Renal fluid and electrolyte handling inBKCa-1/ mice - 《American Journal of Physiology》美国生理学杂志干细胞之家



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发表于 2009-4-21 13:37 |只看该作者 |倒序浏览 |打印

作者：Jennifer L.Pluznick, PeilinWei, Pamela K.Carmines,  Steven C.Sansom作者单位：Department of Physiology and Biophysics, University ofNebraska Medical Center, Omaha, Nebraska 68198-4575 8 O6 }! L! u& d- `( Y





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      【摘要】; z* h; E' i) k+ |; [
   Large-conductanceCa 2  -activated K channels (BK Ca )are composed of pore-forming -subunits and one of four accessory -subunits. The 1-subunit, found predominantly in smooth muscle,modulates the Ca 2  sensitivity and pharmacologicalproperties of BK Ca. BK Ca - 1 null mice(M 1 / ) are moderately hypertensive, consistent withthe role of BK Ca in modulating intrinsic vascular tone.Because BK Ca are present in various renal cells includingthe mesangium and cortical collecting ducts, we determined whetherfluid or electrolyte excretion was impaired in M 1 / under euvolemic, volume-expanded, or high-salt diet conditions. Undereuvolemic conditions, no differences in renal function were foundbetween M 1 / and M 1  / . However,glomerular filtration rate (GFR) and fractional K excretion were significantly impaired in M 1 / inresponse to acute volume expansion. In contrast, M 1 / exhibited enhanced Na excretion and fractionalNa excretion responses to acute volume expansion.Differences in renal function between M 1  /  andM 1 / were not observed when chronically treated witha high-salt diet. These observations indicate that the 1-subunit ofBK Ca contributes to the increased GFR that accompanies anacute salt and volume load and raises the possibility that it is alsoinvolved in regulating K excretion under these conditions.
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large-conductance, calcium-activated potassium channels; maxi Kchannel; glomerular filtration rate; volume expansion; potassiumexcretion * L* p* @% }. m( n& t
      【关键词】 electrolyte handling inBKCa/8 `/ Q  r! Z, m
   INTRODUCTION
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LARGE-CONDUCTANCE, CA 2 -ACTIVATED potassium channels(BK Ca ) are composed of both pore-forming - and accessory -subunits. At least four distinct -subunits, each with atissue-specific distribution, have been described. When the 1-subunit, found primarily in smooth muscle cells, is expressed withthe -subunit, the voltage and calcium sensitivities ofBK Ca are enhanced ( 2 ). Conversely, BK Ca in cerebral artery myocytes from 1 knockout mice(M 1 / ) have a reduced open probability at a givenvoltage and Ca 2  concentration ( 2 ). Inaddition, these mice also have deficient regulation of tone in visceralsmooth muscle, such as in the urinary bladder ( 23 ). Invascular smooth muscle, a lack of the 1-subunit and the resultinglow open probability of BK Ca may cause a reduced hyperpolarizing feedback response to contractile agents, resulting ingreater vascular tone and generalized hypertension ( 16 ). Indeed, the mean arterial pressure (MAP) in M 1 / ofthe C57BL/6 strain is elevated by ~20 mmHg ( 2 ).5 ~" I/ P6 M3 ~+ V: F/ R0 r2 a

Whereas hypertension can originate from elevated intrinsic vasculartone, MAP is regulated by multiple complex mechanisms that includebaroreceptor and renal feedback reflexes, such as pressure-natriuresisand renin release. Indeed, polymorphisms in the humanBK Ca - 1 have been shown to correlate with baroreflex andarterial pressure regulation ( 7 ).
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BK Ca have been reported in several renal cells, includingmesangial cells as well as epithelial cells of the cortical collecting duct ( 11 ), proximal tubule ( 10 ), and thickascending limb ( 20 ). However, the function ofBK Ca in these cells in relation to whole animal electrolytebalance has not been determined. In this study, we designed experimentsto determine the significance of the 1-subunit with respect to fluidand electrolyte balance. Although the open probability ofBK Ca is very low under basal conditions, these channels areimportant mediators of compensatory hyperpolarizing responses afteragonist stimulation. Therefore, we examined M 1 / under both euvolemic and volume-expanded conditions, in which a varietyof possible influences including increased circulating atrialnatriuretic peptide (ANP), stretch, intracellular Ca 2 , andincreased flow of plasma and filtrate could demand proper function ofthe renal BK Ca.

