1 Section of Hypertension and Vascular Research, University of Texas Medical Branch, Galveston, Texas 77555-1065 and 2 Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, North Carolina 27707
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ABSTRACT |
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Renal interstitial fluid Ca2+
concentration ([Ca2+]isf) was
measured in anesthetized Wistar rats by using in situ microdialysis. During perfusion of 20 cm of the proximal small intestine with Ca2+-free buffer, renal
[Ca2+]isf was 1.63 ± 0.19 mmol/l in the cortex (n = 6) and 1.93 ± 0.12 mmol/l in the medulla (n = 5, P = 0.223). When
Ca2+ in the intestinal lumen was increased to 3 mmol/l, no
change was seen in total or ionized serum Ca2+
(SCa), urinary Ca2+ excretion
(UCa), or Ca2+ in a microdialysate of the
kidney cortex. Increasing intestinal Ca2+ further, to 6 mmol/l, was without effect on SCa but significantly increased UCa by 38% and microdialysate Ca2+
by 36% (1.25 ± 0.0.09 vs. 1.70 ± 0.14 mmol/l, n = 4, P < 0.05). Intravenous infusion of 28 ng
· kg1 · min
1
of parathyroid hormone for 1 h during perfusion of the intestinal lumen
with 1 mmol/ Ca2+caused a 7-10% rise in
SCa, a 40% fall in UCa, and a 32% increase in
microdialysate Ca2+ (1.32 ± 0.13 vs. 1.74 ± 0.13 mmol/l, n = 6, P < 0.05). Interlobar arteries with a
mean diameter of 120 µm were studied by using a wire myograph to
determine whether changes in extracellular Ca2+ affect
muscle tone. When precontracted with 5 µmol/l serotonin, the arteries
relaxed in response to cumulative addition of Ca2+
(1-5 mmol/l) with an ED50 value for Ca2+
of 3.30 ± 0.08 mmol/l, n = 3. These data demonstrate that
[Ca2+]isf changes dynamically
during manipulation of whole-animal Ca2+ homeostasis and
that intrarenal arteries relax in response to extracellular
Ca2+ varied over the range measured in vivo.
kidney; calcium; microdialysis; relaxation
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INTRODUCTION |
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THE CONCENTRATION of Ca2+ in the blood is regulated by coordinated mechanisms involving absorption of the cation from the intestinal lumen by epithelial cells, reabsorption from the urine by renal tubular cells, and deposition and resorption from bone by osteoblasts and osteoclasts (16, 18). At each site where Ca2+ undergoes transcellular movement, i.e., from the lumen of the renal tubule into the vascular space, it traverses an interstitial compartment where it is free to interact with adjacent cells. If the cells in these spaces have a mechanism for sensing changes in extracellular Ca2+, then the cation might serve as a stimulus to modulate their physiological activity. Recent work from our laboratory (6) has demonstrated that the perivascular network of sensory dilator nerve fibers expresses a Ca2+ receptor that is homologous with the Ca2+-sensing receptor that was originally described in the bovine and human parathyroid gland (4, 11), kidney (21), and brain (22). This finding has raised the question of whether dynamic changes in the concentration of Ca2+ in the interstitial compartment of tissues involved in transcellular Ca2+ movement can modulate vascular reactivity and local blood flow by altering the release of vasodilator transmitters from perivascular sensory nerves (5).
In initial efforts to address this question, we found that extracellular Ca2+ causes concentration-dependent relaxation of isolated mesenteric branch arteries that is sensory nerve dependent and that the magnitude of this relaxation correlates with the density of Ca2+-receptor-positive nerve fibers in the periadventitial surface of the artery (6, 20, 25). To address the question of whether Ca2+ in the interstitial fluid of any tissue can achieve levels that are high enough to induce relaxation, we used an in situ microdialysis method to test the hypothesis that ionized Ca2+ in the interstitium of the intestinal submucosa changes as a function of the Ca2+ content in the intestinal lumen. The results indicated that Ca2+ in the duodenal interstitium can vary between 1 and 2 mmol/l (19). Of interest, this range of interstitial Ca2+ concentrations is sufficient to induce relaxation of isolated mesenteric branch arteries and supports the hypothesis that duodenal interstitial Ca2+ achieves levels sufficient to stimulate Ca2+-induced relaxation and modulate local vascular reactivity.
