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Am J Physiol Heart Circ Physiol 292: H866-H873, 2007. First published September 29, 2006; doi:10.1152/ajpheart.00771.2006
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Thin-fiber mechanoreceptors reflexly increase renal sympathetic nerve activity during static contraction

Jong Kyung Kim, Shawn G. Hayes, Angela E. Kindig, and Marc P. Kaufman

Division of Cardiovascular Medicine, University of California, Davis, Davis, California

Submitted 18 July 2006 ; accepted in final form 20 September 2006


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
The renal vasoconstriction induced by the sympathetic outflow during exercise serves to direct blood flow from the kidney toward the exercising muscles. The renal circulation seems to be particularly important in this regard, because it receives a substantial part of the cardiac output, which in resting humans has been estimated to be 20%. The role of group III mechanoreceptors in causing the reflex renal sympathetic response to static contraction remains an open question. To shed some light on this question, we recorded the renal sympathetic nerve responses to static contraction before and after injection of gadolinium into the arterial supply of the statically contracting triceps surae muscles of decerebrate unanesthetized and chloralose-anesthetized cats. Gadolinium has been shown to be a selective blocker of mechanogated channels in thin-fiber muscle afferents, which comprise the afferent arm of the exercise pressor reflex arc. In decerebrate (n = 15) and chloralose-anesthetized (n = 12) cats, we found that gadolinium (10 mM; 1 ml) significantly attenuated the renal sympathetic nerve and pressor responses to static contraction (60 s) after a latent period of 60 min; both responses recovered after a latent period of 120 min. We conclude that thin-fiber mechanoreceptors supplying contracting muscle are involved in some of the renal vasoconstriction evoked by the exercise pressor reflex.

exercise; cats; gadolinium; autonomic nervous system; group III muscle afferents

STATIC EXERCISE INCREASES the sympathetic outflow to the heart and the vascular tree; this effect, in turn, increases arterial pressure, heart rate, and peripheral vascular resistance (24, 25). The two neural mechanisms that cause the exercise-induced increase in sympathetic discharge are the exercise pressor reflex (2, 11, 17), the afferent arm of which consists of group III and IV muscle afferents (17), and central command (5, 34). Group III afferents respond primarily to mechanical stimuli arising in statically contracting muscle, whereas group IV afferents respond primarily to metabolic stimuli (12, 13, 23).

The visceral vasoconstriction induced by the sympathetic outflow during exercise (20, 21) serves to direct blood flow from organs such as the kidney toward the exercising muscles. The renal circulation seems to be particularly important in this regard, because at rest it receives a substantial portion of the cardiac output, which in humans has been estimated to be 20% (24). In humans and animals, the exercise pressor reflex has been shown to increase renal sympathetic nerve activity (RSNA) or renal vascular resistance (15, 16, 20, 21, 32). However, the role of group III mechanoreceptors in evoking this reflex increase in renal sympathetic discharge is not clear. Matsukawa et al. (15, 16) and Koba et al. (14) provided convincing evidence that tendon stretch, a purely mechanical stimulus to muscle afferents, reflexly increased RSNA in cats and rats. Unfortunately, tendon stretch, which evokes the muscle mechanoreflex (29), was subsequently shown to stimulate a population of group III mechanoreceptors different from that stimulated by static contraction (8). Consequently, the role of group III mechanoreceptors in causing the renal sympathetic response to static contraction remains an open question.

To answer this question, we recorded the renal sympathetic nerve responses to static contraction before and after injection of gadolinium into the arterial supply of contracting muscle in cats. Gadolinium injected in this manner into decerebrate and chloralose-anesthetized cats has been shown to block the responses of group III afferents to static contraction as well as to tendon stretch (7). In addition, gadolinium injection greatly attenuated the pressor and cardioaccelerator responses to static contraction and tendon stretch (7, 28). We therefore used gadolinium to investigate the role of group III mechanoreceptors in the contraction-induced reflex increase in RSNA in decerebrate and {alpha}-chloralose-urethane-anesthetized cats. In addition, we investigated the role of group III mechanoreceptors in the stretch-induced reflex increase in RSNA in both preparations.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
All procedures were reviewed and approved by the Institutional Care and Use Committee of the University of California, Davis.

