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Sympathetically induced renal vasoconstriction during stimulation of mesencephalic locomotor region in rats
Autonomic Neuroscience: Basic and Clinical 121 (2005) 40 – 46 www.elsevier.com/locate/autneu
Sympathetically induced renal vasoconstriction during stimulation of mesencephalic locomotor region in rats Satoshi Koba a, Takayoshi Yoshida a,b, Naoyuki Hayashi c,* a
Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama-cho, Toyonaka, Osaka, 560-8531, Japan b School of Health and Sport Sciences, Osaka University, 1-17 Machikaneyama-cho, Toyonaka, Osaka, 560-0043, Japan c Institute of Health Science, Kyushu University, 6-1 Kasuga-Kouen, Kasuga, Fukuoka, 816-8580, Japan Received 19 April 2005; received in revised form 28 May 2005; accepted 4 June 2005
Abstract Central command, which is a neural drive originating in the brain during exercise, regulates the sympathetic nervous system and evokes cardiovascular responses to exercise. To examine the role of the central command on sympathetic regulation of renal circulation, we compared responses in renal cortical blood flow and vascular conductance to electrical stimulation of mesencephalic locomotor region (MLR) for 30 s in decerebrate and paralyzed rats between renal nerves that were intact (n = 8) and denervated (n = 8). In rats with renal nerves intact, stimulation of the MLR at 40 AA current intensity significantly ( p < 0.05) decreased renal cortical blood flow ( 17 T 5%, means T S.E.M.) and vascular conductance ( 43 T 4%) and the decrease in renal vascular conductance was dependent on current intensity (between 20 and 60 AA). In renal denervated rats, in contrast, there were no significant changes in either renal cortical blood flow or vascular conductance during stimulation at all current intensities. In a subset of rats (n = 8), the response in renal sympathetic nerve activity to 30 s stimulation of the MLR was investigated. Stimulation of the MLR significantly increased renal sympathetic nerve activity (+ 57 T 14% at 40 AA) and the response was dependent on current intensity (between 20 and 60 AA). These data provide evidence that central command induces renal vasoconstriction by increasing sympathetic activity, depending on central command intensity. D 2005 Published by Elsevier B.V. Keywords: Exercise; Central command; Renal cortical blood flow; Renal sympathetic nerve activity
1. Introduction Two principle neural mechanisms, i.e., exercise pressor reflex (Kaufman and Forster, 1996) and central command (Waldrop et al., 1996), have been proposed to increase sympathetic nerve activity (SNA) and adjust cardiovascular system during exercise. The exercise pressor reflex is a feedback neural drive which originates from metabolic and mechanical activation of afferent nerve endings located in contracting skeletal muscles (Kaufman and Forster, 1996). Central command is a feedforward neural drive which involves a parallel activation of the brain stem that controls locomotor and cardiorespiratory activities (Waldrop et al., 1996). The hypothalamic locomotor region (HLR) (Eldridge * Corresponding author. Tel./fax: +81 92 583 7848. E-mail address: [email protected] (N. Hayashi). 1566-0702/$ - see front matter D 2005 Published by Elsevier B.V. doi:10.1016/j.autneu.2005.06.001
et al., 1985), mesencephalic locomotor region (MLR) (Bedford et al., 1992), and several cortical tissues (Critchley et al., 2000; Thornton et al., 2002; Williamson et al., 2002, 2003) are identified as possible origins of central command. In humans at rest, the kidneys receive blood flow at about 20% of cardiac output (Rowell, 1993). During exercise, blood flow to exercising skeletal muscles increases, while that to the visceral organs including the kidneys decreases (Diepstra et al., 1982). The changes in blood flow are believed to be an attempt to match the increased metabolic demand in the exercising muscles. Thus, renal vasoconstriction contributes to the maintenance of blood pressure and the distribution of blood flow toward the muscles during exercise. Renal circulation is largely regulated by renal sympathetic nerve activity (RSNA) during exercise (Hohimer and Smith, 1979; Mueller et al., 1998). RSNA increases during exercise and is related to
S. Koba et al. / Autonomic Neuroscience: Basic and Clinical 121 (2005) 40 – 46
exercise intensity (Miki et al., 2002; O’Hagan et al., 1993; Schad and Seller, 1975). The exercise pressor reflex and/or central command can be considered as neural triggers to increase RSNA and to induce renal vasoconstriction (Middlekauff et al., 1997). The role of the exercise pressor reflex on sympathetic regulation of renal circulation has been demonstrated in cats (Matsukawa et al., 1992) and humans (Middlekauff et al., 1997; Momen et al., 2003). The exercise pressor reflex induces renal vasoconstriction through an increase in RSNA (Matsukawa et al., 1992; Middlekauff et al., 1997; Momen et al., 2003). On the other hand, the role of central command is not fully understood. Previous studies have shown that central command increases RSNA (Dean and Coote, 1986; Hajduczok et al., 1991; Hayes and Kaufman, 2002) and decreases renal blood flow (Waldrop et al., 1986). However it has not been demonstrated whether central command induces sympathetic vasoconstriction in the kidney. The present study was designed to examine the role of central command on the sympathetic regulation of renal circulation and the effect of central command intensity on the renal sympathetic and circulatory responses. We observed the responses in renal cortical blood flow (RCBF) and renal cortical vascular conductance (RCVC) to graded levels of electrical stimulation of the MLR in decerebrate and paralyzed rats with the renal nerves intact and denervated. Moreover, in a subset of rats, we observed RSNA responses to graded levels of stimulation of the MLR.
