Bennett T, Wilcox RG, Macdonald IA. Post-exercise ... Wilcox RG, Bennett T, Brown AM, Macdonald IA. Is exercise good ... Heesch CM, Carey LA. Acute resetting ...
Sciatic stimulation in hypertensive DaM rats
Research Paper
Clinical Autonomic Research 3, 163--168 (1993)
SUSTAINEDreductions in arterial pressure and sympathetic nerve activity occur after prolonged sciatic nerve stimulation in spontaneously hypertensive and pre-hypertensive Dahl salt-sensitive rats whereas these responses are not observed in renal hypertensive or Dahl resistant rats. These observations suggest that the development of poststimulation hypotension and sympathoinhibition may be related to the genetic predisposition for hypertension rather than to the increased level of arterial pressure. However, it is not known whether the magnitude of the post-stimulation blood pressure and sympathetic nerve responses are influenced by the increased level of arterial pressure in addition to the genetic predisposition to hypertension. In the present study, we sought to determine if sustained sciatic nerve stimulation induces post-stimulation hypotension in hypertensive Dahl sensitive (DS) rats. For this purpose, mean arterial pressure (MAP), heart rate (HR), renal (RSNA) and lumbar (LSNA) sympathetic nerve activity were recorded during and after sciatic nerve stimulation in hypertensive DS rats (n = 17) fed an 8.00 NaCI diet for 7-8 weeks. Sciatic nerve stimulation increased H R (control, 443 + 10 b.p.m.; stimulation, 487 ___8 b.p.m.; p < 0.05) and tended to increase MAP, RSNA and LSNA. Two hours after stimulation, MAP was reduced (control 145 + 5 m m H g ; recovery, 124 + 8 m m H g ; p < 0.01) from control values. In contrast, RSNA and H R remained unchanged whereas LSNA was increased (69 ___20%; 1O< 0.05) from control values 120 min after stimulation. MAP, HR and RSNA were unchanged from control values during and for 2 h after sham stimulation in eight DS rats. These results demonstrate that sustained somatic afferent stimulation induces post-stimulation hypotension but not renal or lumbar sympathoinhibition in hypertensive DS rats.
Sciatic nerve stimulation induces hypotension but not renal or lumbar sympathoinhibition in hypertensive Dahl rats M i c h a e l J. Kenney 1"cA PhD and Donald A. M o r g a n 2 BS
1Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506-5602, USA Department of Biology, Rhodes College, Memphis, TN; 2Department of Internal Medicine, Cardiovascular Center, University of Iowa College of Medicine and Veterans Affairs Medical Center, Iowa City, IA, USA.
CACorresponding Author
Key words: Renal sympathetic nerve activity, Lumbar sympathetic nerve activity, Somatic afferent stimulation, High salt diet
Introduction Arterial blood pressure is reduced compared to control levels after a single bout of exercise in hypertensive, I-6 borderline hypertensive, 7'8 and normotensive, 1'3'4'9 humans, and in spontaneously hypertensive rats. 1°'1~ The results of several studies indicate that the magnitude of the post-exercise reduction in arterial blood pressure is greater in hypertensive compared with normotensive humans. 1'5'6 Since dynamic exercise involves prolonged activation of somatic afferents, electrical stimulation of a sciatic nerve in experimental animals has been used to examine the role of somatic afferents in mediating the reductions in arterial blood pressure observed after exercise. Both hypotension ~>~6 and reductions in post-ganglionic sympathetic nerve discharge 13'14'16 occur after sciatic nerve stimulation in spontaneously hypertensive rats and in pre-hypertensive Dahl sensitive (DS) rats fed low salt diets. In contrast, post-stimulation © Rapid Communications of Oxford Ltd.