The kidney also plays a key role in the regulation of whole-animal Ca2+ homeostasis, serving as a target tissue for the calciotropic hormones, parathyroid hormone (PTH) (3, 13, 24) and 1,25 (OH)2 vitamin D3 (3, 18). In experiments designed to map the distribution of the perivascular sensory nerve Ca2+ receptor, we found that, similar to mesenteric arteries, perivascular nerves of intrarenal arteries express Ca2+ receptor protein (24). This observation raised the question of whether perturbations of whole-animal Ca2+ homeostasis can cause dynamic changes in renal interstitial Ca2+ that are sufficient to affect renovascular function, as has been described for other endocrine and paracrine systems (9). To address this question, we have now used in situ microdialysis to measure Ca2+ in the renal interstitium during manipulation of whole-animal Ca2+ homeostasis and have found that interstitial Ca2+ in the kidney varies over a concentration range that can modulate contractile activity of isolated intrarenal arteries.
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METHODS |
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Animals. All studies were performed by using Wistar rats obtained from Harlan Sprague Dawley and protocols that were approved by the Institutional Animal Care and Use Committee. On delivery to our animal quarters, the rats were housed in microisolator cages maintained at constant temperature, humidity, and fixed dark-light cycles, and given free access to tap water and Purina rodent chow until 8 AM of the morning of the experiment.
Microdialysis. Microdialysis was performed by using established methods (19). The animals were anesthetized with a mixture of ketamine and xylazine (100 mg/kg, 5 mg/kg ip) and the right jugular vein was cannulated by using PE-50 tubing for administration of drugs and fluids. The left kidney was then exposed through a midline incision, and a section of linear dialysis probe (Bioanalytical Systems) was inserted through either the cortex, just below the renal capsule, or the medulla, and fixed in place by using veterinary bonding glue (3M Animal Care Products, St. Paul, MN). The tubing was then perfused at a rate of 1 µl/min with buffer containing 120 mmol/l NaCl and 20 mmol/l HEPES for a 90-min equilibration period. To allow manipulation of the contents of the small intestine, a 20-cm section of the proximal small bowel was cannulated for perfusion with the buffer described above containing known amounts of Ca2+ as described recently (19).
The zero-net-flux method was used to estimate the basal concentration of Ca2+ in the interstitial compartment of the renal cortex or renal medulla during perfusion of the intestinal lumen with nominally Ca2+-free buffer. After a 90-min equilibration period, the microdialysis probe was perfused at 1 µl/min with buffer containing increasing concentrations of Ca2+ (0.5, 1, 2, 3, and 5 mmol/l). After each incremental increase, i.e., from 0.5 to 1.0 mmol/l, a 35-min equilibration period was allowed to elapse before collection of the dialysate over a 15-min period. For each level of Ca2+ in the perfusate, the concentration of free ionized Ca2+ in both dialysate and perfusate was determined by using a microfluorometric method (20). The difference between the amount of Ca2+ in the dialysate (Ca2+dialysate) and the perfusate (Ca2+perfusate) was then plotted as the dependent variable against the concentration of Ca2+ in the perfusate and with the use of linear regression analysis, the point where Ca2+dialysateEffect of intestinal Ca2+ and PTH infusion on renal interstitial Ca2+ concentration ([Ca2+]isf). Experiments were performed to assess the effect of changing the concentration of Ca2+ in the lumen of the gut on Ca2+ in the renal cortical interstitium. Animals (n = 4) were prepared as described above, and a microdialysis probe was placed in the renal cortex and perfused with buffer containing 0.5 mmol/l Ca2+ whereas the intestinal lumen was cannulated and perfused with Ca2+-free buffer. After a 90-min equilibration period, the microdialysate was collected for 15 min and stored until Ca2+ was determined. After this collection period, the concentration of Ca2+ in the buffer perfusing the intestinal segment was increased to 3 mmol/l and, after a 60-min period, the microdialysate was collected for 15 min and stored. The concentration of Ca2+ in the buffer perfusing the intestinal segment was then increased to 6 mmol/l and, after a 60-min period, the microdialysate was collected for a 15-min period. The net effect of increasing intestinal Ca2+ on Ca2+ in the renal interstitium was estimated by calculating the fractional increase in the concentration of Ca2+ in the dialysate that occurred in response to the maneuver. At the end of the experiment, the kidney was removed and fixed in formalin, and sectioned by using a razor blade to verify placement of the microdialysis fiber in the expected site.