Surgical preparation. Adult cats of either sex (n = 27, 3.1 ± 0.3 kg, range 2.2–4.8 kg) were initially anesthetized with a mixture of 5% halothane and oxygen. The right jugular vein and common carotid artery were cannulated for the delivery of drugs and fluids and the measurement of arterial blood pressure, respectively. The arterial blood pressure catheter was connected to a pressure transducer (model P23 XL, Statham) to monitor blood pressure. Heart rate was calculated beat-to-beat from the arterial pressure pulse by a Gould Biotach amplifier. The trachea was cannulated, and the lungs were ventilated mechanically (Harvard Apparatus). Arterial blood gases and pH were measured by an automated blood gas analyzer (model ABL-700, Radiometer). PCO2 and arterial pH were maintained within normal range by adjustment of ventilation or intravenous administration of sodium bicarbonate (8.5%). A temperature probe was passed through the mouth to the stomach. Temperature was continuously monitored throughout each experiment and maintained at 37–38°C by a water-perfused heating pad.

The right common iliac artery and vein were isolated, and snares were placed around these vessels to trap the gadolinium in the leg. The right triceps surae muscles and tibial nerve were isolated. After the right popliteal artery was isolated for the injection of gadolinium, the cat was placed in a Kopf stereotaxic and spinal unit. The calcaneal bone was cut, and its tendon was attached to a force transducer (model FT-10C, Grass) for measurement of the tension developed during tendon stretch and static contraction of the right triceps surae muscles. The knee joint was clamped to a post to secure the right lower limb.

The left renal nerve was exposed using a retroperitoneal approach while the cat was positioned in the Kopf stereotaxic frame and spinal unit. The nerve was suspended in a pool of warm (37°C) mineral oil and then cut; its central end was draped over a monopolar hook electrode attached in series with a high-impedance probe (model HIP 511, Grass) and then amplified (model P511, Grass). RSNA was displayed on a storage oscilloscope (Hewlett-Packard) and made audible. The amplifier was filtered between 100 Hz and 3 kHz.

{alpha}-Chloralose-anesthetized and decerebrate cats. During ventilation of the lungs with the mixture of 3–5% halothane and oxygen, the cats were given an initial dose of {alpha}-chloralose (80 mg/kg iv) and urethane (200 mg/kg iv). After 15 min, the halothane was discontinued. The presence of limb withdrawal to a noxious pinch was checked frequently as a measure of the depth of anesthesia. When the reflex was present, a supplemental dose was given [{alpha}-chloralose (15 mg/kg iv) and urethane (75 mg/kg iv)], and the cats were ventilated mechanically for the remainder of the experiment. In the decerebrate preparation, dexamethasone (0.4 mg) was administered intravenously to minimize brain edema and the left carotid artery was tied off to decrease bleeding in the brain. A midcollicular section was performed under halothane anesthesia. All neural tissues rostral to the section were removed, and the cranial vault was filled with agar. The lungs were then ventilated with room air.

Gadolinium injection. Gadolinium (Aldrich) was dissolved in buffered 10 mM HEPES (pH 7.3–7.45; Aldrich), as described previously (6, 7). After complete occlusion of the right iliac artery and vein by ligatures, 1 ml of 10 mM gadolinium trichloride was injected with a 30-gauge needle into the right popliteal artery. The gadolinium was trapped in the circulation of the lower right leg for 15 min and then released to circulate systematically.