reductions in arterial blood pressure do not occur in either renal hypertensive 12 or Dahl resistant (DR) rats 16 and are abbreviated in Wistar-Kyoto normotensive rats. ~4Moreover, DR rats fed low salt diets do not exhibit renal sympathoinhibition after sciatic nerve stimulation. 16 These observations suggest that the development o f post-stimulation hypotension and sympathoinhibition may be related to the genetic predisposition of the rat to develop hypertension rather than to the increased level of arterial pressure. 16 However, it is not known whether the magnitude of the post-stimulation sympathetic nerve and arterial blood pressure responses are influenced by the increased level of arterial blood pressure in addition to the genetic predisposition for hypertension. In the present study, we sought to determine if sustained somatic afferent stimulation induces post-stimulation hypotension and sympathoinhibition in DS rats fed high salt diets. DS rats become hypertensive when fed high salt diets. We recorded Clinical Autonomic Research.vol 3.1993
163
M. J. Kenned and D. A . Morgan changes in renal sympathetic nerve activity (RSNA), lumbar sympathetic nerve activity (LSNA), mean arterial pressure (MAP), and heart rate (HR) during and after either sciatic nerve stimulation or sham stimulation in hypertensive DS rats.
Methods
General procedures : Experiments were performed on 25 female DS rats weighing 230-300 g. The animals were maintained on a light-dark cycle of 12 h each at a controlled ambient temperature of 21 -t- 2°C and received an 8.0% NaC1 diet for 7-8 weeks. Anaesthesia was initially induced with methohexital sodium (Brevital®,40-60 mg/kg i.p.) followed by alpha chloralose (50 mg/kg i.v., initial dose). The animals were paralysed with gallamine triethiodide (10-15 mgjkgi.v., initial dose) and artificially respired. Tidal volume and respiratory rate were adjusted as needed to maintain arterial blood pH between 7.25 and 7.45 throughout the experiment. Rectal temperature was maintained at 37 -t- 1°C by a temperature-controlled surgical table. Standard procedures were used to record femoral arterial pressure and HR. Maintenance doses of alphachloralose (25-35 mg/kg/h) and gallamine triethiodide (10-15 mg/kg/h) were administered intravenously. The sciatic nerve was isolated after making an incision on the lateral side of the left hindlimb. A pair of platinum stimulating electrodes were placed around either the intact or cut central end of the sciatic nerve. Electrode placement was identical during sham stimulation experiments, however, no current was passed through the electrodes. Neural recordings: Activity was recorded from the cut central end of the left renal and lumbar sympathetic nerves. The renal nerve was exposed retroperitoneally near the renal artery after exiting the celiac ganglion, lv'I8 In separate animals, the left lumbar sympathetic nerve was isolated following a midline laparotomy. 19 The nerve electrode preparation was covered with Wacker silicone gel. Potentials were recorded with a platinum bipolar electrode after capacity-coupled pre-amplification with a band pass of 100-1 000 Hz. Using methods previously described, 1>2° the filtered neurogram was connected to a nerve-traffic analyser which quantitates nerve spikes exceeding a threshold voltage. The threshold voltage was set by placement of a low threshold cursor just above the background level of noise after the administration of phenylephrine hydrochloride (3 #g/kg i.v.) which transiently reduces sympathetic nerve activity while not altering the background level of electrical noise. 17'1s'21 164
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Experimentalprotocols: After surgery, the chloraloseanaesthetized rats were allowed to stabilize for 1 h before initiation of the experimental protocol. MAP and HR were recorded in 17 sciatic nervestimulated DS rats. In one group of DS rats (n = 10) we obtained recordings of RSNA, whereas LSNA was recorded in a second group (n = 7). Basal levels of MAP, HR, RSNA or LSNA were obtained during a control period which lasted between 15 and 30 min. The control period was followed by 30 min of low frequency electrical stimulation of the sciatic nerve at 0.8-2.0 mA, 0.3 ms pulse duration and 3 Hz. These stimulation parameters activate predominantly Group III somatic afferents.= Post-stimulation recordings were obtained for 120 min. Control experiments (n --- 8) were completed by recording MAP, HR and RSNA throughout identical time periods, before, during and after sham stimulation of the sciatic nerve. Data analysis: On-line acquisition and data analysis were performed using a software programme and an IBM-PC. Analogue values of MAP, HR, RSNA and LSNA were digitized every second and then averaged every 30 s. ~:'19 The control values of renal and lumbar sympathetic nerve discharge were taken as 100%. Values in the text, tables and figures are means 4-SE. Statistical analysis was performed using a two-factor repeated measures analysis of variance with the factor study group and the repeated factor time. 23 The overall analysis was followed by Bonferroni pairwise post hoc tests to compare the two groups at different time points and to compare different time points within each group. Data points included in this analysis were; control, sciatic and sham stimulation at 15 min, and recovery at 60 and 120 min (p < 0.05 indicated statistical significance).
