Published online before print January 9, 2006, doi: 10.1161/01.HYP.0000199984.78039.36
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(Hypertension. 2006;47:527.)
© 2006 American Heart Association, Inc.
Part 2 Original Articles |
Sensory Neurons With Afferents From Hind Limbs
Enhanced Sensitivity in Secondary Hypertension
From the Department of Internal Medicine 4/Nephrology and Hypertension (P.L., W.F., T.D., K.F.H., R.V.), Department of Pathology (K.A.), University of Erlangen-Nürnberg, Erlangen, Germany.
Correspondence to Roland Veelken, Department of Medicine 4, University of Erlangen-Nürnberg, Loschgestraße 8, 91054 Erlangen, Germany. E-mail mfm431{at}rzmail.uni-erlangen.de
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Abstract |
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Sensory nerve fibers from the dorsal root ganglia (DRG) may contribute to the regulation of peripheral vascular resistance. Axons of DRG neurons of the lower thoracic cord project mainly to resistance vessels in the lower limbs, likely opposing the vasoconstrictor effects of the sympathetic activity. This mechanism might be of importance in hypertension with increased sympathetic activity. We tested the hypothesis that sensory neurons of the DRG in the lower thoracic cord show an altered sensitivity to mechanical stimuli in hypertension. Neurons from DRG (T11 to L1) of rats with hypertension (2 kidney-1 clip hypertensive rats and 5 of 6 nephrectomized rats) were cultured on coverslips. Current time relationships were established with whole-cell patch recordings. Cells were characterized under control conditions and after exposure to hypoosmotic solutions to induce mechanical stress. Neurons with projections to the kidney were studied for comparison. The hypoosmotic extracellular medium induced a significant change in conductance of the cells in all of the groups of rats. In hypertensive rats, responses of cells with hindlimb axons were significantly different from controls: (2 kidney-1 clip hypertensives:
–351±52 pA and 5 of 6 nephrectomized rats: –372±43 pA versus controls: –190±25 pA; P<0.05). Responses of DRG cells with renal afferents to mechanical stress were unaffected. Neurons from DRG in the lower thoracic cord with projections to the lower limbs exhibited an increased sensitivity to mechanical stress. We speculate that this observation may indicate an increased activity of these neurons, their axons, and neurotransmitters in the control of resistance vessels in hypertension.
Key Words: hindlimb • hypertension, renal • mechanosensitivity • hypertension, secondary • kidney • nephrectomy • rats
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Introduction |
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The autonomic innervation of the cardiovascular system is seen as an important controller of the cardiovascular system.1–3 This is not only true for the efferent sympathetic nerve activity but also for afferent neural pathways.4 Malfunction of these systems is likely to be involved in the development and maintenance of hypertension. Of major importance in this respect are baroreceptor afferents from the carotic arteries and the aortic arch, which exert a strong influence on sympathetic outflow in health and hypertension.5 A comparable lesser role might be attributed to cardiac baroreceptor afferents exerting a considerable control on renal nerve activity6 and renal afferents from baroreceptors in the kidney and its pelvis.7
Interestingly, almost nothings is known about neural afferents from resistance vessels, for example, in the extremities or the skin, although these arteries are exposed to strong mechanical stress because of pulsatile blood pressure that increases in hypertension.8 It seems unlikely that afferent innervation is lacking in the extremities or, if present, without influence on cardiovascular autonomic nerve function under the mentioned physiological conditions.
It is known from other investigations that afferent nerve fibers from skin9 and other organs can be electrophysiologically characterized as C-fibers10 that, in addition, were often observed to be peptidergic secreting substances like substance P (SP) and calcitonin gene-related peptide (CGRP).11,12 Again, little is known about perivascular innervation of vessels relevant in hypertension. Some investigations were published on the perivascular CGRP-containing innervation of the mesenteric artery.13,14 Only scarce reports on hindlimb circulation are available.15 However, those latter investigations would be more relevant to answer the question about the extent to which vascular sensory, peptidergic afferent nerves are of importance in hypertension.