Other experiments assessed the effect of PTH-induced increases in serum Ca2+ on interstitial Ca2+ in the renal cortex. Animals (n = 7) were instrumented, and a segment of the proximal small intestine was perfused with buffer containing 1 mmol/l Ca2+. The dialysis membrane was then perfused at a rate of 1 µl/min with buffer containing 0.5 mmol/l Ca2+ and, after a 90-min equilibration period, dialysate was collected for 15 min for measurement of the basal concentration of Ca2+. PTH was then infused through the jugular cannula at 28 ng · kgAnalysis of serum Ca2+. A separate series of animals was used to assess the effect of changing the concentration of Ca2+ in the intestinal lumen or infusing parathyroid hormone on serum total and ionized Ca2+ and urinary Ca2+ excretion. In these experiments, the rats were anesthetized with ketamine and xylazine, and the jugular vein and carotid artery were cannulated for the administration of compound and withdrawal of blood, respectively; the proximal small intestine was cannulated for lumenal perfusion; and ureters were cannulated for urine collection.
When the effect of increasing concentrations of intestinal Ca2+ was assessed, the lumen of the bowel was perfused with nominally Ca2+-free buffer for a 1-h equilibration period, during which time urine was collected. After this period a blood sample (1 ml) was taken from the carotid artery for preparation of serum, and volume was replaced by intravenous injection of 1 ml 0.9% saline. The concentration of Ca2+ in the buffer perfusing the intestinal segment was then increased to 6 mmol/l, and the perfusion was allowed to continue for a 1-h period, during which time urine was collected and at the end of which a final blood sample was taken. Total Ca2+ in the serum and urine was analyzed by using flame photometry, and ionized Ca2+ was determined by using a Ca2+-selective electrode (Radiometer). When the effect of PTH was assessed, the cannulated segment of the intestine was perfused with buffer containing 1 mmol/l Ca2+ and urine was collected for a 1-h equilibration period. At the end of this period, 1 ml of blood was taken from the carotid artery for preparation of serum and volume was replaced as described above. Infusion of PTH was then initiated as described above in the microdialysis section, and urine was collected for a 1-h period after which a second 1 ml blood sample was taken.Myography. A separate set of animals (n = 3) was used to study the contractile function of isolated intrarenal arteries. Kidneys were removed from anesthetized rats, immediately hemisected, and placed in ice-cold physiological solution containing (in mmol/l) 140 NaCl; 4.7 KCl; 1.17 MgSO47H2O; 5 NaHCO3; 1.15 KH2PO4; 1.10 Na2HPO4; 1.0 CaCl2; 20 HEPES; and 5 glucose, pH 7.4. Cortical interlobar arteries were microdissected from the renal matrix and placed on a wire myograph (Kent Scientific, Litchfield, CT) by means of tungsten wires with a 27-µm diameter. After a 15-min equilibration period at 37°C, the arteries were stretched to a circumference that yielded an inner diameter of ~120 µm and allowed to equilibrate for an additional 15 min. The vessels were exposed one time to 5 µmol/l serotonin for a 4-5 min period, washed with fresh physiological salt solution, and; then recontracted with 5 µmol/l serotonin. Ca2+ was then cumulatively added, and the response was recorded. Relaxation was calculated by using the level of the steady-state precontraction as 100% of the amount that the vessel could relax.
Drugs and chemicals . Serotonin was obtained from Sigma Chemical, St Louis, MO; Mag fura 5 from Molecular Probes, Junction City, OR; ketamine and xylazine from University of Texas Medical Branch Pharmacy; and PTH was purchased from Peninsula Laboratories.
Statistical analysis. Statistical analysis was made by using the SYSTAT software package. Data are presented as means ± SE. Linear regression analysis was performed by using a routine that provided the best fit to the equation y = mx + b, where m and b are regression coefficients. Comparisons among groups were made using by ANOVA or unpaired Student's t-test. A P value of <0.05 was taken to indicate statistically significant difference.
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RESULTS |
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Zero-net-flux analysis of interstitial
Ca2+.
The zero-net-flux method was used to estimate the concentration of
Ca2+ in the renal cortex and medulla of rats during
perfusion of a 20-cm segment of the proximal small intestine with
Ca2+-free buffer. Interstitial Ca2+ was
estimated from plots of the difference in Ca2+ content of
the dialysate less the perfusate determined for each concentration of
Ca2+ that was infused into the dialysis membrane, as
described in METHODS and illustrated in
Fig. 1. The mean concentration of
Ca2+ in the cortical interstitium was estimated to be 1.62 ± 0.19 mmol/l; n = 6 (Fig. 1A), and the
concentration of Ca2+ at the level of the medulla was 1.93 ± 0.12 mmol/l, n = 5 (Fig. 1B). Although the
concentration of interstitial Ca2+ tended to be higher in
the medulla, the difference did not achieve statistical significance
(P = 0.209).