Results
Effects of sciatic nerve and sham stimulation in D S rats." Fig. 1A shows segments of original recordings of MAP and RSNA during control, sciatic nerve stimulation, and recovery following stimulation in a hypertensive DS rat. Sciatic nerve stimulation increased MAP and RSNA from control levels. At 120min after stimulation, MAP was reduced whereas RSNA remained at control values. Figure 1B shows segments of original recordings of MAP and LSNA from a separate experiment. Note that MAP was reduced whereas LSNA remained increased from control values 120 min after sciatic nerve stimulation. Baseline MAP values were not different in experiments in which renal (146_+6mmHg; n = 1 0 ) and lumbar ( 1 4 5 ± 8 m m H g ; n=7)
Sciatic stimulation in hypertensive Dahl rats
A Control
Sciatic nerve stimulation
sympathetic nerve activities were recorded. The results obtained in 17 sciatic nerve-stimulated DS rats are summarised in Fig. 2 and Table 1. Sciatic nerve stimulation increased HR (p < 0.05) and tended to increase MAP, RSNA and LSNA. Two hours after stimulation, MAP was significantly reduced from control values (p < 0.01).. In contrast, RSNA and HR were unchanged from control values for 2 h after sciatic nerve stimulation whereas LSNA was significantly increased (p < 0.05) from control levels at 60 and 120 min after stimulation. Control MAP values were not different in sciatic nerve-stimulated and sham-stimulated DS rats (Tables 1 and 2). MAP, RSNA and HR remained unchanged from control values during and for 2 h after sham stimulation (n = 8) (Table 2).
Recovery
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Discussion
200f (Hz) 0 FIG. 1. (A) Segments of original records showing mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) in a hypertensive Dahl sensitive rat during control, sciatic nerve stimulation, and 2 h after stimulation. (B) Segments of original records from a separate experiment showing MAP and lumbar sympathetic nerve activity (LSNA) in a hypertensive Dahl salt sensitive rat during the same periods as described in A.
MAP (mmHg)
This study examined the arterial blood pressure and sympathetic nerve responses during and after sustained somatic afferent stimulation in hypertensive DS rats. Our results provide experimental support for two new findings. First, our data indicate that sustained stimulation of sciatic nerve somatic afferents induces poststimulation hypotension in hypertensive DS rats. This hypotensive response is not simply an effect of time since MAP remained unchanged from control RSNA (%)
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Time (min) Time (mln) FIG. 2. Responses (mean + SE) of mean arterial pressure (MAP), heart rate (HR), renal sympathetic nerve activity (RSNA) and lumbar sympathetic nerve activity (LSNA) to sciatic nerve stimulation in hypertensive DS rats. RSNA and LSNA are expressed as percent of control. Time periods shown include (1) control (0-30 rain), (2) sciatic nerve stimulation (30-60 rain; indicated by the shaded area), and (3) recovery from stimulation (60-180 rain). *Significant difference from control at p < 0.05. Clinical Autonomic Research.vol 3 . 1 9 9 3
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M. J. Kenney and D. A . Morgan Table 1. Responses of mean arterial pressure (MAP), heart rate (HR), renal sympathetic nerve activity (RSNA) and lumbar sympathetic nerve activity (LSNA) before, during and after sciatic nerve stimulation in hypertensive Dahl salt sensitive rats
Control Stimulation (15 rain) Stimulation (30 min) Recovery (60 min) Recovery (120 rain)
MAP
HR
RSNA
LSNA
(mmHg)
(b.p.m.)
