) demonstrating that the ipsilateral excitatory renorenal reflex evoked by backflow of concentrated urine into the renal pelvis or whole ischemia of the kidney was augmented in the spinalized condition, as mentioned above.
On the contrary, the spinal transection abolished the decreased response in the ipsilateral RSNA response to the nonischemic region. This finding suggests that the inhibitory ipsilateral reflex, which has a supraspinal origin, may act on at least the renal sympathetic preganglionic neurons to the nonischemic region. This concept of the supraspinal inhibitory ipsilateral reflex is supported by the previous results that an excitatory ipsilateral reflex during renal ischemia or backflow of concentrated urine into the pelvis was augmented by spinal cord transection (18, 21). Taking these findings into consideration, we propose a novel hypothesis that the supraspinal component of the ipsilateral renorenal reflex evoked by partial renal ischemia has an inhibitory influence on all renal sympathetic preganglionic motoneurons innervating the whole kidney, whereas the spinal excitatory component of the ipsilateral renorenal reflex acts on only the renal sympathetic preganglionic motoneurons innervating the ischemic region, as illustrated in Fig. 7. If so, the ipsilateral RSNA to the ischemic region of the kidney seems unchanged during the partial renal ischemia because of a net balanced output between the supraspinal inhibitory and spinal excitatory responses. The same thing will be true in the case of whole renal ischemia. Indeed, the ipsilateral RSNA did not change during the whole renal artery occlusion in this study. Similarly, Kimura et al. (11) reported in the somato-cardiovascular reflex that when the effects of noxious stimulation of various segmental areas are examined, the supraspinal component of the reflex has characteristics of diffuse reflex organization, whereas the propriospinal one has strong segmental and lateral organization.
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Fig. 7. A proposed neural circuit as explanation of the ipsilateral renorenal reflex during partial renal ischemia. The supraspinal component of the ipsilateral renorenal reflex evoked by partial renal ischemia has an inhibitory influence on all renal sympathetic preganglionic motoneurons innervating the whole kidney, whereas the spinal excitatory component of the ipsilateral renorenal reflex acts on only the renal sympathetic preganglionic motoneurons innervating the ischemic region. If so, the ipsilateral RSNA to the ischemic region of the kidney seems unchanged during the partial renal ischemia because of a net balanced output between the supraspinal inhibitory and spinal excitatory responses.
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Physiopathological significance of sympathetic outflow control during partial renal ischemia.
We have shown that RSNA to the nonischemic region of the kidney decreased during partial renal ischemia, whereas RSNA to the ischemic region did not change. A decrease in renal sympathetic outflow is known to decrease renal vascular resistance and increase urine flow rate and urinary sodium excretion (5). Thus it can be expected that after renal blood flow is suddenly limited to nearly one-half due to the partial renal ischemia, the ipsilateral inhibitory response in RSNA to the nonischemic region may develop so as to reduce vascular resistance and enhance urine flow rate and urinary sodium excretion. To test this hypothesis, it will be necessary to examine the changes in ipsilateral urinary volume and sodium excretion during renal partial ischemia using the same animal preparations as in the present study. In preliminary experiments, we compared responses between the intact and denervated conditions of the same kidney to identify the neural contribution. Although urinary volume and sodium excretion were reduced by the partial ischemia, we found that their reduction tended to be less in the intact kidney than that in the denervated kidney (unpublished observation). Thus it is suggested that the ipsilateral inhibitory response in RSNA to the nonischemic renal region may compensate, at least partly, for renal dysfunction induced by the partial renal ischemia. On the other hand, a significance of ipsilateral excitatory renorenal reflex to the ischemic region of the same kidney remains to be interpreted.
In conclusion, this study has provided for the first time the concept that a reflex from a localized ischemic part of the kidney may cause heterogeneous fine control of RSNA to the ischemic region and to the nonischemic region of the same kidney.
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GRANTS
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This study was supported by a Grant-in-Aid for Scientific Research (B) from Japan Society for the Promotion of Science and by a Grant-in-Aid for Exploratory Research from the Ministry of Education, Culture, Sports, Science and Technology.
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FOOTNOTES
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Address for reprint requests and other correspondence: K. Matsukawa, Dept. of Physiology, Graduate School of Health Sciences Hiroshima Univ., 1–2-3 Kasumi, Minami-ku, Hiroshima 734–8551, Japan (e-mail: matsuk{at}hiroshima-u.ac.jp)
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.
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Copyright © 2006 by the American Physiological Society.
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ABSTRACT
METHODS
) and during ischemia of the ventral half of the kidney (RSNA to the nonischemic region; 
). B: the responses in RSNA, obtained from 5 renal nerve bundles that innervated an area in the ventral half of the kidney, during ischemia of the ventral half of the kidney (RSNA to the ischemic region; 
) and after (
) intra-arterial injection of a prostaglandin synthesis inhibitor (meclofenamate). The reduction in RSNA to the nonischemic region was abolished by meclofenamate (A), whereas the RSNA to the ischemic region was not influenced (B). Values are means ± SE.