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Effect of intestinal Ca2+.
The effect of increasing the concentration of Ca2+ in the
buffer that was used to perfuse the lumen of a section of the small intestine on renal cortical interstitial Ca2+ was
determined by measuring the concentration of Ca2+ in the
dialysate under control conditions, where the intestine was perfused
with Ca2+-free buffer, and after increasing lumenal
Ca2+ to 3 and then 6 mmol/l. During perfusion of the
intestinal lumen with Ca2+-free buffer, the concentration
of Ca2+ in the renal cortical dialysate was 1.22 ± 0.11 mmol/l, n = 4. After the concentration of Ca2+ in
the lumen of the gut was increased to 3 mmol/l, the concentration of
Ca2+ in the renal dialysate was 1.27 ± 0.09 mmol/l, which
was not different from the control condition (P > 0.05). In
contrast, raising Ca2+ in the lumen of the gut from 3 to 6 mmol/l increased the concentration of Ca2+ in the dialysate
to 1.72 ± 0.13 mmol/l, a value that was significantly greater than
control at P < 0.05 (Fig. 2).
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Effect of PTH infusion.
The effect of infusion of PTH on renal cortical interstitial
Ca2+ was determined by measuring the change in the
concentration of Ca2+ in the dialysate under control
conditions and after infusion of PTH. Under basal conditions the
concentration of Ca2+ in the dialysate was 1.32 ± 0.13 mmol/l and increased to 1.74 ± 0.13 mmol/l after PTH infusion (Fig.
3). This represents a 32 ± 7.5% increase
above baseline (significant at P < 0.05). Infusion of the
same concentration of PTH into a second set of animals (n = 6)
caused an increase in total serum Ca2+ from 9.42 ± 0.09 to 10.08 ± 0.12 mg/dl, P < 0.05, and of ionized serum
Ca2+ from 1.19 ± 0.02 to 1.31 ± 0.03 mmol/l, P < 0.05 (Table 1). PTH also caused a significant fall in urinary
Ca2+ excretion from 13.0 ± 1.7 to 7.86 ± .08 µg/h,
P < 0.05, without affecting the volume of urine output (366 ± 25 vs. 335 ± 83 µl/h).
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Response of isolated intrarenal arteries to extracellular
Ca2+.
Renal interlobar arteries were isolated from a separate set of rats
(n = 3) and mounted on a wire myograph for measurement of
isometric force responses. These arterial segments contracted in
response to 5 µmol/l serotonin and relaxed in a dose-dependent manner
in response to the cumulative addition of extracellular Ca2+ (Fig. 4). The maximal
relaxation in response to 5 mmol/l Ca2+ was 66 ± 1.7% of
the initial tension, and the ED50 value for Ca2+ was 3.30 ± 0.08 mmol/l.
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DISCUSSION |
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The present studies were initiated as an extension of our recent work that identified a Ca2+-sensing receptor on the periadventitial nerve network of intrarenal arteries (24), which we have postulated may mediate the relaxation response to physiological concentrations of interstitial Ca2+. In support of this thesis are our demonstration that Ca2+-induced relaxation is sensory nerve dependent (20) and our recent finding that the concentration of free Ca2+ in the duodenal interstitium undergoes dynamic changes in response to physiological stimuli over a range that can induce significant relaxation of isolated arteries (19).
Because of the potential importance of this system as a regulatory mechanism and the well-established role of the kidney in transcellular Ca2+ transport, the present experiments were designed to determine the basal concentration of Ca2+ in interstitial space of the renal cortex and medulla, assess the effect of increasing the concentration of Ca2+ present in the lumen of a segment of the small bowel or infusion of PTH on interstitial Ca2+ in the renal cortex, and to learn whether isolated intrarenal arteries relax in response to graded increases in extracellular Ca2+. The results include what to our knowledge is the first measurement of interstitial Ca2+ in the kidney, the demonstration that the concentration of interstitial Ca2+ changes in response to alterations in whole-animal Ca2+ balance, and the finding that isolated intrarenal arteries relax in response to extracellular Ca2+.
Ca2+ is freely filtered into the urine at the level of the
glomerulus, and the amount that is filtered per unit time is a function of its concentration in the plasma and the glomerular filtration rate.