2. Materials and methods 2.1. General All experimental procedures of the present study were approved by the Research Ethic Committee of the School of Health and Sport Sciences, Osaka University and were conducted in accordance with the Guiding Principles in the Care and Use of Animals in the Fields of Physiological Sciences published by the Physiological Society of Japan. Twenty-four male Sprague – Dawley rats (7 – 9 weeks, weight: 250 –350 g) were used in the present study. The rat was anesthetized with a mixture of halothane (< 4%) and oxygen. The trachea was cannulated and then the lungs were artificially ventilated with a respirator (SN-480-7, Shinano, Japan) at 60 – 70 times per minute in frequency and 2 ml in tidal volume. The left jugular vein and common carotid artery were also cannulated to administer drags and to measure arterial pressure (AP), respectively. The carotid artery catheter was attached to a pressure transducer (P23XL-1, Ohmeda, USA). Arterial pH was continually measured with a pH meter (B-212, Horiba, Japan). It was maintained within normal limits by infusing sodium bicarbonate solution intravenously or by changing the ventilation frequency. Two syringe needles were set in the back to measure the electrocardiogram (ECG). The variable was amplified with a
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differential amplifier (AB-621G, Nihon Kohden, Japan). Heart rate (HR) was calculated beat to beat by detecting the time between successive R waves in the ECG. Body temperature was adequately maintained with a heating lamp. 2.2. RCBF recording In 16 rats, RCBF was recorded. The left kidney was exposed retroperitoneally through the left trunk incision. The left RCBF was measured with a laser-Doppler flowmetry with a needle-type probe (ALF21, Advance, Japan), which measures blood flow within a 1 mm radius from the tip of the probe. The probe was placed and stabilized vertically on the dorsal surface of the kidney. In 8 rats of the 16, all visible left renal nerves were dissected (RD group). 2.3. RSNA recording In another 8 rats, RSNA was recorded. A visible bundle of renal nerves was carefully dissected from other connective tissues. A piece of laboratory film was placed under the isolated nerve bundle and two tips of a bipolar electrode to measure RSNA were placed between the nerve bundle and the film. The third tip of the electrode was attached with the adipose tissue near the nerve bundle, which served as a grounding electrode. The exposed nerve bundle and the tips were embedded in a silicon gel. Once the silicon gel hardened, the silicon rubber was fixed to the surrounding tissue with a glue containing alpha-cyanoacrylate. The signal of RSNA was amplified with a differential amplifier (MEG2100, Nihon Kohden, Japan) with band-pass filters at 150 Hz low-cut frequency and 1 kHz high-cut frequency and made audible with an amplifier. RSNA was confirmed by observing the decreased and increased activities during the intravenous infusion of phenylephrine (5 Ag) and nitroprusside (5 Ag), respectively. 2.4. Decerebration The rat was placed in a stereotaxic apparatus (ST-7, Narishige, Japan). Decerebration was performed with a modified method reported in a previous study (Hayashi, 2003). Dexamethasone (0.2 mg) was given intravenously to minimize brain edema. Immediately before the decerebration, the right carotid artery, not used for recording of AP, was occluded to reduce brain bleeding. The upper skull and dura matter were removed and then the cortical tissue was removed with an aspirator. After the site of superior and inferior colliculus was confirmed, the brain was sectioned vertically with a blade at 2.0 mm rostral from the junction of superior and inferior colliculus. All neural tissue rostral to the section and the cortical tissues covering the cerebellum were aspirated. Immediately after the decerebration, the halothane anesthesia was withdrawn. The cranial vault was filled with mineral oil. To replace the blood lost during decerebration (approximately < 1 ml), saline was given
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Table 1 Baseline of MAP and HR in each group MAP (mmHg)
HR (bpm)
RCBF recording in CON rats (n = 8) 20 AA 87 T 6 40 AA 77 T 6 60 AA 80 T 7
332 T 10 316 T 15 319 T 14
RCBF recording in RD rats (n = 8) 20 AA 81 T11 40 AA 83 T 9 60 AA 81 T10
336 T 15 336 T 13 335 T 14
RSNA recording (n = 8) 20 AA 40 AA 60 AA
337 T 15 338 T 15 336 T 15
87 T 5 89 T 4 90 T 4
There were no significant differences between the groups.