(%)
(%)
145 ± 5 160 ± 5 156 -+ 7 136 _+ 7 124±8"
443 ± 10 487 ± 8* 490 _+ 6 452 + 10 445+8
100 +38 + 31 +47 _+ 27 + 10 _+ 23 +17±24
100 +28 -+ 21 + 2 4 + 18 + 35 _+ 21 * +69+20*
Values are means -+ SE; n = 17 for MAP and HR; n = 10 for RSNA; n = 7 for LSNA. * p < 0.05 vs. respective control value.
Table 2. Responses of mean arterial pressure (MAP), heart rate (HR) and renal sympathetic nerve activity (RSNA) before, during and after sham stimulation in hypertensive Dahl salt sensitive rats
Control Sham stimulation (15 min) Sham stimulation (30 min) Recovery (60 min) Recovery (120min)
MAP (mmHg)
HR
RSNA
(b.p.m.)
(%)
151 ± 6 150_+5 150+7 154_+10 158±9
424 ___18 423+13 425___12 419+18 409±13
100 +12___10 +5+9 +8_+15 +10±12
Values are means ___SE; n = 8.
during and for 2 h after sham stimulation. The results of the current study provide no information concerning the duration of post-stimulation hypotension in hypertensive DS rats. Shyu et al. 13 observed hypotensive responses which persisted for 3-6 h after sciatic nerve stimulation in chloraloseanaesthetized, spontaneously hypertensive rats. The magnitude of the post-stimulation hypotens±re response in hypertensive DS rats ( - 2 1 mmHg) in this study was similar to that in pre-hypertensive DS rats ( - 2 0 mmHg) reported in our previous studyJ 6 These results suggest that the magnitude of the post-stimulation reduction in arterial blood pressure in Dahl rats is not influenced by the initial level o f arterial pressure. However, the time-course of the hypotensive response differs between hypertensive and pre-hypertensive DS rats. Hypertensive DS rats exhibited a progressive reduction in arterial blood pressure which was significantly different from control 2 h after stimulation. A similar slow onset of hypotension has been observed after sciatic nerve stimulation in spontaneously hypertensive rats. 14 In contrast, the results of our previous study demonstrate that in pre-hypertensive DS rats arterial blood pressure is significantly reduced from control values 45-60 min after cessation of stimulationJ 6 Factors which contribute to this temporal difference between the post-stimulation arterial blood pressure responses in pre-hypertensive and hypertensive DS rats are not known. 166
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Our second finding is that renal and lumbar sympathetic nerve activities were not reduced from control levels after sustained somatic afferent stimulation in hypertensive DS rats. In fact, LSNA was significantly increased from control levels 2 h after cessation of sciatic nerve stimulation. These findings reject our original hypothesis that sustained stimulation of somatic afferents would induce a significant sympathoinhibition in hypertensive DS rats. To our knowledge, the results of the current study are the first to show a dissociation between the hypotensive and sympathoinhibitory responses observed after sciatic nerve stimulation. As stated previously, sympathetic nerve activity is reduced after sciatic nerve stimulation in prehypertensive DS rats ~6 and in spontaneously hypertensive rats. 13'14 In fact, post-stimulation inhibition of sympathetic nerve discharge has been considered to be a contributing factor mediating the reduction in arterial blood pressure after sciatic nerve stimulation. However, the results of the current study suggest that factors besides inhibition of renal and lumbar sympathetic nerve activity are likely to participate in mediating post-stimulation hypotension in hypertensive DS rats. The concept that a high salt diet can influence the responses of efferent sympathetic nerve activity is not new. Mark et al. 24 observed that a high sodium diet increased forearm vascular resistance and arterial pressure in borderline hypertensive humans. Moreover, high sodium intake augmented the forearm vasoconstrictor responses to lower body negative pressure. Takeshita and Mark 2s demonstrated that a high salt diet in DS rats potentiates the vasoconstrictor response to sympathetic nerve stimulation. The results of these studies demonstrate that high salt diets can augment arterial pressure and sympathetic nerve activity. The results of the present study provide evidence suggesting that a high salt diet can attenuate a sympathoinhibitory response induced by sustained somatic afferent stimulation. Along these lines, Victor e t a ] . 