Published online before print February 2, 2004, doi: 10.1161/01.HYP.0000117140.52220.85
(Hypertension. 2004;43:643.)
© 2004 American Heart Association, Inc.
Scientific Contributions |
Selective Increase in Renal Arcuate Innervation Density and Neurogenic Constriction in Chronic Angiotensin II-Infused Rats
From Department of Physiology, Monash University, Melbourne, Victoria 3800, Australia.
Correspondence to Dr H.C. Parkington, Department of Physiology, Monash University, Victoria, 3800, Australia. E-mail helena.parkington{at}med.monash.edu.au
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Abstract |
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This study investigated the effects of angiotensin II "slow pressor" hypertension on structure and function of nerves supplying the renal vasculature. Low-dose angiotensin II (10 ng/kg per minute, initially sub-pressor) or saline vehicle was infused intravenously for 21 days in rats, and the effects were compared in renal and mesenteric arteries. Mean arterial pressure averaged 12±2 mm Hg higher than in vehicle-infused rats at 21 days. Using electron microscopy, the innervation density of renal arcuate, but not mesenteric arteries of equivalent size, was significantly higher in angiotensin II-infused than in vehicle-infused rats. Functional testing on a pressure myograph revealed that constrictions evoked by nerve stimulation in arcuate arteries were 2.3±0.7-fold greater in vessels from angiotensin II-infused compared with vehicle-infused rats (P<0.0001), whereas there was no significant difference in nerve-induced constrictions in mesenteric arteries. Sensitivity to and maximum amplitude of constrictions evoked by phenylephrine were not different in renal or mesenteric arteries between groups, suggesting that the increased neurally evoked constriction in renal arcuate arteries was not caused by postsynaptic changes. Endothelium-dependent vasorelaxation and the vessel wall physical properties were not different between the two groups in either artery. Thus, angiotensin II infusion appeared to evoke renal-specific increases in vessel innervation and increased vasoconstriction to nerve stimulation. These changes appear early and occur before changes in renal endothelial function are apparent. Thus, "slow pressor" angiotensin II hypertension is associated with increased renal innervation, compatible with a pathogenetic role.
Key Words: sympathetic nervous system • endothelium
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Introduction |
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Infusion of low doses of angiotensin II (Ang II) that do not cause an immediate increases in blood pressure (sub-pressor) may induce the development of a slow and progressive ("slow pressor") hypertension.1 The mechanisms involved in the pathogenesis of this hypertension have not been established unequivocally but are presumed to involve the progressive potentiation or amplification of one or more actions of Ang II. These may involve increased vasoconstriction via mechanisms including enhanced sensitivity to spasmogens,2 increased activity of the sympathetic nervous system,3 or the production of reactive oxygen species4 leading to endothelial vasodilator dysfunction.5 Other possible mechanisms include progressive structural changes (via alterations in the physical properties of the vessel wall eg, stiffness,6 or vessel wall smooth muscle hypertrophy7) and progressive renal Na+ retention (via direct effects on tubular reabsorption or stimulation of aldosterone secretion8).
Here we investigated the effects of Ang II on renal blood vessel innervation. As Hall et al have pointed out, long-term changes in arterial pressure require that the relationship between arterial pressure and renal Na+ excretion be shifted to higher pressure.8,9 There is increasing evidence that Ang II may cause changes in the structure of renal blood vessels and in their innervation.10,11 We found that 6 weeks of inhibition of Ang II production using enalapril in rabbits led to a marked increase in the density of innervation, as well as phenotypic transformation of smooth muscle cells in the wall of 20- to 35-µm diameter afferent arterioles into renin-containing secretory cells.12 Casellas et al13 subsequently found that infusion of doses of Ang II that have immediate pressor effects reduced the density of the plexus innervating renal vessels in rats across a wider range of vessel diameters (30 to 300 µm). The innervation of rabbit12 and rat13,14 kidney is mainly sympathetic. Thus, the aim of this study was to clarify whether chronic low doses of Ang II, documented as barely pressor initially, can affect the sympathetic innervation of arteries within the kidney. We used morphological12 and functional approaches and also studied a similar size artery from a non-renal systemic vascular bed, namely the well-characterized mesenteric artery.6,7,17,24
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Methods |
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Please see online Methods at http://hyper.ahajournals.org.