METHODS0 Y' p) }5 b* H+ j  H3 h3 x
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All experiments were performed under the guidelines of theInstitutional Animal Care and Use Committee of the University of Nebraska Medical Center. This study utilized M 1 / mice (with a homogeneous C57BL/6 background) generated by Brenner etal. ( 2 ) and C57BL/6 control mice (M 1  /  ) ofboth sexes, which were approximately 3 mo of age. Mice received standard chow containing 0.4% NaCl and water ad libitum. Some micereceived a high-salt (8% NaCl) diet for 2-3 wk before surgery.
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Surgical procedures. Surgical and clearance procedures were performed as previouslydescribed by Wang et al. ( 30 ). In brief, mice wereanesthetized with Inactin [0.14 mg/g body wt (BW)] and kept at a bodytemperature near 36°C, using a heat lamp. As required, additionaldoses of Inactin were used to maintain anesthesia. A tracheostomy wasperformed using polyethylene (PE)-50 tubing, and the end of thetracheal cannula was exposed to a stream of oxygen-rich air. The leftexternal jugular vein was cannulated with PE-10 tubing for the infusion of fluids, and the bladder was cannulated with PE-50 tubing for urinecollection. The right common carotid artery was cannulated with PE-10tubing for arterial pressure measurements and blood sampling. Arterialpressure was monitored continually and recorded at 5-min intervals.Urine was collected and stored under mineral oil. Physiological salinesolution (PSS) containing (in mM) 135 NaCl, 5.0 KCl, 2.0 MgCl 2, 1.0 CaCl 2, and 10 HEPES as well as 10 µg/ml FITC-inulin was infused at a rate of either 0.4 (euvolemic) or2.0 ml · h 1 · 25 g BW 1 (volume expanded). Because FITC-inulin is lightsensitive, all syringes, tubing, and collection vials were protectedfrom light. The length of the equilibration period was 2 h for theeuvolemic treatment and 1 h for the volume-expansion treatment.After an equilibration period, a blood sample (~20 µl) was takenand urine was collected for a 30-min period. At the end of the period,a larger plasma sample was taken for measurements of plasmaNa ([Na ]), K ([K ]), and inulin concentrations (). Urinaryvolume was determined gravimetrically, and the  of the twoplasma samples was averaged for calculation of the glomerularfiltration rate (GFR).
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Measurements of [Na ],[K ], and [FITC-inulin] in urine andplasma. After the completion of an experiment, urine and plasma samples werestored in the dark at 70°C. [Na ] and[K ] in urine and plasma were measured using anInstrumentation Laboratory 443 Flame Photometer. Plasma samples wererun in duplicate. Within 1 wk of the experiment, [FITC-inulin] wasmeasured using a fluorescent microplate reader (Cary EclipseFluorescence Spectrophotometer, Varian) as described by Lorenz andGruenstein ( 17-19 ). For each analysis of FITC-inulinsamples, a standard curve was generated and used for calculating[FITC-inulin]. All standards and urine samples were run intriplicate; most plasma samples were run in duplicate. Very small bloodsamples (~20 µl) were taken to minimize the effect of plasmasampling on blood pressure. Occasionally, a plasma sample was too smallto analyze more than once.
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Statistics. All data are presented as means ± SE. Groups were compared usingthe unpaired t -test, with P significant.( p$ K# }1 ^2 I3 r( C
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RESULTS% {8 t9 K2 A. @5 G5 D$ Y

Other than the hypertensive phenotype, no other overt physicaldifferences were observed between wild-type mice andM 1 /. When animals were on the normal-salt diet, themean BWs of M 1  /  (24 ± 0.5 g, n = 18) and M 1 / (25 ± 1.0 g, n = 18) were not significantly different. The kidney weights of M 1  /  (0.29 ± 0.01 g, n = 16) and M 1 / (0.30 ± 0.02 g, n = 17) were also similar. The high-saltdiet did not significantly affect the BWs (M 1  /  24 ± 1.0 g, n = 5; M 1 / 24 ± 0.5 g, n = 9) or kidney weights(M 1  /  0.30 ± 0.01 g, n = 5;M 1 / 0.32 ± 0.01 g, n = 8)of M 1  /  or M 1 /. BecauseM 1  /  and M 1 / fed the same diet(normal or high salt) exhibited similar weight gains with age, it isassumed that they ingested equivalent amounts of mice chow.
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MAP. In the present study, measurements of MAP were made in anesthetizedmice. Although the depth of anesthesia was difficult to determine, apositive correlation between GFR and MAP was observed when MAP was autoregulation, weexcluded data from further analysis if the average MAP during thecollection period was found that eight mice (of 49)had a MAP of 1 shows theMAP in M 1  /  and M 1 / during theequilibration periods under euvolemic, volume-expanded, and high-saltdiet conditions. During the euvolemic equilibration periods, the MAP inM 1 / was significantly higher than that inM 1  / . However, during the volume-expanded equilibrationperiod, the MAP in M 1  /  was significantly higher thanthe M 1  /  euvolemic value, whereas the MAP inM 1 / was not significantly different from theM 1 / euvolemic value. The MAP in neitherM 1  /  nor M 1 / was significantlyaffected by treatment with a high-salt diet.$ K0 }9 b# J* r- H' [