Experimental protocol. The effect of gadolinium on the reflex pressor, cardioaccelerator, and renal sympathetic responses to two stimuli were assessed: 1) static contraction of the right triceps surae muscles and 2) stretch of the right calcaneal (Achilles) tendon, which in turn stretched the triceps surae muscles. Static contraction is a combined mechanical and metabolic stimulus, whereas tendon stretch is a pure mechanical stimulus. Both stimuli were applied for 60 s. Contraction of the triceps surae muscles was accomplished by electrical stimulation of the right tibial nerve (40 Hz, 25 µs, 1.5–2 times motor threshold), and a rack-and-pinion apparatus was turned to stretch the calcaneal tendon. Baseline tension was set at 0.3–0.5 kg. Attempts were made to match the tension-time index and peak developed tension. Arterial blood pressure, heart rate, and RSNA were recorded for 60 s before, during, and after static contraction or tendon stretch. These protocols were repeated 60 and 120 min after injection of gadolinium into the popliteal artery. We used these intervals because, in our previous study (7), the peak attenuating effect of gadolinium occurred 60 min after injection; similarly, recovery from the effect of gadolinium occurred after 120 min (7). Near the end of the experiment, each cat was given sodium nitroprusside in a dose (200–400 µg iv) that decreased mean arterial pressure by ≥50 mmHg. This decrease in arterial pressure was used to evoke a baroreflex-induced increase in RSNA that was near maximal. Renal postganglionic sympathetic activity was confirmed by intravenous injection of hexamethonium (20 mg/kg) at the end of data collection in each cat.

Data analysis. Mean arterial blood pressure, heart rate, and RSNA values are expressed as means ± SE. Baseline mean arterial blood pressure and heart rate were measured immediately before a maneuver, and peak mean arterial blood pressure and heart rate were measured during 60 s of tendon stretch and static muscle contraction. RSNA was rectified (Gould) and integrated, and 60-s values were used to compare the differences between baseline and the response to each maneuver. The criterion voltage level for integration was set at the start of each experiment and was not changed. Statistical comparisons were performed with two-way repeated-measures ANOVA. If significant main effects were found, Tukey's post hoc tests were performed to determine significant differences between individual means. The criterion for statistical significance was P < 0.05.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
The effect of gadolinium injected into the popliteal artery on the renal sympathetic, pressor, and cardioaccelerator responses to static contraction and tendon stretch was assessed in 15 decerebrate and 12 chloralose-anesthetized cats. The postganglionic sympathetic nature of the neural discharge was confirmed by its abolition by hexamethonium bromide (20 mg/kg iv).

Decerebrate cats. Gadolinium significantly attenuated the renal sympathetic nerve and pressor responses to static contraction (n = 15) and tendon stretch (n = 15) after a latent period of 60 min (Figs. 1–3). These responses to both maneuvers recovered after a latent period of 120 min (Figs. 1 and 2). Heart rate did not increase significantly in response to static contraction or tendon stretch (Fig. 2). The tension-time indices before gadolinium injection for static contraction or tendon stretch were not significantly different from those 60 or 120 min after injection (Table 1). The time courses of the renal sympathetic nerve responses to static contraction and tendon stretch paralleled the time courses of their respective tension traces (Fig. 3).


Figure 1
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  		Fig. 1. Renal sympathetic nerve responses to static contraction (A; n = 15) and stretch (B; n = 15) of triceps surae muscles in decerebrate cats before and 60 and 120 min after injection of gadolinium into the popliteal artery. Solid bars, baseline mean activity before contraction or stretch; open bars, mean activity during 60 s of contraction or stretch. Vertical error bars, SE. *Significantly different (P < 0.05) from mean activity during 60 s of contraction or stretch. Horizontal brackets connect significantly different (P < 0.05) increases in renal sympathetic nerve activity [RNA, expressed in arbitrary units (AU)] before or after gadolinium injection.

 

Figure 3
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  		Fig. 3. Time courses of renal sympathetic nerve responses to static contraction (A, n = 15) and tendon stretch (B, n = 15) in decerebrate cats. {circ}, baseline renal nerve activity before static contraction or tendon stretch (at time 0) and changes from baseline in RNA 60 min after gadolinium injection; bullet, changes from baseline in RNA before gadolinium injection into the popliteal artery. First symbol following baseline RNA represents change from baseline in RNA 2 s after onset of contraction or stretch; subsequent symbol represents change from baseline in RNA 5 s after onset of contraction or stretch, and each symbol thereafter represents change from baseline in RNA in 5-s increments. Contraction and stretch lasted for 60 s. C and D: time courses of mean increases in developed tension during 60 s of static contraction or tendon stretch before gadolinium injection into the popliteal artery. Error bars, SE.