intravenously in an amount sufficient to maintain basal AP. A recovery period for 90 min was allowed before experimental protocols to eliminate the effect of anesthesia and to stabilize the preparation. 2.5. Experimental protocols The procedure to find the site of the MLR and to stimulate it followed a previous study reported by Bedford et al. (1992). After the recovery period, the junction of the superior and inferior colliculus in the midbrain was searched to detect the site of the MLR with an Elgiloy-alloy electrode (diameter: 560 Am, impedence: 0.9 –1.4 MV at 1 kHz). The
(A)
site of the MLR was at the border of the colliculus, 0.5– 0.7 mm anterior, 1.8– 2.0 mm lateral, and 4.0 –4.5 mm deep from the surface of the colliculus, as reported by Bedford et al. (1992). The electrode was designated the cathode and the anode was placed in exposed muscle and skin tissue in the head wound. The site of the MLR was affirmed from physiological criteria. When successful, stimulation of the MLR at either the left or right side (< 40 AA in current intensity, 1 ms in pulse duration, 60 Hz in pulse frequency) evoked locomotor activity. After finding the site of the MLR (the left MLR was stimulated in 20 rats and right MLR was stimulated in 4 rats), the rat was paralyzed by injecting vecuronium bromide intravenously (1 mg kg 1). After collection of baseline data for 30 s, the MLR was electrically stimulated for 30 s at 20, 40, and 60 AA in current intensity (1 ms in pulse duration, 60 Hz in pulse frequency), respectively (Bedford et al., 1992). The order of current intensity for stimulation was randomized. The waiting time between the recordings was sufficient to allow that AP returned to the baseline level (2– 3 min). After all protocols, the rat was humanely killed with an anesthetic overdose (sodium pentobarbital), and the artifacts of RCBF or the background noise of RSNA were recorded. 2.6. Data acquisition and statistical analyses AP, ECG, HR, and RCBF or RSNA were continuously displayed on a computer monitor and stored on a hard disk thorough an analog – digital conversion (Powerlab/8s, AD Instruments, Australia) at 1 kHz sampling rate. Artifacts,
(B)
Fig. 1. Examples of AP, HR (1 s averaged), and RCBF in a CON (A) and a RD rat (B) before, during, and after 30-s stimulation of the MLR at 40 AA current intensity. Black bar indicates duration of stimulation of the MLR. Stimulation of the MLR increased AP in both preparations and it decreased RCBF in the CON ratl; on the other hand, it did not decrease but slightly increased RCBF in the RD rat.
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which were less than 5% of RCBF at baseline, were subtracted from RCBF recordings. Recorded RSNA was transformed into absolute value, integrated, and then subtracted by the integrated background noise. The absolute values of RCBF and the integrated RSNA varied among rats (RCBF: from 0.11 to 0.87 V; 1 s integrated RSNA: from 0.43 to 2.52 mV s, at baseline). Therefore, to quantify RCBF and RSNA responses to stimulation of the MLR, relative changes from pre-stimulation were obtained by taking the mean of the values during a 30 s pre-stimulation period as 100%. RCVC was obtained by dividing RCBF by MAP and the relative changes from pre-stimulation were quantified in the same way with RSNA and RCBF. The data are expressed as means T S.E.M. The values averaged for 30 s immediately before stimulation of the MLR were evaluated as baseline. Baseline values were compared with unpaired t-tests among each group. Twoway analysis of variance (ANOVA) was used to evaluate the differences between the baseline level and the responses during stimulation of the MLR and to test the effect of stimulation intensity on the magnitudes of the responses. Where significant F-ratios were found with the ANOVA, post hoc analysis was performed with Tukey’s procedure. The level of the statistical significance was set at p < 0.05.
3. Results MAP and HR at baseline were not significantly different among groups (Table 1). Fig. 1 shows original recordings of AP, HR (averaged over 1 s), and RCBF before, during, and after the 30 s stimulation of the MLR at 40 AA in current intensity in a renal nerves intact (CON) rat and a RD rat. Stimulation of the MLR increased AP and slightly increased HR in both rats. It decreased RCBF in the CON rat, whereas it slightly increased RCBF in the RD rat. The RCBF fluctuated in synchronization with both the heart beat and the artificial respiratory frequency. Fig. 2 shows changes averaged over 30 s in MAP, HR, RCBF, and RCVC from baseline during stimulation of the MLR. In the CON rats, MAP significantly increased and RCVC significantly decreased by stimulation at all current intensities. RCBF significantly decreased by stimulation at 40 and 60 AA. HR did not significantly change by stimulation at all current intensities. The increase in MAP at 20 AA was significantly lower than that at 60 AA but not at 40 AA. The decrease in RCVC at 20 AA was significantly lower than that at 40 and 60 AA. The decrease in RCBF was not significantly affected by current intensity. In the RD rats, MAP significantly increased at all current intensities and HR, RCBF, and RCVC were not significantly changed by stimulation. The increase in MAP at 20 AA was significantly lower than that at 60 AA but not at 40 AA. In a subset of rats (n = 8), RSNA response to stimulation of the MLR was investigated. Fig. 3 shows an original
Fig. 2. Changes averaged over 30 s in MAP, HR, RCBF, and RCVC from baseline during stimulation of the MLR in CON (n = 8, left) and RD rats (n = 8, right). Values are means T S.E.M. *p < 0.05 vs. baseline. .p < 0.05 vs. responses at 20 AA. There were no significant differences between responses at 40 and 60 AA.
recording of AP, HR (averaged over 1 s), and RSNA before, during, and after the 30 s stimulation of the MLR at 40 AA in current intensity. Stimulation of the MLR increased AP and also increased RSNA. After the abrupt increase in RSNA at the onset of stimulation, it decreased but remained above the baseline level. Fig. 4 shows the changes averaged over 30 s in MAP, HR, and RSNA from baseline during stimulation of the MLR. MAP and RSNA significantly increased by stimulation at all current intensities and the increases in MAP and RSNA at 20 AA were significantly lower than those at 60 AA, but not those at 40 AA. HR did not significantly change by stimulation at all current intensities.