Tubular reabsorption of Ca2+ from the urine is complex and
occurs at multiple sites along the nephron. Passive driving forces are
the major determinants of Ca2+ transport in the proximal
convoluted tubule where ~55% of the filtered Ca2+ load
is absorbed, and in the proximal straight tubule where an additional
10% is absorbed (2). In these segments, Ca2+ transport is
coupled to Na+ and fluid reabsorption (10). Transport of
Ca2+ is also passive in the medullary portion of the thick
ascending limb of the loop of Henle, where it is driven by the
potential gradient created by furosemide sensitive
Cl reabsorption (7, 15). In contrast to these
proximal and medullary segments of the nephron, Ca2+
absorption is an active process in the cortical portion of the thick
ascending limb and is stimulated by PTH. Ca2+ transport is
also an active process in the distal convoluted tubule, where 10% of
the filtered Ca2+ load is reabsorbed and undergoes major
regulation by both PTH and 1,25 (OH)2 vitamin
D3 (7, 23).
Because of the differential handling of tubular Ca2+ by different segments of the nephron, including cortical and medullary aspects, we first tested whether there were differences in the basal concentration of Ca2+ in the interstitium of the cortex vs. the medulla. Our results indicate that during perfusion of the proximal small intestine with Ca2+-free medium, the basal level of interstitial Ca2+ tends to be higher in the medulla than the cortex, but the difference is not statistically significant. The values in both compartments are somewhat higher than that which we observed in the duodenal submucosa during infusion of the lumen with Ca2+-free buffer (1.08 mmol/l) (21), and in the absence of data to the contrary, may reflect a true tissue-to-tissue difference. In view of the fact that the renal cortex is a major site of Ca2+ reabsorption and that medullary and cortical Ca2+ levels do not vary significantly, our subsequent studies were focused on Ca2+ in the renal cortex.
As noted above, experiments were performed to learn whether interstitial Ca2+ in the renal cortex could be increased by perfusing the lumen of the proximal small intestine with increasing amounts of the cation. The rationale behind this series was based in part on our observation that increasing Ca2+ in the lumen of the bowel causes a large increase in interstitial Ca2+ in the submucosa and the logical extrapolation that this Ca2+ would be absorbed into the blood and filtered at the glomerulus. The results show that raising Ca2+ in the gut from 0 to 3 mmol/l, which results in a rise in submucosal Ca2+ from 1.0 to 1.45 mmol/l does not alter renal cortical Ca2+, but that increasing Ca2+ further to 6 mmol/l, which increases submucosal Ca2+ to 1.8 mmol/l, causes a significant rise in interstitial Ca2+ in the cortex.
We also studied the effect of infusion of PTH on renal cortical
interstitial Ca2+ because the cortex is a major site of the
calciotropic action of the peptide on tubular Ca2+
transport (2, 12, 23). As expected, infusion of PTH at 28 ng
· kg1 · min
1
for 1 h resulted in a significant rise in total and ionized serum Ca2+ and a decrease in urinary Ca2+ excretion.
Concomitant with these changes in Ca2+ homeostasis, PTH
increased the concentration of Ca2+ in the renal cortical
dialysate an average of 32%, demonstrating that infusion of PTH can
alter renal interstitial Ca2+. Although the amount of PTH
that was used is likely to be more pharmacological than physiological,
significant increases in serum PTH do occur in conditions such as
primary or secondary hyperparathyroidism (14) and can be predicted to
accompany calcilytic-based pulse therapy for the treatment of
osteoporosis (13).
In view of our studies linking the perivascular sensory nerve CaR with Ca2+-induced relaxation (6, 19), we have speculated that increasing interstitial Ca2+ in the kidney could serve to cause a local vasodilation (5). The results of our myograph studies show that isolated interlobar arteries relax in response to cumulative addition of extracellular Ca2+. It should be noted that the ED50 for Ca2+ in the interlobar artery is 3.3 vs. ~1.8 mmol/l for the isolated mesenteric branch artery (19). At the present time it is not known whether the relative decrease in sensitivity of the small renal artery is an intrinsic property of the artery and reflects a true tissue-to-tissue variation, similar to the difference in interstitial Ca2+, or whether it reflects damage to the perivascular nerve network that was caused during isolation of the renal artery segment from the renal parenchyma. Regardless, the data indicate that the intrarenal vasculature is sensitive to elevations of extracellular (or interstitial Ca2+) as might occur under the conditions of the present study.
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ACKNOWLEDGEMENTS |
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This work was supported by National Heart, Lung, and Blood Institute Grants HL-54901, HL-64761, and HL-59868 and the John Sealy Memorial Endowment.
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FOOTNOTES |
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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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: R. Bukoski, Cardiovascular Disease Research Program, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central Univ., 700 George St., Durham, NC 27707 (E-mail: rbukoski{at}wpo.nccu.edu).
Received 22 July 1999; accepted in final form 16 December 1999.
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