Table 1. Mean arterial pressure in euvolemic, acutely volume-expanded, andchronically volume-expanded mice8 E6 r1 f$ j4 }5 T+ I0 y& y
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GFR. Figure 1 shows the GFR under euvolemicand acutely volume-expanded conditions for M 1  /  andM 1 /. Under euvolemic conditions, the GFRs inM 1  /  and M 1 / did not differsignificantly. For M 1  / , GFR was significantly higherunder volume-expanded conditions (2.5 ± 0.4 ml · min 1 · 100 g BW 1, n = 6) compared with euvolemicconditions (1.3 ± 0.2 ml · min 1 · 100 g BW 1, n = 8; P 1 /, GFR (1.4 ± 0.1 ml · min 1 · 100 gBW 1, n = 7) was significantly higher thanin euvolemic M 1 / (1.0 ± 0.1 ml · min 1 · 100 g BW 1, n = 6; P 1  /  wassignificantly higher than the GFR in volume-expandedM 1 / ( P diet on the GFR of either genotype(data not shown: M 1  /  1.0 ± 0.1 ml · min 1 · 100 g BW 1, n = 5; M 1 / 0.8 ± 0.2 ml · min 1 · 100 g BW 1, n = 9).
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Fig. 1. The effect of acute volume expansion on glomerularfiltration rate (GFR) in large-conductance, Ca 2  -activatedK channel 1-subunit control (M 1  /  ) andnull mice (M 1 / ). For both M 1  /  andM 1 /, the euvolemic GFR was significantly less thanthe volume-expanded GFR (* P 1 / was significantly lower thanthe GFR in volume-expanded M 1  /  ( P  s+ [! r* W4 M7 U' H
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Na handling inM 1 /. Figure 2, A and B,shows the effects of acute and chronic volume expansion onNa excretion (U Na V) and fractional excretionof Na (FE Na ) in M 1  /  andM 1 /. Plasma [Na ] data are shown inTable 2. Under conditions of volumeexpansion, the U Na V in M 1  /  wassignificantly higher (4.3 ± 1.1 µeq · min 1 · 100 g BW 1, n = 10) than that observed undereuvolemic conditions (0.3 ± 0.1 µeq · min 1 · 100 g BW 1, n = 8; P Na V in M 1 / wassignificantly higher under volume-expanded conditions (2.7 ± 0.6 µeq · min 1 · 100 g BW 1, n = 9) compared with euvolemicconditions (0.3 ± 0.1 µeq · min 1 · 100 g BW 1, n = 8; P Na V undervolume-expanded or euvolemic conditions. There was no significant effect of the high-salt diet on U Na V for either genotype(data not shown), with U Na V averaging 0.4 ± 0.1 µeq · min 1 · 100 g BW 1 ( n = 5) in M 1  /  and0.6 ± 0.2 µeq · min 1 · 100 g BW 1 ( n = 5) in M 1 /.

Fig. 2. The response of urinary Na excretion rate(U Na V) and fractional excretion (FE Na ) to acutevolume expansion in M 1  /  and M 1 /. A : under volume-expanded conditions, U Na V wassignificantly elevated compared with euvolemic conditions in bothM 1  /  (* P 1 / (* P Na V were observed betweenM 1  /  and M 1 /. B :FE Na during euvolemia was similar in M 1  /  and M 1 /, and there was a significant differencebetween euvolemic and volume-expanded values of FE Na forboth M 1  /  and M 1 / (* P P Na in volume-expanded M 1 / wassignificantly higher than the FE Na in volume-expandedM 1  /  ( P$ ^3 R" ?- ~6 V8 Z( R' ]5 N" ]