4. Discussion We investigated the role of central command on sympathetic regulation of renal circulation. The major findings of the present study were: 1) stimulation of the
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(A)
stimulation of the MLR 160
AP (mmHg)
100 40
420
HR (bpm)
400 380 30
RSNA ( )
0
-30
(a)
(b)
(c)
10 s
(B)
RSNA ( )
(a) baseline
(b) 2-3s
(c) 22-23s
30
30
30
0
0
0
-30
-30
-30
500 ms Fig. 3. (A) An example of AP, HR, and RSNA before, during, and after 30-s stimulation of the MLR at 40 AA current intensity. Black bar indicates duration of stimulation of the MLR. Stimulation of the MLR abruptly increased RSNA. (B) Detailed data of RSNA for 1 s before (a) and during stimulation of the MLR (b: 2 – 3 s after onset of stimulation, c: 22 – 23 s after onset of stimulation). Recorded duration of these data are indicated by arrows in A.
MLR significantly increased AP and RSNA and significantly decreased RCBF and RCVC; 2) magnitudes of the changes in MAP, RSNA, and RCVC during stimulation of the MLR at lower current intensity (20 AA) were lower than those at higher current intensity (40 and/or 60 AA); and 3) the decreases in RCBF and RCVC during stimulation of the MLR were abolished by renal denervation. These results provide strong evidence that central command induces renal vasoconstriction through sympathetic outflow, depending on central command intensity. The present results indicate that renal vasoconstriction during stimulation of the MLR is induced mainly by an increase in RSNA because renal denervation abolished the decrease in RCVC during stimulation. Mueller et al. (1998) suggested that the decrease in renal vascular conductance during dynamic exercise is primarily due to the neural mediation because a-adrenergic blockade, which blocks the effect of circulating catecholamines, cannot abolish the decrease in RCVC completely. When the RSNA is at a high
level, not at a low level such as during daily life, it induces renal vasoconstriction (DiBona and Kopp, 1997). In the present study, the increase in RSNA during stimulation of the MLR must have been great enough to induce renal vasoconstriction and consequently to decrease RCBF. The pressor response to stimulation of the MLR was greater with current intensity for stimulation, consistent with the previous study of Bedford et al. (1992). The present results extend their finding. Not only the increase in MAP but also the increase in RSNA and the decrease in RCVC during stimulation of the MLR were related to current intensity. The other studies which investigated the effect of exercise intensity on RSNA in conscious animals indicated that the running speed for treadmill exercise relates to the magnitude of RSNA responses (Miki et al., 2002; O’Hagan et al., 1993; Schad and Seller, 1975). Moreover in humans, it was reported that dynamic exercise produces an intensitydependent renal vasoconstriction (Tidgren et al., 1991). It is suggested that the magnitude of central command, which
S. Koba et al. / Autonomic Neuroscience: Basic and Clinical 121 (2005) 40 – 46
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because central command is an integrated neural drive from several areas including the MLR. Previous studies suggested several areas as the origins of central command, for example, HLR (Eldridge et al., 1985), insular cortex (Critchley et al., 2000; Williamson et al., 2002, 2003), anterior cingulated cortex (Critchley et al., 2000; Williamson et al., 2002, 2003), and basal ganglia (Thornton et al., 2002). Since anatomic connections must exist among these areas, it is difficult to focus on the individual and/or integrated roles played by these areas as central command on cardiovascular regulation during exercise in the present study.
Acknowledgements This study was supported by a grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan to N. Hayashi (No. 15700418) and a Sasagawa science grant of the Japan Science Society to S. Koba. The present affiliation of T. Yoshida is Graduate School of Medicine, Osaka University, Japan.
Fig. 4. Changes averaged over 30 s in MAP, HR, and RSNA from baseline during stimulation of the MLR. Values are means T S.E.M. *p < 0.05 vs. baseline. .p < 0.05 vs. responses at 20 AA. There were no significant differences between responses at 40 and 60 AA.
should be an analogue of exercise intensity, affects the amount of RSNA response and the degree of renal vasoconstriction during exercise. In the present study, the increase in MAP occurred but that in HR did not occur. Exercise increases not only arterial pressure but also heart rate, although heart rate negatively changes in accordance with changes in arterial pressure through aortic and carotid baroreflex. The concomitant increases in both arterial pressure and heart rate during exercise resulted from the resetting of baroreflex function, which is characterized by attenuation of the effect to decrease heart rate during the arterial pressure increase (Rowell et al., 1996). It is reported that the baroreflex resetting is triggered by central command (Komine et al., 2003). In the present preparation, aortic, but not carotid, baroreceptors were intact (see Materials and methods). Thus, central command evoked by stimulating the MLR must have reset the aortic baroreflex function. We suppose that the resetting should not have been enough to increase HR with increases in AP in the present study. We stimulated the MLR electrically in paralyzed preparations to evoke only central command. The MLR is an origin of central command and stimulating it induces both locomotor and cardiovascular activation (Bedford et al., 1992). However the neural drive originating in the MLR should not be equal to central command in nature