 

Figure 2
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  		Fig. 2. Effects of gadolinium on pressor and cardioaccelerator responses to static contraction (n = 15) and stretch (n = 15) of the triceps surae muscles in decerebrate cats before and 60 and 120 min after gadolinium injection into the popliteal artery. Vertical axes represent peak increases in mean arterial pressure ({Delta}MAP) and heart rate ({Delta}HR); values inside open bars are baseline values. *Significant difference (P < 0.05) between peak and baseline. Horizontal brackets connect significantly different (P < 0.05) increases in mean arterial pressure before or after gadolinium injection.

 

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  		Table 1. Tension-time indexes for static contraction and tendon stretch in decerebrate and {alpha}-chloralose-anesthetized cats

 
In 4 of the 15 decerebrate cats, static contraction initially inhibited RSNA, an effect that lasted ≤2 s. At 60 min after gadolinium injection, static contraction still caused this inhibition in three of the decerebrate cats and prevented it in the remaining one cat. During the first 2 s of static contraction, average renal sympathetic discharge in these four cats decreased to 51 ± 7% of baseline before and to 55 ± 13% of baseline after gadolinium injection (n = 4, P = 0.83). Tendon stretch caused an initial inhibition in 8 of the 15 cats (Fig. 4). Similar to static contraction, tendon stretch inhibited RSNA for ≤2 s. At 60 min after gadolinium injection, tendon stretch still caused the inhibition in five of the eight cats. During the first 2 s of tendon stretch, average renal sympathetic discharge in these eight cats decreased to 60 ± 8% of baseline before and to 70 ± 15% of baseline after gadolinium injection (n = 8, P = 0.31).


Figure 4
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  		Fig. 4. Brief initial inhibitory renal nerve response to static contraction. Int RNA, integrated renal nerve activity; BP, arterial blood pressure.

 
As a control in two cats, we injected 1 ml of HEPES-buffered saline, the vehicle for gadolinium, into the popliteal artery and trapped it in the leg for 15 min. HEPES-buffered saline had no effect on the RSNA responses to static contraction or tendon stretch (data not shown). Finally, intravenous injection of sodium nitroprusside, which decreased arterial pressure, increased RSNA to a much higher level than that evoked by static contraction or tendon stretch (Fig. 5).


Figure 5
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  		Fig. 5. Effect of intravenous injection of 200–400 µg of sodium nitroprusside (NP) on renal sympathetic nerve activity. Level of renal nerve activity evoked by sodium nitroprusside-induced decrease in arterial pressure was greater than the increase in renal nerve activity evoked by static contraction 120 min after gadolinium injection in decerebrate and chloralose-anesthetized cats (see Figs. 1 and 6). *Significant difference (P < 0.05) between control and NP conditions.

 
Chloralose-anesthetized cats. Gadolinium significantly attenuated the renal sympathetic nerve and pressor responses to static contraction (n = 12) and tendon stretch (n = 11) after a latent period of 60 min (Figs. 6–8). The renal sympathetic responses to static contraction and tendon stretch recovered after a latent period of 120 min, whereas the pressor responses to these maneuvers did not (Figs. 6 and 7). Neither static contraction nor tendon stretch significantly increased heart rate before gadolinium injection (Fig. 7). The tension-time indexes before gadolinium injection for static contraction or tendon stretch were not significantly different from those at 60 or 120 min after injection (Table 1). The time course of the renal sympathetic nerve response to static contraction paralleled the time course of the tension trace (Fig. 8). In contrast, the time course of the renal sympathetic nerve response to tendon stretch showed substantial attenuation, even though the time course of the tension trace showed minimal attenuation (Fig. 8). Intravenous injection of sodium nitroprusside into these chloralose-anesthetized cats increased RSNA to a higher level than that evoked by static contraction or tendon stretch (Fig. 5).