One reason why putative perivascular fibers of resistance vessels were as yet not or seldom investigated is the fact that they are very difficult to study with available neurophysiological methods, which prove to be tedious even with respect to easier accessible sensory axons.16 This problem could be partly overcome with recently developed approaches using neuronal cell cultures in vitro from, for example, the nodose ganglion, where the first neuron of afferent pathways from arterial or cardiac baroreceptors1718 can be found that were investigated with the patch clamp technique, because it is likely that the neuronal cell body responds to mechanical stimuli in a similar manner to the endings of afferent axons.19 The respective neuronal cell bodies could be identified by applying specialized dyes to the very sites on the carotic arteries or the surface of the heart where the nerve endings of the afferent axons could be found to retrogradely stain neurons in the nodose ganglion.18 The described experimental procedure can be easily adapted to other sites of interest to identify the first neurons of other sensory afferent pathways. Furthermore, this approach allows us to elucidate the potential mechanisms responsible for the mechanosensitivity of sensory nerve endings,20 although really specific inhibitors of mechanosensitive ion channels, for example, are still not available, and existing concepts to explain the mechanosensitivity of afferent nerve fibers are far from being undisputed.6 Hence, we wanted to test the hypothesis that the response of neurons from dorsal root ganglia (DRG) with axons to the hindlimb vasculature of rats exhibit an altered sensitivity to mechanical stimulation in models of secondary hypertension, namely in 2 kidney 1 clip rats and 5 of 6 nephrectomized rats as compared with respective normotensive animals.
We investigated neurons from DRG with axons to the kidneys as control samples, because we knew from preliminary experiments that both groups of neurons can be found in the DRG of the vertebrae Th 11 to L2. We used hypoosmolar media to expose cultivated neurons to mechanical stress as described previously.
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Methods |
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For the experiments, male Sprague-Dawley rats (Ivanovas, Kisslegg, Germany) weighing 250 to 300 g were maintained in cages at 24±2°C. They were fed a standard rat diet (no. C-1000, Altromin) containing 0.2% sodium by weight and were allowed free access to tap water. All of the procedures performed on animals were done in accordance with the guidelines of the American Physiological Society and approved by the local government.
Preparation of Hypertensive Models in Rats
All of the procedures performed in animals were done in accordance with guidelines of the American Physiological Society. 2K1C renovascular hypertension was induced in male Sprague-Dawley rats as described previously.21 Control animals were sham operated. The animals were followed by weekly measurements of weight and systolic blood pressure by tail-cuff plethysmography. In contrast to the model used by Mann et al,22 lower perfusion pressure of the poststenotic kidney does not occur immediately after the procedure but develops slowly with the growth of the animal over a period of 
1 week. Animals were only included in the 2K1C groups if systolic blood pressure was >150 mm Hg. Animals that failed to thrive or lost weight were excluded after 2 weeks.
Hypertension after 5/6 nephrectomy was induced by subtotal nephrectomy or sham operation and subsequently fed using a pair-feeding protocol to assure a similar food intake in sham and animals that had undergone surgery. As described before,23 the rats underwent 2-step subtotal nephrectomy (removal of right kidney; 7 days later, weight-controlled surgical removal of cortical tissue of the hypertrophied left kidney corresponding to 66% of the weight of the right kidney).
Measurement of Arterial Blood Pressure
After the development of increased blood pressure (median time of 4 weeks) in clipped or renally ablated rats, animals were equipped with a femoral artery catheter under ketamine/xylazine anesthesia, and intraarterial blood pressure was measured in conscious rats 4 hours after anesthesia via a transducer connected to a polygraph (Hellige).
Labeling of Mechanosensitive Dorsal Root Ganglion Neurons With Hindlimb or Renal Afferents
To identify putative mechanosensitive neurons with renal or hindlimb afferents, we labeled these cells using the dicarbocyanine dye 1,1' dioleyl-3,3,3' tetramethyl-indocarbocyaline methansulfonate (D9–DiI, 50 mg/mL in dimethyl sulfoxide, Molecular Probes) either by subcapsular application of DiI (5 µL of 10 mg/mL) in both kidneys or application underneath the fascia onto the large muscles of both upper hindlimbs 1 week before harvesting of respective neurons from DRG T11 to L2.17,18 Care was taken to prevent back leak or spreading of the substance to surrounding tissue. Initially rats were anesthetized with a 500-µL bolus injection of hexobarbital (20 mg/mL) IP. After the insertion of a venous line, appropriate anesthesia was achieved with an IV maintenance infusion of hexobarbital (80 µg/100 g per minute) through the venous femoral catheter. We allowed 1 week for DiI to be transported back to the neuronal cells in the DRG. The subscapsular renal injection of DiI could be brought about with minor surgery. Only small incisions through skin and muscles were necessary to expose renal poles. Analgetic drugs were not necessary, and the animals recovered readily.