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at the onset of voluntary static exercise in cats. Am. J. Physiol, Heart Circ. Physiol. 285, H516 – H526. Matsukawa, K., Wall, P.T., Wilson, L.B., Mitchell, J.H., 1992. Neurally mediated renal vasoconstriction during isometric muscle contraction in cats. Am. J. Physiol, Heart Circ. Physiol. 262, H833 – H838. Middlekauff, H.R., Nitzsche, E.U., Nguyen, A.H., Hoh, C.K., Gibbs, G.G., 1997. Modulation of renal cortical blood flow during static exercise in humans. Circ. Res. 80, 62 – 68. Miki, K., Kosho, A., Hayashida, Y., 2002. Method for continuous measurements of renal sympathetic nerve activity and cardiovascular function during exercise in rats. Exp. Physiol. 87, 33 – 39. Momen, A., Leuenberger, U.A., Ray, C.A., Cha, S., Sinoway, L.I., 2003. Renal vascular responses to static handgrip: role of the muscle mechanoreflex. Am. J. Physiol, Heart Circ. Physiol. 285, H1247 – H1253. Mueller, P.J., O’Hagan, K.P., Skogg, K.A., Buckwalter, J.B., Clifford, P.S., 1998. Renal hemodynamic responses to dynamic exercise in rabbits. J. Appl. Physiol. 85, 1605 – 1614. O’Hagan, K.P., Bell, L.B., Mittelstadt, S.W., Clifford, P.S., 1993. Effect of dynamic exercise on renal sympathetic nerve activity in conscious rabbits. J. Appl. Physiol. 74, 2099 – 2104. Rowell, L.B., 1993. Cardiovascular adjustments to isometric contraction. In: Rowell, L.B. (Ed.), Human Cardiovascular Control. Oxford University Press, New York, NY, pp. 302 – 325. Rowell, L.B., O’leary, D.S., Kellogg Jr., D.L., 1996. Integration of cardiovascular control systems in dynamic exercise. Handbook of
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Sympathetically induced renal vasoconstriction during stimulation of mesencephalic locomotor region in rats Satoshi Koba a, Takayoshi Yoshida a,b, Naoyuki Hayashi c,* a
Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama-cho, Toyonaka, Osaka, 560-8531, Japan b School of Health and Sport Sciences, Osaka University, 1-17 Machikaneyama-cho, Toyonaka, Osaka, 560-0043, Japan c Institute of Health Science, Kyushu University, 6-1 Kasuga-Kouen, Kasuga, Fukuoka, 816-8580, Japan Received 19 April 2005; received in revised form 28 May 2005; accepted 4 June 2005
Abstract Central command, which is a neural drive originating in the brain during exercise, regulates the sympathetic nervous system and evokes cardiovascular responses to exercise. To examine the role of the central command on sympathetic regulation of renal circulation, we compared responses in renal cortical blood flow and vascular conductance to electrical stimulation of mesencephalic locomotor region (MLR) for 30 s in decerebrate and paralyzed rats between renal nerves that were intact (n = 8) and denervated (n = 8). In rats with renal nerves intact, stimulation of the MLR at 40 AA current intensity significantly ( p < 0.05) decreased renal cortical blood flow ( 17 T 5%, means T S.E.M.) and vascular conductance ( 43 T 4%) and the decrease in renal vascular conductance was dependent on current intensity (between 20 and 60 AA). In renal denervated rats, in contrast, there were no significant changes in either renal cortical blood flow or vascular conductance during stimulation at all current intensities. In a subset of rats (n = 8), the response in renal sympathetic nerve activity to 30 s stimulation of the MLR was investigated. Stimulation of the MLR significantly increased renal sympathetic nerve activity (+ 57 T 14% at 40 AA) and the response was dependent on current intensity (between 20 and 60 AA). These data provide evidence that central command induces renal vasoconstriction by increasing sympathetic activity, depending on central command intensity. D 2005 Published by Elsevier B.V. Keywords: Exercise; Central command; Renal cortical blood flow; Renal sympathetic nerve activity
1. Introduction Two principle neural mechanisms, i.e., exercise pressor reflex (Kaufman and Forster, 1996) and central command (Waldrop et al., 1996), have been proposed to increase sympathetic nerve activity (SNA) and adjust cardiovascular system during exercise. The exercise pressor reflex is a feedback neural drive which originates from metabolic and mechanical activation of afferent nerve endings located in contracting skeletal muscles (Kaufman and Forster, 1996). Central command is a feedforward neural drive which involves a parallel activation of the brain stem that controls locomotor and cardiorespiratory activities (Waldrop et al., 1996). The hypothalamic locomotor region (HLR) (Eldridge * Corresponding author. Tel./fax: +81 92 583 7848. E-mail address: [email protected] (N. Hayashi). 1566-0702/$ - see front matter D 2005 Published by Elsevier B.V. doi:10.1016/j.autneu.2005.06.001
et al., 1985), mesencephalic locomotor region (MLR) (Bedford et al., 1992), and several cortical tissues (Critchley et al., 2000; Thornton et al., 2002; Williamson et al., 2002, 2003) are identified as possible origins of central command. In humans at rest, the kidneys receive blood flow at about 20% of cardiac output (Rowell, 1993). During exercise, blood flow to exercising skeletal muscles increases, while that to the visceral organs including the kidneys decreases (Diepstra et al., 1982). The changes in blood flow are believed to be an attempt to match the increased metabolic demand in the exercising muscles. Thus, renal vasoconstriction contributes to the maintenance of blood pressure and the distribution of blood flow toward the muscles during exercise. Renal circulation is largely regulated by renal sympathetic nerve activity (RSNA) during exercise (Hohimer and Smith, 1979; Mueller et al., 1998). RSNA increases during exercise and is related to
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exercise intensity (Miki et al., 2002; O’Hagan et al., 1993; Schad and Seller, 1975). The exercise pressor reflex and/or central command can be considered as neural triggers to increase RSNA and to induce renal vasoconstriction (Middlekauff et al., 1997). The role of the exercise pressor reflex on sympathetic regulation of renal circulation has been demonstrated in cats (Matsukawa et al., 1992) and humans (Middlekauff et al., 1997; Momen et al., 2003). The exercise pressor reflex induces renal vasoconstriction through an increase in RSNA (Matsukawa et al., 1992; Middlekauff et al., 1997; Momen et al., 2003). On the other hand, the role of central command is not fully understood. Previous studies have shown that central command increases RSNA (Dean and Coote, 1986; Hajduczok et al., 1991; Hayes and Kaufman, 2002) and decreases renal blood flow (Waldrop et al., 1986). However it has not been demonstrated whether central command induces sympathetic vasoconstriction in the kidney. The present study was designed to examine the role of central command on the sympathetic regulation of renal circulation and the effect of central command intensity on the renal sympathetic and circulatory responses. We observed the responses in renal cortical blood flow (RCBF) and renal cortical vascular conductance (RCVC) to graded levels of electrical stimulation of the MLR in decerebrate and paralyzed rats with the renal nerves intact and denervated. Moreover, in a subset of rats, we observed RSNA responses to graded levels of stimulation of the MLR.