Figure 6
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  		Fig. 6. Renal sympathetic nerve responses to static contraction (A; n = 12) and stretch (B; n = 11) of the triceps surae muscles in chloralose-anesthetized cats before and 60 and 120 min after injection of gadolinium into the popliteal artery. Solid bars, baseline mean activity before contraction or stretch; open bars, mean activity during 60 s of contraction or stretch. Vertical error bars, SE. *Significantly different (P < 0.05) from mean activity during contraction or stretch. Horizontal brackets connect significantly different (P < 0.05) increases in renal sympathetic nerve activity before or after gadolinium injection.

 

Figure 8
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  		Fig. 8. Time courses of renal sympathetic nerve responses to static contraction (A; n = 12) and tendon stretch (B; n = 11) in chloralose-anesthetized cats. See Fig. 3 legend for explanation of symbols. C and D: time courses of mean increases in developed tension during 60 s of static contraction or tendon stretch before gadolinium injection into the popliteal artery. Error bars, SE.

 

Figure 7
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  		Fig. 7. Pressor and cardioaccelerator responses to static contraction (n = 12) and stretch (n = 11) of the triceps surae muscles in chloralose-anesthetized cats before and 60 and 120 min after gadolinium injection into the popliteal artery. Vertical axes represent increases in mean arterial pressure ({Delta}MAP) and heart rate ({Delta}HR); values inside open bars represent baseline values (means ± SE). For other symbols see legend of Figure 2.

 
Static contraction did not evoke an initial inhibition of renal sympathetic nerve discharge in any of the 11 chloralose-anesthetized cats. In contrast, tendon stretch caused an initial inhibition lasting ≤2 s in 4 of the 12 cats. In two of the four cats the initial inhibitory response to tendon stretch remained 60 min after gadolinium injection, and in the other two cats the inhibitory response was abolished. During the first 2 s of tendon stretch, average renal sympathetic discharge in these four cats decreased to 83 ± 8% of baseline before and increased to 108 ± 19% of baseline after gadolinium injection (n = 4, P = 0.21).


   DISCUSSION
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The major new finding in this study is that the increases in RSNA evoked by static contraction in decerebrate cats are greatly attenuated by blockade of mechanogated channels in the triceps surae muscles. We presume that these mechanogated channels are located, for the most part, on the endings of thin-fiber afferents innervating the triceps surae muscles. Our findings are consistent with a previous study from this laboratory that found that gadolinium attenuated the reflex pressor response to static contraction in decerebrate cats (7). In addition, our findings support the hypothesis that the mechanical stimuli evoking the exercise pressor reflex play an important role in inducing renal vasoconstriction through activation of sympathetic renal efferents in cats.

Previously, tendon stretch was used extensively to stimulate thin-fiber mechanoreceptors in skeletal muscle (12, 14, 29, 35). The assumption underlying the use of tendon stretch was that it stimulated the same afferents that were stimulated by the mechanical component of the exercise pressor reflex. Recently, this assumption was negated by the finding that many of the thin-fiber (i.e., group III) mechanoreceptors stimulated by tendon stretch were not stimulated by static contraction (8). Similarly, many of the group III mechanoreceptors stimulated by static contraction were not stimulated by tendon stretch (8). These findings led to the conclusion that tendon stretch is not an optimal technique to examine the role of mechanical stimuli in evoking the exercise pressor reflex.

Gadolinium, however, has shown promise as a tool to block the mechanical component of the exercise pressor reflex. This trivalent lanthanide has been shown to block mechanogated channels in a variety of tissues, including the chick heart and Xenopus oocytes (26, 36). Gadolinium injected into the arterial supply of the triceps surae muscles blocked the responses of group III mechanoreceptors to static contraction (7), whereas it had no effect on the responses of group IV metaboreceptors to capsaicin, a chemical stimulant of TRPV 1 channels, or to static contraction (7). This evidence suggests that blockade of mechanogated channels with gadolinium is the technique of choice to study the mechanical component of the stimuli evoking the exercise pressor reflex.