20 reported that a high salt diet attenuated the sympathoinhibitory response to
3ciatic stimulation in hypertensive Dab/rats
volume expansion in DS rats. In contrast, the reflex inhibition of sympathetic nerve discharge to volume expansion was augmented in DR rats fed high salt diets. 2° These authors speculated that the sensitization of baroreceptor-induced inhibition of sympathetic nerve discharge in DR rats may provide a protective effect against the development of salt-induced hypertension whereas the attenuation of this sympathoinhibitory response in DS rats might contribute to the development of hypertension. 2° In the present study, despite the lack of post-stimulation sympathoinhibition in hypertensive DS rats, arterial blood pressure was significantly reduced from control values after sciatic nerve stimulation. The fact that sustained sciatic nerve stimulation induces post-stimulation hypotension but not renal or lumbar sympathoinhibition in hypertensive DS rats suggests that inhibition of activity in other sympathetic nerves and/or factors independent of sympathetic vasoconstrictor nerves may play a role in mediating this hypotensive response. Many examples of sympathetic selectivity and differentiation are evident during acute stress and in specific behavioural states. 26-32 Thus, inhibition of sympathetic nerve activity to other target organs could be involved in mediating post-stimulation hypotension. In this regard, Esler and colleagues33-3s have reported that cardiac sympathetic nerve activity in humans can be selectively altered during various experimental interventions and pathological states. Moreover, Floras and colleaguesv reported reductions in systolic arterial blood pressure and muscle sympathetic nerve activity after treadmill exercise in hypertensive humans. Alternatively, circulating hormones and/or local metabolic factors may play a role in producing post-stimulation hypotension. Endothelium-derived relaxing factor is an endogenous vasodilator which is released by the vascular endothelium. 36-39 Moncade et al. 38 have proposed that mechanical factors associated with increased arterial blood flow are one possible mechanism by which these substances are released from the endothelium. It is possible that the increased levels of arterial blood pressure in response to sciatic nerve stimulation may contribute to vasodilation of skeletal muscle during and possibly after exercise. Several other local metabolic and humoral factors may play a role in mediating post-exercise hypotension. For example, acute exercise increases plasma levels of immunoreactive atrial natriuretic peptide 4°,41 which may mediate decreases in arterial pressure. Reduced vascular responsiveness to adrenergic receptor stimulation may also contribute to post-exercise hypotension. 42 Howard and DiCarlo 42 reported that the reduction in iliac blood flow velocity, at the same dose of phenylephrine (an c~-adrenergic receptor agonist)