2. Materials and methods 2.1. General All experimental procedures of the present study were approved by the Research Ethic Committee of the School of Health and Sport Sciences, Osaka University and were conducted in accordance with the Guiding Principles in the Care and Use of Animals in the Fields of Physiological Sciences published by the Physiological Society of Japan. Twenty-four male Sprague – Dawley rats (7 – 9 weeks, weight: 250 –350 g) were used in the present study. The rat was anesthetized with a mixture of halothane (< 4%) and oxygen. The trachea was cannulated and then the lungs were artificially ventilated with a respirator (SN-480-7, Shinano, Japan) at 60 – 70 times per minute in frequency and 2 ml in tidal volume. The left jugular vein and common carotid artery were also cannulated to administer drags and to measure arterial pressure (AP), respectively. The carotid artery catheter was attached to a pressure transducer (P23XL-1, Ohmeda, USA). Arterial pH was continually measured with a pH meter (B-212, Horiba, Japan). It was maintained within normal limits by infusing sodium bicarbonate solution intravenously or by changing the ventilation frequency. Two syringe needles were set in the back to measure the electrocardiogram (ECG). The variable was amplified with a
41
differential amplifier (AB-621G, Nihon Kohden, Japan). Heart rate (HR) was calculated beat to beat by detecting the time between successive R waves in the ECG. Body temperature was adequately maintained with a heating lamp. 2.2. RCBF recording In 16 rats, RCBF was recorded. The left kidney was exposed retroperitoneally through the left trunk incision. The left RCBF was measured with a laser-Doppler flowmetry with a needle-type probe (ALF21, Advance, Japan), which measures blood flow within a 1 mm radius from the tip of the probe. The probe was placed and stabilized vertically on the dorsal surface of the kidney. In 8 rats of the 16, all visible left renal nerves were dissected (RD group). 2.3. RSNA recording In another 8 rats, RSNA was recorded. A visible bundle of renal nerves was carefully dissected from other connective tissues. A piece of laboratory film was placed under the isolated nerve bundle and two tips of a bipolar electrode to measure RSNA were placed between the nerve bundle and the film. The third tip of the electrode was attached with the adipose tissue near the nerve bundle, which served as a grounding electrode. The exposed nerve bundle and the tips were embedded in a silicon gel. Once the silicon gel hardened, the silicon rubber was fixed to the surrounding tissue with a glue containing alpha-cyanoacrylate. The signal of RSNA was amplified with a differential amplifier (MEG2100, Nihon Kohden, Japan) with band-pass filters at 150 Hz low-cut frequency and 1 kHz high-cut frequency and made audible with an amplifier. RSNA was confirmed by observing the decreased and increased activities during the intravenous infusion of phenylephrine (5 Ag) and nitroprusside (5 Ag), respectively. 2.4. Decerebration The rat was placed in a stereotaxic apparatus (ST-7, Narishige, Japan). Decerebration was performed with a modified method reported in a previous study (Hayashi, 2003). Dexamethasone (0.2 mg) was given intravenously to minimize brain edema. Immediately before the decerebration, the right carotid artery, not used for recording of AP, was occluded to reduce brain bleeding. The upper skull and dura matter were removed and then the cortical tissue was removed with an aspirator. After the site of superior and inferior colliculus was confirmed, the brain was sectioned vertically with a blade at 2.0 mm rostral from the junction of superior and inferior colliculus. All neural tissue rostral to the section and the cortical tissues covering the cerebellum were aspirated. Immediately after the decerebration, the halothane anesthesia was withdrawn. The cranial vault was filled with mineral oil. To replace the blood lost during decerebration (approximately < 1 ml), saline was given
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Table 1 Baseline of MAP and HR in each group MAP (mmHg)
HR (bpm)
RCBF recording in CON rats (n = 8) 20 AA 87 T 6 40 AA 77 T 6 60 AA 80 T 7
332 T 10 316 T 15 319 T 14
RCBF recording in RD rats (n = 8) 20 AA 81 T11 40 AA 83 T 9 60 AA 81 T10
336 T 15 336 T 13 335 T 14
RSNA recording (n = 8) 20 AA 40 AA 60 AA
337 T 15 338 T 15 336 T 15
87 T 5 89 T 4 90 T 4
There were no significant differences between the groups.