Animal Preparation
Under anesthesia, the tip of an osmotic minipump (model 2ML4; Alzet) was inserted into the vena cava of male Sprague-Dawley rats. The pump delivered either vehicle (0.9% NaCl containing heparin 10 IU/mL, n=21) or Ang II (10 ng/kg per minute, n=21), a dose that had negligible pressor effects (<3 mm Hg in preliminary experiments) when administered acutely. All experiments were conducted in accordance with the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes.
On day 21 of infusion, arterial pressure was measured in freely moving rats via a tail artery catheter.15 At the end of the recording period, blood was taken via the catheter for determination of plasma renin activity,16 creatinine concentration (Beckman Synchron CX5 Clinical System Analyser), and hematocrit.
Morphological Studies of the Innervation
In anesthetized rats, a bolus vasodilator solution was delivered, and paraformaldehyde (4%) and glutaraldehyde (1%) solution perfused at the conscious arterial pressure.17 Kidneys and mesenteric blood vessels were immersed in fixative overnight at 4°C. Three second-order branches of mesenteric artery and three arcuate arteries were studied. Vessels were post-fixed and embedded in epoxy resin as described.17 Ultrathin (100 nm) longitudinal sections were cut, stained with uranyl acetate, and viewed in a transmission electron microscope (Jeol 100S) at a magnification of x10 000.
Functional Properties
Segments of renal arcuate and third-order mesenteric artery were isolated and all branches tied off. The proximal end of each segment was secured in a pressure myograph (Living Systems) and was continuously superfused with bicarbonate-buffered physiological saline solution (PSS) at 15 mL/min-1 and 35°C. The distal end of the segment was secured to a closed cannula, ensuring no flow through the segment. The pressure in mesenteric segments was set at 55 mm Hg (as recorded in vivo, Parkington, unpublished observations) and arcuate segments were set 10 mm Hg higher for comparison, because the pressure decrease in the renal vessels to the capillary bed (glomeruli) is less than for other systemic beds. The myograph was transferred to the stage of an inverted microscope fitted with a video camera. Vessel diameter was monitored using Diamtrak.18,19
Drugs were added externally via the superfusing PSS. Perivascular nerves in the segment were stimulated, via 2 platinum electrodes, at frequencies of 0.5 to 10 Hz at 0.1 ms duration using a Grass S88 stimulator. That the constrictions recorded reflected nerve stimulation was confirmed in all tissues using tetrodotoxin (100 nmol/L).20
Cumulative concentration–response curves to phenylephrine and acetylcholine were obtained to assess 
-adrenoceptor and endothelial function, respectively. Endothelium-independent smooth muscle relaxation was tested using sodium nitroprusside, 10 µmol/L, in the presence of phenylephrine. Passive lumen diameter and wall thickness were measured in PSS containing 0 mmol/L Ca2+ and EGTA (5 mmol/L). All drugs were purchased from Sigma Chemical.
Data Analysis
Anatomical Properties
Varicosities, intervaricosities, and neuromuscular junctions have been defined previously.17 All densities were expressed as number per mm2 of vessel surface.17 Data were analyzed for significant differences between n animals using unpaired Student t tests.
Functional Properties
Sigmoid curves were fitted to phenylephrine and acetylcholine responses, and the concentration required to evoke a half maximal response, EC50, was calculated. Instat software (GraphPad) tested for statistical significance of treatments using two-way ANOVA followed by Student t test. Mean±SE for n animals are given, and P
0.05 was deemed statistically significant.
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Results |
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After 21 days of infusion, mean arterial pressure in rats infused with Ang II was 12±2 mm Hg (n=9) higher than in vehicle-infused animals (Table). Creatinine concentration was significantly higher and plasma renin activity markedly reduced in Ang II-infused rats compared with vehicle controls (Table). There was no significant effect of treatment on heart rate (329±7 versus 342±10 bpm), left ventricle-to-body weight ratio (2.3±0.1x10-3 versus 2.4±0.4x10-3), hematocrit (0.40±0.01 versus 0.41±0.01), kidney wet weight (2.2±0.1 versus 2.1±0.1 g), or body weight (361±8 versus 353±11 g).