Neuronal Cell Culture
Respective rats were anesthetized with hexobarbital as described above, the animals decapitated, and DRG from T11 to L2 dissected. Primary cultures of neurons from the DRG were obtained by mechanical and enzymatic dissociation by adapting protocols described previously by others.17 The ganglia were incubated with trypsin (1 mg/mL), collagenase (1 mg/mL), and DNase (0.1 mg/mL) in modified L-15 medium for 1 hour at 37°C. Enzymatic activity was terminated by the addition of soybean trypsin inhibitor (2 mg/mL), BSA (1 mg/mL), and CaCl2 (3 mmol/L) in modified L-15 medium, and the ganglia were triturated using sterile siliconized Pasteur pipettes to dissociate individual cells. After centrifugation, the cells were resuspended in a modified L-15 medium with 5% rat serum and 2% chick embryo extract and plated on polylysine-coated glass coverslips. 5-Fluorodeoxy-2-uridine (80 µmol/L) was added to prevent the proliferation of nonneuronal cells. The cells were plated on coverslips for 1 day for electrophysiological experiments in a modified L-15. To demonstrate that labeled cells were neurons, all of the cells used for experimental procedures were tested for fast sodium currents during repolarization, which are characteristic for neuronal cells. Furthermore, a small laser beam (480 nm) powered by a storage battery was mounted to the patch clamp recording setup. This equipment allowed for the detection of DiI-stained DRG cells during the experiments using respective optical filters.
Patch Clamp
Patch recordings18 were obtained from respective neurons using a recording solution containing 104 mmol/L KCL, 16 mmol/L KOH, 1 mmol/L magnesium ATP, and 10 mmol/L HEPES. The resistances of the electrodes ranged from 3 to 6 mol/L
. The seal resistance was between 2 and 10 G, and the series resistance was >100 mol/L. Whole-cell voltage clamp recordings were obtained with the help of a 200 B Axopatch amplifier (Axon Instruments). Data were sampled at 5 kHz and stored on a computer hard disk using a commercially available software package (pClamp, Axon Instruments). Current time relationships were obtained by exposing neurons to hypoosmolar solution for 5 minutes followed by a 10-minute recovery period.
In general, cells were placed in a 1-chamber laminar flow bath and perfused at a rate of 0.5 to 1 mL/min by gravity feed lines connected to fluid reservoirs. Fluid was removed by carefully applied suction to the bath. The composition of the control bath solution was 120 mmol/L NaCl, 2 mmol/L CaCl2, 1 mmol/L MgCl2, 1 mmol/L KCl, 10 mmol/L HEPES, and 40 mmol/L mannitol obtaining a solution of 290 osM. The hypoosmotic solution had the same ionic content without the mannitol. This solution exhibited an osmolality of 255 osM. The osmolality of each solution was controlled for using an osmometer (Micro-Osmometer).
We first exposed the cells to control medium. After we had achieved stable current time relationships in this solution (5 minutes), the extracellular medium was changed, and the cells were exposed to the hypoosmotic medium for 5 minutes to induce mechanical stress. The hypoosmotic medium was then again replaced with the original extracellular control solution. We only included neurons in the analysis if their resting membrane potentials was <–40 mV.
Experimental Protocols
In all groups of rats, blood pressure was not only assessed by tail-cuff plethysmography but also measured directly with an arterial line as mentioned above. Only cells that stained brightly for DiI in the light of the laser beam were used for the experiments after harvest and culturing. Cells with putative neurons from the hindlimbs of hypertensive animals (2K1C or 5/6 nephrectomy) and their respective controls underwent the protocol for osmomechanical stimulation. The experimental protocol was also performed in neurons with putative renal afferents likewise located in DRG of vertebrae T11 to L2 to use the results from a neuron population with afferents of a different anatomic site as comparison. The neurons had to be recorded during the first 2 days after harvesting, because it turned out that putative differences in the response pattern of different groups of neurons to mechanical stress gradually diminished in the days to follow and, eventually, were no longer observable.