The exercise pressor reflex in humans has been conceived as the cardiovascular response to an imbalance between blood/oxygen supply and demand in contracting muscles. This imbalance was thought to generate metabolites in the muscles, which, in turn, stimulated thin-fiber muscle metaboreceptors, thereby evoking the reflex. The onset of the metabolic component of the exercise pressor reflex was slow, often having a latency of 60 s in response to static contraction (27, 30, 33). Only within the past decade has the mechanical component of the exercise pressor reflex been investigated in humans. Recently, this investigation has been extended to include the control of the renal circulation. Specifically, signal-averaging techniques demonstrated that muscle sympathetic nerve activity, which is primarily under the control of the exercise pressor reflex (10, 31), increased within 4–6 s of the onset of static contraction of the quadriceps muscles in humans (9). This increase in sympathetic activity was attributed to the contraction-induced stimulation of thin-fiber mechanoreceptors. In addition, involuntary contraction of the biceps brachii muscles in healthy humans, as well as in those with heart failure, increased renal vascular resistance, a reflex effect that was also attributed to stimulation of thin-fiber mechanoreceptors (19, 21). Finally, the renal vasoconstrictor response to involuntary biceps contraction was not influenced by decreasing baroreceptor discharge in the heart or great vessels (22). This surprising lack of influence of disengagement of the baroreflex was attributed to neural occlusion (22).

Over the course of our experiments, baseline arterial pressure decreased in the decerebrate and the chloralose-anesthetized cats but decreased more in the former than in the latter. This greater decrease in baseline arterial pressure, which unloaded the baroreceptors, as well as the lack of anesthesia, might be reasons for the greater increase over time in baseline RSNA in the decerebrate than in the anesthetized cats. Whatever the reason, this increase in baseline renal nerve activity cannot explain the attenuation of the renal nerve response to static contraction in our experiments 60 min after injection of gadolinium, because the response was restored 120 min after injection, even though baseline renal nerve activity was higher than at 60 min after injection. In addition, baroreceptor unloading induced by sodium nitroprusside injections revealed that, in our preparations, RSNA could increase to an extent far greater than that elicited by static contraction 120 min after gadolinium injection. This finding further reinforces the concept that the gadolinium-induced attenuation of RSNA was not caused by a "ceiling effect."

The small and nonsignficant cardioaccelerator responses to static contraction and tendon stretch are an aspect of our findings that require comment. These small effects were most likely caused by the relatively small tensions developed when we statically contracted the triceps surae muscles or stretched the calcaneal tendon. Specifically, the tensions developed by these maneuvers were probably less than half-maximal. We purposely evoked relatively small increases in tension, because we were attempting to minimize nociceptive stimuli, which occur during muscle tetanization or tendon stretch to more than "physiological levels."

The initial transient, although infrequent, decreases in renal nerve activity evoked by tendon stretch and static contraction appeared identical to those reported previously (16); nevertheless, they also require comment. We speculate that these transient inhibitory effects were a spinal reflex that was eventually overwhelmed by supraspinal pathways, causing sympathoexcitation (1). Although there is no evidence for this speculation, it is patterned after a previous report (4) that a transient ventilatory inhibition was evoked by stimulation of muscle afferents in spinal cats. In addition, the transient inhibition was probably caused by group III muscle afferents conducting impulses at >15 m/s (3). Finally, gadolinium did not seem to be a particularly effective blocker of the transient inhibitory responses to contraction and stretch. We can only speculate as to why this is the case, but it might be due to another mechanogated channel that is not susceptible to blockade by gadolinium.

In conclusion, we have shown that there is a substantial mechanical component to the stimuli evoking the reflex renal sympathoexcitation during static contraction in decerebrate and chloralose-anesthetized cats. Our findings confirm and extend those previously reported in anesthetized cats (16, 32) and in humans (18, 19, 21, 22). In addition, our findings raise the possibility that mechanical stimuli arising in contracting muscles play a role in causing some of the renal vasoconstriction during exercise.


   GRANTS
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant RO1-AR-051503.


   ACKNOWLEDGMENTS
 
We thank Yao Dong for technical assistance.


   FOOTNOTES
 

Address for reprint requests and other correspondence: M. P. Kaufman, Division of Cardiovascular Medicine, TB-172, Univ. of California, Davis, Davis, CA 95616 (e-mail: mpkaufman{at}ucdavis.edu)

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.


   REFERENCES
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