was attenuated after exercise compared to nonexercise control days suggesting that the ability of the hindlimb vasculature to constrict in response to activation of ~-adrenergic receptors is reduced after acute exercise in conscious rabbits. Whether these humoral and metabolic alterations contribute to post-stimulation hypotension remains to be elucidated. In conclusion, our data indicate that sustained sciatic nerve stimulation induces prolonged poststimulation hypotension in hypertensive DS rats. However, in contrast to pre-hypertensive DS and spontaneously hypertensive rats, sympathetic nerve activity (renal and lumbar) is not reduced after sciatic nerve stimulation in hypertensive DS rats. References 1. Bennett T, Wilcox RG, Macdonald IA. Post-exercise reduction of blood pressure in hypertensive men is not due to acute impairment of baroreflex function. C/in Sci 1984; 67: 97-103. 2. Hagberg JM, Montain SJ, Martin WH. Blood pressure and haemodynamic responses after exercise in older hypertensives. J Appl Physio/1987; 63: 270-276. 3. Kaufman FL, Hughson RL, Schaman JP. Effect of exercise on recovery blood pressure in normotensive and hypertensive subjects. Med Sci Sports Exer. 1987; 19: 17-20. 4. Wilcox RG, Bennett T, Brown AM, Macdonald IA. Is exercise good for high blood pressure? Br Med J 1982; 285: 767-769. 5. Pescatello LS, Fargo AE, Leach CN, Scherzer HH. Short-term effect of dynamic exercise on arterial blood pressure. Circulation 1991 ; 83: 1567-1561. 6, Cleroux J, N'Guessan Kouame, Nadeau A, Coulombe D, Lacourciere Y. After effects of exercise on regional and systemic hemodynamics in hypertension. Hypertension 1992; 19:183-191. 7. Floras JS, Sinkey CA, Aylward PE, Seals DR, Thoren PN, Mark AL. Post-exercise hypotension and sympathoinhibition in borderline hypertensive men. Hypertension 1989; 14: 28-35. 8. Somers VK, Conway J, Lewinter M, Sleight P. The role of baroreflex sensitivity in post-exercise hypotension. J Hypertens 1985; 3: S129-Sl 30. 9. Coats AJS, Conway J, Isea JE, Pannarale G, Sleight P, Somers VK. Systemic and forearm vascular resistance changes after upright bicycle exercise in man. J Physiol (Lond) 1989; 413: 289-298. 10. Overton JM, Joyner MJ, Tipton CM. Reductions in blood pressure after acute exercise by hypertensive rats. J Appl Physiol 1988; 64(2) : 748-752. 11. Shyu B-C, Thoren P. Circulatory events following spontaneous muscle exercise in normotensive and hypertensive rats. Acta Physiol Scand 1986; 128: 515-524. 12. Hoffman P, Thoren P. Long-lasting cardiovascular depression induced by acupuncture-like stimulation of the sciatic nerve in unanaesthetized rats. Effects of arousal and type of hypertension, Acta Physiol Scand 1986; 127:119-126. 13. Shyu B-C, Andersson SA, Thoren P. Circulatory depression following low frequency stimulation of the sciatic nerve in anaesthetized rats. Acta Physiol Scand 1984; 121 : 97-102. 14. Yao T, Andersson S, Thoren P. Long-lasting cardiovascular depression induced by acupuncture-like stimulation of the sciatic nerve in unanaesthetized spontaneously hypertensive rats. Brain Res 1982; 240: 77-85. 15. Yao T, Andersson S, Thoren P. Long-lasting cardiovascular depressor response following sciatic stimulation in spontaneously hypertensive rats. Evidence for the involvement of the central endorphin and serotonin systems, Brain Res 1982; 244: 295-303. 16. Kenney M J, Morgan DA, Mark AL. Sympathetic nerve responses to sustained stimulation of somatic afferents in Dahl rats. J Hypertens 1991 ; 9: 963-968. 17. Kenney M J, Morgan DA, Mark AL. Prolonged renal sympathoinhibition following sustained elevation in arterial pressure. Am J Physiol (Heart Circ Physio127) 1990; 288: H1476-H1481. 18. Dibona GF, Sawin LL. Renal nerve activity in conscious rats during volume expansion and depletion. Am J Physiol (Renal Fluid Electrolyte Physiol 17) 1985; 248: F15-F23. 19. Morgan DA, Balon "I3N, Ginsberg BH, Mark AL. Nonuniform regional sympathetic nerve responses to hyperinsulinaemia in rats. Am J Physiol (Regulatory Integrative Comp Physiol 33) 1993; 264: R423-R427. Clinical Autonomic Research.vol 3 . 1 9 9 3
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Received 1 September 1992; accepted with revision 29 May 1993.