Table 2. Plasma Na andK concentration in euvolemic, acutelyvolume-expanded, and chronically volume-expanded mice/ j9 d! S3 L$ h, g% l
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Under euvolemic conditions, FE Na (Fig. 2 B ) wassimilar in M 1  /  (0.15 ± 0.03%, n = 8) and M 1 / (0.23 ± 0.07%, n = 5). Both M 1  /  and M 1 / exhibitedhigher FE Na on volume expansion compared with their respective euvolemic values ( P P FE Na involume-expanded M 1 / (1.93 ± 0.35%, n = 5) was significantly greater than that in volume-expanded M 1  /  (0.83 ± 0.29%, n = 6; P Na tended to be elevated in mice fed the high-salt diet (data not shown)compared with the normal diet for both M 1  /  (0.29 ± 0.09%, n = 5) and M 1 / (1.08 ± 0.63%, n = 9), although the increases were notsignificant. No significant differences in plasma [Na ]were observed between groups./ m% E3 p: p' R- H/ J

K handling inM 1 /. Figure 3, A and B,shows the rate of K excretion (U K V) and thefractional excretion of K (FE K ), respectively,for M 1  /  and M 1 / under euvolemic andacute volume-expanded conditions. For M 1  / , theU K V in the euvolemic group was 0.9 ± 0.2 µeq · min 1 · 100 g BW 1 ( n = 8), whereas theU K V in the volume-expanded group was significantly higherat 2.7 ± 0.4 µeq · min 1 · 100 g BW 1 ( n = 9; P 1 /, the U K V under euvolemicconditions was 0.5 ± 0.2 µeq · min 1 · 100 g BW 1 ( n = 7), whereas theU K V during volume expansion was significantly greater(1.2 ± 0.1 µeq · min 1 · 100 gBW 1, n = 9; P K V in M 1  /  andM 1 / did not differ significantly during euvolemia,U K V in volume-expanded M 1 / wassignificantly less than that in volume-expanded M 1  /  ( P K V for any treatment group (data not shown), averaging0.5 ± 0.1 µeq · min 1 · 100 g BW 1 ( n = 5) in M 1  /  and0.3 ± 0.1 µeq · min 1 · 100 g BW 1 ( n = 9) in M 1 /.# Y1 W5 u0 b' V  I4 ~
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Fig. 3. The effect of acute volume expansion on renalK handling in M 1  /  andM 1 /. A : urinary K excretionrate (U K V) in M 1  /  andM 1 / was significantly higher during volume expansioncompared with euvolemia (* P P K V in volume-expandedM 1 / was significantly less than the U K Vin volume-expanded M 1  /  ( P B : under euvolemic conditions, urinary fractionalK excretion (FE K ) was similar inM 1  /  and M 1 /. With volume expansion,the FE K in M 1  /  but not inM 1 / was significantly higher than the euvolemicvalue (* P
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FE K is shown in Fig. 3 B. Under euvolemicconditions, FE K was similar in M 1  /  andM 1 /. With volume expansion, the FE K inM 1  /  was 33 ± 7% ( n = 5), avalue significantly higher than the FE K for euvolemicM 1  /  (13 ± 2%, n = 8; P K foreuvolemic M 1 / and volume-expandedM 1 / were not significantly different (12 ± 4, n = 5 and 19 ± 2%, n = 5, respectively). Treatment with the high-salt diet did not alterFE K (data not shown: M 1  /  12 ± 3, n = 5; M 1 / 10 ± 2%, n = 9).# ~/ i, q5 ~* D/ I

Plasma [K ] data are shown in Table 2. Although plasma[K ] values tended to be lower in bothM 1  /  and M 1 / under volume-expandedconditions, this decrease achieved statistical significance only inM 1  /  ( P ] for eithergenotype on the high-salt diet (M 1  /  5.1 ± 0.2, n = 5; M 1 / 5.1 ± 0.3 mM, n = 9).