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Structure of Nerves in Renal Arcuate Arteries
Axon bundles were located predominantly adjacent to the medio-adventitial border of renal arcuate arteries from all animals (Figure 1). The density of axon bundles was significantly greater in rats that received Ang II than in vehicle-infused animals (P=0.006) (Figure 2). The average number of axons per bundle was similar in the two groups (3.6±0.3 versus 3.2±0.1 axons per bundle, n=5 in the Ang II-infused and vehicle-infused groups; P=0.2). Within the axon bundles of vessels from Ang II-infused rats, 57%±2% (n=5) of profiles were varicosities, whereas the remaining 43%±2% (n=5) were intervaricosities. In arteries from vehicle controls, 59%±2% of profiles were varicosities and 41%±2% were intervaricosities (n=5 each). There were numerous clear synaptic vesicles within all varicosities. Microtubules were present in most intervaricosities whereas mitochondria were rarely identified (Figure 1).
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There was a greater density of intervaricosities in the adventitia of renal arcuate arteries from Ang II-infused compared with vehicle-infused rats (P=0.022) (Figure 2). There was also a higher density of varicosities in the adventitia of arteries of Ang II-infused rats (P=0.01) (Figure 2). Varicosities were identified as forming neuromuscular junctions (contacting) or as noncontacting (Methods17). There was no difference in the density of neuromuscular junctions in renal arcuate arteries of Ang II-infused versus vehicle-infused rats (P=0.4) (Figure 2) and no difference in the percentage of varicosities that formed a neuromuscular junction with a smooth muscle cell in the two groups (3.2%±0.3% and 3.3±0.3%, respectively).
Structure of Nerves in Mesenteric Arteries
The density of axon bundles in mesenteric arteries did not differ between Ang II-infused and vehicle-infused groups (P=0.8) (Figure 2). The average number of axons per bundle was also not different (10.7±0.4 versus 10.9±0.6 axons per bundle, P=0.8) and neither the density of intervaricosities (P=0.6) in vessels from the two groups nor the density of varicosities (P=0.8) differed between the two groups (Figure 2). Neuromuscular junctions occurred in 0.6%±0.3% of varicosities of mesenteric vessels of Ang II-infused rats and in 1.0%±0.3% of varicosities in vessels from vehicle-infused rats (P=0.4) (Figure 2).
Functional Properties of Isolated Renal Arcuate and Mesenteric Vessels
Measured at 65 mm Hg, the outside diameters of segments of renal arcuate artery averaged 250±17 µm (n=9) and 278±18 µm (n=9) from Ang II-infused and vehicle-infused animals (P=0.3). In segments of mesenteric artery at 55 mm Hg, the outside diameters averaged 225±9 µm (n=9) and 232±7 µm (n=9), respectively (P=0.5).
Nerve Stimulation
Transmural stimulation of the nerves evoked brief constrictions whose amplitudes increased as the frequency or duration of stimulation was increased. In arcuate arteries obtained from Ang II-infused rats, responses were larger than those from the vehicle-infused group (P<0.0001) (Figure 3). For mesenteric arteries, these was no difference in the responses to nerve stimulation in the Ang II-infused versus vehicle-infused group (P=0.3).
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Responses to nerve stimulation were reduced by 
two-thirds in the presence of the -adrenoceptor antagonist phentolamine (0.2 µmol/L) in both arteries (data not shown).
Sensitivity of the Smooth Muscle to Phenylephrine
The -adrenoceptor agonist phenylephrine evoked concentration-dependent constriction of renal arcuate and mesenteric segments (Figure 4A). Sensitivity to and maximum constriction evoked by phenylephrine were similar in arcuate artery segments from Ang II-infused (to 126±9 µm, EC50 0.33±0.05 µmol/L, n=8) and vehicle-infused rats (to 130±11 µm, EC50 0.27±0.02 µmol/L, n=9). The maximum constriction and sensitivity to phenylephrine were also not different in mesenteric segments from Ang II-treated (constriction to 145±13 µm, EC50 0.96±0.10 µmol/L, n=8) versus vehicle-infused rats (constriction to 131±12 µm, EC50 0.79±0.09 µmol/L, n=8) (Figure 4A).
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Constrictions evoked by PSS containing 100 mmol/L KCl for 1 minute were similar in arcuate segments from Ang II-infused (constriction to 169±15 µm, n=9) and vehicle-infused rats (to 186±17 µm, n=9). Likewise, in mesenteric arteries, the KCl-induced constrictions were to 134±8 µm (n=9) and to 143±10 µm (n=9), respectively.