Data Analyses
The data were statistically analyzed with ANOVA and Newman–Keuls post hoc test (where appropriate) using a CSS statistical software package (StatSoft Inc). Only a priori fixed comparisons were tested. Statistical significance was defined as P<0.05. Data are given as mean±SEM.24
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Animals and Blood Pressure
Blood pressure in 5/6 nephrectomized animals (n=8) increased up to a mean blood pressure of 138±10 mm Hg, whereas the respective pressure in 2 kidney/1 clip rats (n=10) was significantly higher with 188±10 mm Hg (P<0.05). Pooled Sham controls exhibited a mean arterial pressure of 90±8 mm Hg (n=12).
Labeled Cells In Situ and in Culture
Slices of harvested DRG cells positively stained with DiI were viewed under epifluorescence with modulation contrast optics as yellow cells (Figure 1). A clear difference in the pattern of distribution between neurons with hindlimb or renal afferents could not be served, although the neurons with renal afferents appeared to be found more often closer to the ventral portion of the ganglia. After 1 day in culture, DRG cells could be distinguished in most cases from fibroblast and other cells by their larger soma. A fraction of these cells (between 15% and 25%) was brightly labeled with DiI as seen in the respective cross-sections (Figure 1). The cells clearly labeled were classified as putative DRG cells with hindlimb or renal afferents. These cells were used in our experiments after primary cultures of neurons from the respective DRG were obtained by mechanical and enzymatic dissociation. No differences in size could be detected between labeled and unlabeled cells.
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Neuron Investigation
During mechanical osmotic stress, dorsal root ganglion cells with hindlimb afferents exhibited a significantly higher inward current in 2 kidney/1 clip hypertensive rats than in the respective controls. However, neurons with renal afferents showed a completely different pattern in these rats, because no differences in inward current to osmotic stress could be observed between hypertensive and control animals. Furthermore, the peak inward current of neurons with renal afferents was numerically identical in renal neurons of hypertensive and control animals as compared with dorsal root ganglion cells with hindlimb afferents of 2 kidney/1 clip hypertensive rats (Figure 2). Interestingly, no difference could be observed in the responsiveness of renal neurons that could have pointed to differences because of the fact that in this model 1 kidney is clipped and 1 kidney is exposed to the increased blood pressure. In some rats of the clipped group, we labeled right and left kidneys selectively. Because no differences in the response pattern could be observed, we subsequently returned to the standard protocol injecting DiI subcapsularly into both kidneys at the same time.
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In 5 of 6 nephrectomized rats, a similar pattern to the 2 kidney/1 clip rats was observed. Again, DRG neurons with putative hindlimb afferents were significantly more sensitive to mechanical stress in hypertensive animals than in controls, whereas such a difference could not be observed with respect to cells with renal afferents. As in 2 kidney/1 clip rats, the peak inward current of neurons with renal afferents was again numerically identical in renal neurons of hypertensive and control animals as compared with dorsal root ganglion cells with hindlimb afferents of rats with renal ablation (Figure 3).
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Discussion |
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We demonstrated for the first time that neurons with hindlimb afferents of 2 different rat models with secondary hypertension that putatively innervate resistance vessels revealed an altered sensitivity to mechanical stress in a cell culture model that potentially allows for the mechanistic investigations of mechanosensitivity and its alteration in vascular afferent nerve fibers. The observed differences in neurons from hypertensive and normotensive control rats cannot be completely unspecific, because this response pattern to mechanical stress could not be observed in neurons with afferents from the kidneys. Furthermore, in normotensive animals, we observed differences in the peak inward currents between neurons with afferents from different sites (hindlimb and kidney). Finally, the alterations observed in dorsal root cells with projections from the hindlimb might reflect a general alteration of the sensitive innervation of muscular vasculature, for example, resistance vessels, because the degree of the increase in blood pressure was obviously not directly associated with the increased sensitivity of these cells to mechanical stress. Other than resistance vessels, we cannot completely exclude that some hindlimb afferents and the respective neurons innervated other structures of the hindlimb serving, for example, muscle receptors, nociceptors, or thermoceptors. However, because the observed responses were relatively homogenous, we assume in any case that a quite uniform and specific alteration in the sensory innervation of the hindlimb afferents occurred in the models of secondary hypertension used.