DISCUSSION
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Although BK Ca are expressed in several types of renalcells ( 10, 11, 20 ), the role of BK Ca - 1 withrespect to renal function has not been investigated. The results ofthis study provide several novel findings related to renal function inBK Ca - 1 knockout mice. In the euvolemic conditions ofthese experiments, no genotype-related differences were found inexcretion rates of inulin, Na  , or K  . Incontrast, with acute volume expansion, 1 knockout mice exhibited adepressed GFR and FE K response, and an increasedFE Na response, compared with M 1  / .Therefore, BK Ca, in conjunction with its 1 auxiliarysubunit, may be an important contributor to the maintenance ofelectrolyte balance during acute volume expansion.
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MAP. 1 Knockout mice, now studied by several groups of investigators,express moderate but significant hypertension. Brenner et al.( 2 ) have reported that M 1 / (C57BL/6strain) were hypertensive by ~20 mmHg. Using a different M 1 / model (129/SvJ strain), Plüger et al.( 24 ) reported that MAP was elevated by ~14 mmHg. Both ofthese measurements were made in conscious mice using arterialcatheters. In the anesthetized (C57BL/6) mice in the present study,M 1 / were hypertensive by ~11 mmHg under euvolemicconditions, whereas the MAP in M 1 / andM 1  /  was similar when the animals were volume expanded.
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Volume handling. Because the FITC-inulin method only requires 20 µl of plasma, we wereable to obtain accurate GFR measurements while avoiding the hypotensiveeffects of sampling blood. Hence, the values for GFR in this studycorrespond well with previously reported values ( 3, 17, 30 ).- G- H- a+ H+ y0 d
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Consistent with previous studies in rats ( 8 ) and mice( 3, 5 ), the GFRs in both M 1  /  andM 1 / were significantly higher in the volume-expandedgroups compared with the euvolemic groups. However, the GFR involume-expanded M 1 / was significantly less than thatin volume-expanded M 1  / . This was not related toperfusion pressure because the MAPs in M 1  /  andM 1 / did not differ during volume-expandedconditions. The failure of the GFR in M 1 / toappropriately respond to volume expansion implies that the 1-subunitof BK Ca has an important role in mediating the renal response to an increased volume load.9 G  w# |  q& N) G9 P. p
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The reason for the attenuated GFR response to volume expansion inM 1 / is not understood. However, a hemodynamic effectis likely because BK Ca are present in both renal afferentarterioles ( 4, 6 ) and glomerular mesangial cells( 25, 27, 28 ). In afferent renal arterioles,BK Ca play a relatively minor role in opposing constriction( 4 ), whereas in mesangial cells BK Ca are amajor component of the counteractive response to constriction( 28 ). In addition, the 1-subunit is present in humanmesangial cells (24a), which are phenotypicallysimilar to smooth muscle and express an abundance of BK Ca.When activated by ANP, BK Ca have a role in relaxingglomerular mesangial cells, which can contribute to an elevated GFR byincreasing the capillary surface area available for filtration( 12, 28 ). This notion is consistent with a recent findingin our laboratory that the 1-subunit is required for PKG activationof mesangial BK Ca ( 14 ). Therefore, anattenuated GFR response to volume expansion can be explained by theabsence of the 1, which renders the mesangial BK Ca lessresponsive to ANP.$ d$ t5 L/ q' J- T8 I

If the 1-subunit plays a role in promoting the vascular response toANP, M 1 / would be expected to exhibit acutehypertension with volume expansion. A recent study by Holtwick et al.( 9 ), using a mouse model with a smooth muscle-selectivedeletion of guanylyl cyclase, demonstrated that acute vascular volumeexpansion caused a rapid increase in the blood pressure of theseknockout mice. This hypertensive response would be expected if theresponse to ANP is attenuated; however, in this study we observed nosuch response in arterial pressure. The fact that arterial pressure inM 1 / was not influenced by volume expansion suggeststhat the 1-subunit does not have a role in the vascular response toANP. Whereas BK Ca may be the primary effector forcGMP-mediated relaxation of mesangial cells ( 28 ), vascularsmooth muscle may have a variety of additional cGMP-mediated responsesleading to relaxation ( 15 ).
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Alternatively, it is possible that the absence of the 1-subunitcauses the mesangial cells to be less responsive to either aCa 2  increase or stretch that occurs with volume expansion.Although BK Ca have been shown to be stretch activated insome cells ( 22, 29 ), the potential role of the 1-subunit in this process has not been investigated.. n$ ?& N8 P; b! ~: o- T