Endothelium-Dependent Relaxation
Segments of renal arcuate and mesenteric arteries were constricted to 70% of control diameter with phenylephrine. Stimulation of the endothelium with acetylcholine evoked relaxation to 0.86±0.06 of maximum, with an EC50 of 0.87±0.28 µmol/L (n=6) in renal arcuate arteries of Ang II-infused rats. This was not different from responses in segments of vehicle-infused animals (maximum relaxation to 0.87±0.09, EC50, 0.80±0.52 µmol/L, n=7) (Figure 4B).
Acetylcholine elicited almost complete relaxation in mesenteric segments from Ang II-infused and vehicle-infused rats (maximum: 0.96±0.04, n=8 and 0.98±0.02, n=8) (Figure 4B), and sensitivity to acetylcholine was not different with Ang II versus vehicle infusion (EC50 0.26±0.07 µmol/L, n=8 and 0.21±0.04 µmol/L, n=8).
Endothelium-independent smooth muscle relaxation evoked by sodium nitroprusside was not different in arcuate arteries obtained from Ang II-infused (0.78±0.04, n=7) compared with vehicle-infused rats (0.75±0.05, n=7). Similarly, for mesenteric arteries, nitroprusside-induced relaxation was not different in Ang II-treated (0.93±0.02, n=8) versus vehicle-treated animals (0.93±0.02, n=8).
Passive Wall Properties
In Ca2+-free, EGTA-containing PSS, there was no difference in passive wall properties in either renal arcuate or mesenteric arteries obtained from Ang II-infused versus vehicle-infused rats. Parameters tested included external diameter (Figure 4D), media (wall) cross-sectional area (arcuate artery Ang II 17 395±1457 µm2 versus control 17 676±1664 µm2, n=6; mesenteric artery Ang II 10 751±1855 µm2 versus control 10 385±1514 µm2, n=6), and media/lumen ratio (Figure 4C).
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Discussion |
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This study has demonstrated that chronic low-dose intravenous Ang II infusion results in a significant increase in the density of the nerve network supplying the renal arcuate artery. This low dose of Ang II induced a barely detectable effect on arterial pressure in acute experiments but produced a modest elevation of arterial pressure of approximately 12 mm Hg by 21 days of infusion, at which time there was no evidence of endothelium-dependent vasodilator dysfunction. The changes in innervation structure were associated with an increase in the functional response to nerve stimulation, with a 2.5-fold greater constriction of arcuate arteries of Ang II-infused rats compared with vehicle controls. In contrast, this increase in nerve-evoked constriction was not observed in the mesenteric arteries. Thus, in mesenteric arteries from the same animals, chronic Ang II infusion was without significant effect on either the innervation density or the amplitude of nerve-induced constriction.
Chronic Ang II treatment induced a significant 150% greater density in axon bundles in the renal arcuate artery without a change in the number of axons per bundle and an increase in the density of varicosities and intervaricosities. This suggests that there may have been an increase in the number of varicosities along individual axons as well as an increase in the length and/or branching of axons. Whereas overall varicosity density was greater in arcuate arteries exposed to Ang II, there was no observed difference in the density of neuromuscular junctions, ie, varicosities that make specific close contacts.17 This suggests that most of the new varicosities that appeared during Ang II treatment did not form specific neuromuscular junctions. We hypothesized that the functional consequence might be an increased effector response to neurotransmitter release via diffusion after release from the varicosity, and we tested for this. The renal vasculature in the rat is innervated by sympathetic nerves.13,14,21,22 The marked augmentation of the response of the renal arcuate artery to nerve stimulation is unlikely to reflect an action of Ang II on the density of -adrenoceptors on the smooth muscle cells, or on postreceptor mechanisms accessed by stimulation of these receptors because neither the maximum response nor the sensitivity to applied phenylephrine were different between the Ang II-infused and vehicle-infused groups, similar to previous observations.11 Therefore, we propose that the most likely explanation for the augmented response to nerve stimulation is the increase in the density of nerves evident in the renal vessels of rats infused with Ang II for 21 days. This confirms previous observations in which the slow pressor response to Ang II was reduced after denervation of the kidney.10,11 Although the greater number of non-contacting sympathetic nerve varicosities found in the electron microscopy studies is the most economical explanation for the increase in the nerve-evoked constrictions, the present study cannot exclude the possibility that a reduction in re-uptake of released norepinephrine by varicosities contributes to the enhanced responses.