intravenously in an amount sufficient to maintain basal AP. A recovery period for 90 min was allowed before experimental protocols to eliminate the effect of anesthesia and to stabilize the preparation. 2.5. Experimental protocols The procedure to find the site of the MLR and to stimulate it followed a previous study reported by Bedford et al. (1992). After the recovery period, the junction of the superior and inferior colliculus in the midbrain was searched to detect the site of the MLR with an Elgiloy-alloy electrode (diameter: 560 Am, impedence: 0.9 –1.4 MV at 1 kHz). The
(A)
site of the MLR was at the border of the colliculus, 0.5– 0.7 mm anterior, 1.8– 2.0 mm lateral, and 4.0 –4.5 mm deep from the surface of the colliculus, as reported by Bedford et al. (1992). The electrode was designated the cathode and the anode was placed in exposed muscle and skin tissue in the head wound. The site of the MLR was affirmed from physiological criteria. When successful, stimulation of the MLR at either the left or right side (< 40 AA in current intensity, 1 ms in pulse duration, 60 Hz in pulse frequency) evoked locomotor activity. After finding the site of the MLR (the left MLR was stimulated in 20 rats and right MLR was stimulated in 4 rats), the rat was paralyzed by injecting vecuronium bromide intravenously (1 mg kg 1). After collection of baseline data for 30 s, the MLR was electrically stimulated for 30 s at 20, 40, and 60 AA in current intensity (1 ms in pulse duration, 60 Hz in pulse frequency), respectively (Bedford et al., 1992). The order of current intensity for stimulation was randomized. The waiting time between the recordings was sufficient to allow that AP returned to the baseline level (2– 3 min). After all protocols, the rat was humanely killed with an anesthetic overdose (sodium pentobarbital), and the artifacts of RCBF or the background noise of RSNA were recorded. 2.6. Data acquisition and statistical analyses AP, ECG, HR, and RCBF or RSNA were continuously displayed on a computer monitor and stored on a hard disk thorough an analog – digital conversion (Powerlab/8s, AD Instruments, Australia) at 1 kHz sampling rate. Artifacts,
(B)
Fig. 1. Examples of AP, HR (1 s averaged), and RCBF in a CON (A) and a RD rat (B) before, during, and after 30-s stimulation of the MLR at 40 AA current intensity. Black bar indicates duration of stimulation of the MLR. Stimulation of the MLR increased AP in both preparations and it decreased RCBF in the CON ratl; on the other hand, it did not decrease but slightly increased RCBF in the RD rat.
S. Koba et al. / Autonomic Neuroscience: Basic and Clinical 121 (2005) 40 – 46
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which were less than 5% of RCBF at baseline, were subtracted from RCBF recordings. Recorded RSNA was transformed into absolute value, integrated, and then subtracted by the integrated background noise. The absolute values of RCBF and the integrated RSNA varied among rats (RCBF: from 0.11 to 0.87 V; 1 s integrated RSNA: from 0.43 to 2.52 mV s, at baseline). Therefore, to quantify RCBF and RSNA responses to stimulation of the MLR, relative changes from pre-stimulation were obtained by taking the mean of the values during a 30 s pre-stimulation period as 100%. RCVC was obtained by dividing RCBF by MAP and the relative changes from pre-stimulation were quantified in the same way with RSNA and RCBF. The data are expressed as means T S.E.M. The values averaged for 30 s immediately before stimulation of the MLR were evaluated as baseline. Baseline values were compared with unpaired t-tests among each group. Twoway analysis of variance (ANOVA) was used to evaluate the differences between the baseline level and the responses during stimulation of the MLR and to test the effect of stimulation intensity on the magnitudes of the responses. Where significant F-ratios were found with the ANOVA, post hoc analysis was performed with Tukey’s procedure. The level of the statistical significance was set at p < 0.05.
3. Results MAP and HR at baseline were not significantly different among groups (Table 1). Fig. 1 shows original recordings of AP, HR (averaged over 1 s), and RCBF before, during, and after the 30 s stimulation of the MLR at 40 AA in current intensity in a renal nerves intact (CON) rat and a RD rat. Stimulation of the MLR increased AP and slightly increased HR in both rats. It decreased RCBF in the CON rat, whereas it slightly increased RCBF in the RD rat. The RCBF fluctuated in synchronization with both the heart beat and the artificial respiratory frequency. Fig. 2 shows changes averaged over 30 s in MAP, HR, RCBF, and RCVC from baseline during stimulation of the MLR. In the CON rats, MAP significantly increased and RCVC significantly decreased by stimulation at all current intensities. RCBF significantly decreased by stimulation at 40 and 60 AA. HR did not significantly change by stimulation at all current intensities. The increase in MAP at 20 AA was significantly lower than that at 60 AA but not at 40 AA. The decrease in RCVC at 20 AA was significantly lower than that at 40 and 60 AA. The decrease in RCBF was not significantly affected by current intensity. In the RD rats, MAP significantly increased at all current intensities and HR, RCBF, and RCVC were not significantly changed by stimulation. The increase in MAP at 20 AA was significantly lower than that at 60 AA but not at 40 AA. In a subset of rats (n = 8), RSNA response to stimulation of the MLR was investigated. Fig. 3 shows an original
Fig. 2. Changes averaged over 30 s in MAP, HR, RCBF, and RCVC from baseline during stimulation of the MLR in CON (n = 8, left) and RD rats (n = 8, right). Values are means T S.E.M. *p < 0.05 vs. baseline. .p < 0.05 vs. responses at 20 AA. There were no significant differences between responses at 40 and 60 AA.
recording of AP, HR (averaged over 1 s), and RSNA before, during, and after the 30 s stimulation of the MLR at 40 AA in current intensity. Stimulation of the MLR increased AP and also increased RSNA. After the abrupt increase in RSNA at the onset of stimulation, it decreased but remained above the baseline level. Fig. 4 shows the changes averaged over 30 s in MAP, HR, and RSNA from baseline during stimulation of the MLR. MAP and RSNA significantly increased by stimulation at all current intensities and the increases in MAP and RSNA at 20 AA were significantly lower than those at 60 AA, but not those at 40 AA. HR did not significantly change by stimulation at all current intensities.