Na handling inM 1 /. Like the GFR, the U Na V was similar in M 1  /  and M 1 / under euvolemic conditions. However, evenunder volume-expanded conditions, the U Na V inM 1 / was not significantly different from that ofM 1  / . The fact that the GFR in volume-expandedM 1 / was attenuated whereas the U Na Vapproached a normal rate implies that changes in Na reabsorption account for the majority of the Na excretoryresponse to volume expansion in M 1 /. Indeed, theFE Na in M 1 / was significantly greaterthan that in M 1  / , indicating thatM 1 / were able to compensate for decreased filteredNa by reducing Na reabsorption. This isconsistent with previous studies showing that volume expansion causes adecrease in distal Na reabsorption in addition to itshemodynamic effects ( 13, 26 ).+ R$ n1 q, Z# h
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K handling inM 1 /. Consistent with previous studies ( 1, 3, 26 ), theU K V and FE K in wild-type mice weresubstantially greater in the volume-expanded condition. However, inM 1 /, the FE K was statistically the samein the euvolemic and volume-expanded groups. Similar toM 1  / , the U K V in M 1 / wassignificantly greater in the volume-expanded group compared with theeuvolemic group. However, in the volume-expanded condition, theU K V in M 1 / was significantly less thanthe U K V in M 1  / . Our experimental design(unpaired data) does not permit genotypic comparisons of the changes inU K V from baseline. Therefore, we cannot draw anyconclusions about relative increases from baseline. For example, therewas a genotypic difference in the volume-expanded but not euvolemicgroups with respect to U K V; however, because of the lowvalues and the baseline variability in U K V in the euvolemic groups, it is possible that there may be similar fold-increases in U K V with volume expansion in M 1  /  andM 1 / that were undetectable.% [% i9 S4 ^9 V, b* g3 X
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Our data imply that a diminished K secretory response tovolume expansion in M 1 / may reflect a role forBK Ca to promote K efflux from cells of thedistal nephron during high volume flow. In support of this notion, Wodaet al. ( 31 ) have recently shown that flow-mediatedK secretion in rabbit cortical collecting duct (CCD) ismediated by BK Ca. Moreover, Lu et al. ( 21 )provided evidence for an additional K secretory channel inthe CCD of ROMK (Kir1.1) knockout mice. BK Ca, described asstretch activated in the rat and rabbit CCD ( 22 ) as wellas the rabbit medullary thick ascending limb ( 29 ), may beactivated by high-volume-induced pressure on the cell membrane. Ourdata specifically implicate the 1-subunit of the BK Ca channel as an important component in the mediation of K secretion under conditions of volume expansion. However, it is notknown whether the 1-subunit, either alone or with other -subunits, is associated with the BK- in the CCD.6 Q/ z+ Q' q; J. i; {. c6 _
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An alternative explanation for the diminished K secretoryresponse to volume expansion in M 1 / is that thecompensatory reduction in Na reabsorption decreased thedriving force for K secretion. This would be true if thereduction in Na reabsorption resulted in a less negativemembrane potential in the CCD, where the predominant amount ofK is secreted. However, to our knowledge, there is noevidence that ANP (the major hormone responding to volume expansion)affects membrane potential or K secretion in the CCD. Astudy by Zeidel et al. ( 32 ) demonstrated that ANPinhibited potential-stimulated Na uptake in the innermedullary collecting duct (IMCD); however, little or no K secretion occurs in the IMCD. In addition, a study using ANP transgenic(overexpressing) mice demonstrated enhanced K excretion inresponse to volume expansion ( 5 ). Although it is possiblethat the diminished K secretory response inM 1 / is due to a decrease in Na reabsorption, for the reasons stated above, a primary defect inK secretion is the best explanation for this result.
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Effect of a high-salt diet. Although the high-salt diet did not significantly affect GFR or therates of Na and K excretion, it did tend toincrease Na excretion and decrease K excretion compared with the normal diet. This result is consistent withthe low aldosterone levels expected with a high-salt diet. The factthat M 1  /  and M 1 / had similarresponses to the high-salt diet indicates that the loss of theBK Ca - 1 does not alter the compensatory renal response. In addition, the finding that MAP in M 1 / was notincreased with the high-salt diet indicates that the hypertensiondescribed for M 1 / is not salt sensitive.
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In conclusion, this study demonstrates the importance of theBK Ca - 1 in the renal response to volume expansion.BK Ca - 1 may have a role in the glomerulus to mediate anelevated GFR during volume expansion and could potentially be importantin the distal nephron for the elevation of K secretionassociated with high flow rates. To more clearly define these roles,future studies must elucidate the specific pathway(s) involved in therenal responses to volume expansion and the specific expressionpatterns of the -subunits associated with BK Ca within the kidney.
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ACKNOWLEDGEMENTS

The authors thank Drs. Robert Brenner and Richard Aldrich (StanfordUniv.) for graciously supplying the BK Ca - 1 mice used inthis study. We also thank Drs. Tong Wang and Gerhard Giebisch (YaleUniv.) for advice and guidance regarding the surgical procedures foranalyzing renal function in mice.
      【参考文献】
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