ATP, another cotransmitter, when released from sympathetic nerves, activates purinergic P2X receptors on vascular smooth muscle to give rise to a brisk depolarization, an excitatory junction potential that requires that the neuromuscular junction be "contacting."23–29 The density of neuromuscular junctions was not increased by Ang II, suggesting that increases in ATP release are unlikely to be the cause of the increased sensitivity of the renal arcuate arteries to nerve stimulation after treatment. However, the low incidence of neuromuscular junctions and the possibility of a diffuse distribution of purinoceptors mean that this conclusion is made cautiously.
In contrast to the arcuate artery, the constrictor response to stimulating the nerves in mesenteric arteries of rats was not influenced by Ang II pretreatment, and this concurred with the morphological evidence of no change in the density of innervation in this bed.
This study provides further evidence that the renal innervation may be plastic and that chronic Ang II levels may be an important factor in establishing renal innervation density. We have previously reported that prolonged (6 weeks) treatment of rabbits with enalapril resulted in changes in the innervation of the renal vasculature,12 which were, paradoxically, similar to those seen here from low-dose Ang II infusion. In another recent case, Casellas et al13 reported that high doses of Ang II (400 ng/Kg per minute subcutaneous) infused for 10 days, which produced a marked (50 mm Hg) increase in systolic pressure, resulted in a decrease in innervation density in renal arcuate arteries. The reason for the differences in these results and those of the present study is not clear but may be explained by the higher dose of Ang II used, resulting in considerably higher arterial pressures achieved, in the study by Casellas.13 Alternatively, in contrast with the current study in which vessels were fixed rapidly in situ for examination with electron microscopy, Casellas et al13 excised, isolated, and permeabilized the vessels before fixation and light microscopic visualization with a marker for synaptic vesicles (synaptophysin). This approach may have lead to synaptic vesicle release before fixation and thus may, in combination with the low resolution of the light microscope, have led to underestimation of nerve densities in their study.
Ang II infusion at the low dose used in the present experiments led to a small increase in arterial pressure after 21 days but had no detectable effects on cardiac mass or renal arcuate and mesenteric vessel dimensions. Although it is not possible to rule out that the small increase in blood pressure contributed to the greater innervation density and enhanced constriction to nerve stimulation evoked by Ang II, this effect was apparently specific to the renal vasculature and was not detectable in the mesenteric artery. Regardless of the mechanism by which the Ang II acted, the increased innervation density seen in the renal vasculature could be pro-hypertensive via a number of mechanisms. For example, increased neurotransmitter release during sympathetic nerve activity in the kidney could increase renal vasoconstriction and/or tubular Na+ reabsorption, resulting in a rightward shift of the renal arterial pressure/body fluid balance ("pressure natriuresis") relationship30 and thus higher arterial pressure.9,10,30 Interestingly, human studies have shown that sympathetic nerve activity is increased predominantly in the kidney, but not the mesenteric circulation, early in some forms of hypertension,31–34 including in borderline forms of the disease.35 The exact contribution of these changes in renal sympathetic structure and function to the increase in blood pressure in this model of experimental hypertension remains to be determined. Furthermore, the fate of the innervation in the smaller arterioles in the present study is unknown. Although Ang II had no effect on the density or function of the innervation in mesenteric vessels, further studies are required to examine whether Ang II affects the innervation density of other components of the cardiovascular system.
Perspectives
This study has demonstrated that Ang II induces significant increases in the sympathetic vasoconstrictor innervation in the kidney, but not in the mesenteric bed, within 21 days. This is achieved at a dose that has negligible pressor effects acutely and that is without effects on vascular endothelial vasodilator function or passive wall properties in either bed. These results provide support of strengthened cooperative interaction between the renin–angiotensin and sympathetic nervous systems. Although this would be beneficial in blunting pressure changes and restoring homeostasis after hypovolemic perturbation in young healthy individuals, subtle increases in Ang II in the absence of such stimulus are likely to contribute to an increase in blood pressure. The "feed-forward" interaction between the two systems requires more extensive study to determine whether the effects of Ang II on the innervation properties of the kidney may be an important factor in long-term arterial pressure regulation.
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Acknowledgments |
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The authors thank Drs James Brock, Roger Evans, and Michelle Kett for comments on the manuscript. The work was supported by the Commonwealth Department of Health & Ageing and the National Health & Medical Research Council of Australia (grants 124404 [WPA] and 124470 [HCP]).
Received October 21, 2003; first decision November 7, 2003; accepted January 5, 2004.
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