The differences in mechanosensitivity that we observed between neurons in hypertensive and normotensive animals during the first 2 days after harvesting were obviously related to the hypertensive state, because they disappeared during the subsequent days. The importance of these alterations in mechanosensitivity could be only assessed in animals with selective ablation of neurons with hindlimb afferents to observe whether under these circumastances hypertension is less pronounced, hindlimb resistance decreased, or structural changes in resistance vessels or other areas of the hindlimbs ameliorated.
The question of how far the putatively altered nerve traffic from hindlimb afferents will control efferent sympathetic nerve activity to hindlimb vessels can not as yet be answered. It is likely that this afferents will decrease sympathetic nerve activity comparable to central input from arterial,25 cardiac,26 or renal baroreceptors.27 However, sympathoexcitatory afferents have been described as well.28
We did not determine the peptide content of our neurons; however, production of substances like CGRP is likely. Results of experiments in rats suggested that CO2 liberated from exercising skeletal muscle activated capsaicin-sensitive perivascular sensory nerves locally, which resulted in the release of CGRP from their peripheral endings, and then the released peptide caused local vasodilatation.15 In spontaneously hypertensive rats, long-term treatment with angiotensin II–inhibiting drugs significantly increased the density of CGRP-containing nerve fibers in mesenteric arteries, that is, those normally reduced in hypertensive animals as compared with normotensive controls.29 These results suggested that long-term inhibition of the renin-angiotensin system in SHR prevents remodeling of CGRP-ergic nerve fibers and prevents the reduction of CGRP-ergic nerve function in this hypertensive model.30 Nothing is known about the relation of putative afferent nerve traffic and impaired mechanosensitivity to an altered production and release of CGRP by perivascular nerves of the mesenteric artery or resistance vessels.
With respect to neurons with renal afferents, we could not observe any differences between normotensive and hypertensive animals. One could argue that this is a sign for the fact that mechanical forces with respect to the hypertensive kidneys and their afferent nerve fibers are certainly not involved in the development and maintenance of hypertension. The fact that renal afferent deafferentiation could delay the rise in blood pressure in most of hypertensive animals known16 could be disputed with the argument that chemical stimulation of these fibers might be predominantly involved.31 However, one should take into account that increases of renal interstitial pressure have been monitored in pathological situations in rats 32 so that more tonic mechanical forces within the kidney might induce less severe alterations in neuronal structures than the more severe forces of an increased pulsatile blood pressure, eventually even inducing vascular damage8. A better argument against the importance of altered stimulation of renal afferents by mechanical forces in hypertension might be, rather (at least in the 2 kidney/1 clip model), the fact that the responsiveness of renal neurons from respective DRG was obviously not influenced by the origin of the afferent axons from the clipped or the contralateral kidney in our experiments.8 Does this also mean that a release of CGRP is unlikely from renal afferents in these models? We cannot comment on this question from our experiments, but recent results on the renoprotective properties of CGRP in experimental hypertension do not support this assumption.33–35 Rather, one could hypothesize that afferent sensory nerve impulses and efferent release of peptides from endings of these very nerves might be controlled independently from one another.
Perspectives
An additional elucidation of the functional role of afferent nerve fibers from the hindlimb compartment in hypertensive models, for example, in rats, cannot rely on neurophysiological nerve recordings because of the delicate nature of the fiber elements involved. Rather, selective dorsal rhizotomies combined with blood flow assessments and morphological investigations of vascular damage, as well as the role of neuronally secreted peptides, like CGRP, in resistant vessels, might be helpful. Those investigations could answer the question of how far mechanosensitive vascular afferent nerve fibers might be involved in hypertension and related vascular damage.
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Acknowledgments |
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This work was supported by a grant-in-aid from the Deutsche Forschungsgemeinschaft (KFO 106-1 and 106-2).
Received October 4, 2005; first decision October 22, 2005; accepted November 29, 2005.
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