4. Discussion We investigated the role of central command on sympathetic regulation of renal circulation. The major findings of the present study were: 1) stimulation of the
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(A)
stimulation of the MLR 160
AP (mmHg)
100 40
420
HR (bpm)
400 380 30
RSNA ( )
0
-30
(a)
(b)
(c)
10 s
(B)
RSNA ( )
(a) baseline
(b) 2-3s
(c) 22-23s
30
30
30
0
0
0
-30
-30
-30
500 ms Fig. 3. (A) An example of AP, HR, and RSNA before, during, and after 30-s stimulation of the MLR at 40 AA current intensity. Black bar indicates duration of stimulation of the MLR. Stimulation of the MLR abruptly increased RSNA. (B) Detailed data of RSNA for 1 s before (a) and during stimulation of the MLR (b: 2 – 3 s after onset of stimulation, c: 22 – 23 s after onset of stimulation). Recorded duration of these data are indicated by arrows in A.
MLR significantly increased AP and RSNA and significantly decreased RCBF and RCVC; 2) magnitudes of the changes in MAP, RSNA, and RCVC during stimulation of the MLR at lower current intensity (20 AA) were lower than those at higher current intensity (40 and/or 60 AA); and 3) the decreases in RCBF and RCVC during stimulation of the MLR were abolished by renal denervation. These results provide strong evidence that central command induces renal vasoconstriction through sympathetic outflow, depending on central command intensity. The present results indicate that renal vasoconstriction during stimulation of the MLR is induced mainly by an increase in RSNA because renal denervation abolished the decrease in RCVC during stimulation. Mueller et al. (1998) suggested that the decrease in renal vascular conductance during dynamic exercise is primarily due to the neural mediation because a-adrenergic blockade, which blocks the effect of circulating catecholamines, cannot abolish the decrease in RCVC completely. When the RSNA is at a high
level, not at a low level such as during daily life, it induces renal vasoconstriction (DiBona and Kopp, 1997). In the present study, the increase in RSNA during stimulation of the MLR must have been great enough to induce renal vasoconstriction and consequently to decrease RCBF. The pressor response to stimulation of the MLR was greater with current intensity for stimulation, consistent with the previous study of Bedford et al. (1992). The present results extend their finding. Not only the increase in MAP but also the increase in RSNA and the decrease in RCVC during stimulation of the MLR were related to current intensity. The other studies which investigated the effect of exercise intensity on RSNA in conscious animals indicated that the running speed for treadmill exercise relates to the magnitude of RSNA responses (Miki et al., 2002; O’Hagan et al., 1993; Schad and Seller, 1975). Moreover in humans, it was reported that dynamic exercise produces an intensitydependent renal vasoconstriction (Tidgren et al., 1991). It is suggested that the magnitude of central command, which
S. Koba et al. / Autonomic Neuroscience: Basic and Clinical 121 (2005) 40 – 46
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because central command is an integrated neural drive from several areas including the MLR. Previous studies suggested several areas as the origins of central command, for example, HLR (Eldridge et al., 1985), insular cortex (Critchley et al., 2000; Williamson et al., 2002, 2003), anterior cingulated cortex (Critchley et al., 2000; Williamson et al., 2002, 2003), and basal ganglia (Thornton et al., 2002). Since anatomic connections must exist among these areas, it is difficult to focus on the individual and/or integrated roles played by these areas as central command on cardiovascular regulation during exercise in the present study.
Acknowledgements This study was supported by a grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan to N. Hayashi (No. 15700418) and a Sasagawa science grant of the Japan Science Society to S. Koba. The present affiliation of T. Yoshida is Graduate School of Medicine, Osaka University, Japan.
Fig. 4. Changes averaged over 30 s in MAP, HR, and RSNA from baseline during stimulation of the MLR. Values are means T S.E.M. *p < 0.05 vs. baseline. .p < 0.05 vs. responses at 20 AA. There were no significant differences between responses at 40 and 60 AA.
should be an analogue of exercise intensity, affects the amount of RSNA response and the degree of renal vasoconstriction during exercise. In the present study, the increase in MAP occurred but that in HR did not occur. Exercise increases not only arterial pressure but also heart rate, although heart rate negatively changes in accordance with changes in arterial pressure through aortic and carotid baroreflex. The concomitant increases in both arterial pressure and heart rate during exercise resulted from the resetting of baroreflex function, which is characterized by attenuation of the effect to decrease heart rate during the arterial pressure increase (Rowell et al., 1996). It is reported that the baroreflex resetting is triggered by central command (Komine et al., 2003). In the present preparation, aortic, but not carotid, baroreceptors were intact (see Materials and methods). Thus, central command evoked by stimulating the MLR must have reset the aortic baroreflex function. We suppose that the resetting should not have been enough to increase HR with increases in AP in the present study. We stimulated the MLR electrically in paralyzed preparations to evoke only central command. The MLR is an origin of central command and stimulating it induces both locomotor and cardiovascular activation (Bedford et al., 1992). However the neural drive originating in the MLR should not be equal to central command in nature
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