(Hypertension. 1995;26:137-142.)
© 1995 American Heart Association, Inc.
Articles |
Effects of Furosemide and Verapamil on the NaCl Dependency of Macula Densa–Mediated Renin Secretion
From the Departments of Physiology and Internal Medicine, the University of Michigan, Ann Arbor.
Correspondence to Dr Jürgen Schnermann, University of Michigan, Department of Physiology, Medical Science Bldg II, No 7712, Ann Arbor, MI 48109.
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Abstract |
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Abstract The present studies in perfused specimens of the juxtaglomerular apparatus microdissected from rabbit kidneys were performed to quantitatively evaluate the relation between macula densa NaCl concentration and renin secretion and to study the effect of furosemide and verapamil on NaCl dependency of renin release. Renin secretion was found to decrease exponentially when macula densa NaCl concentration was increased from 26/7 mmol/L (Na/Cl) to 46/27, 66/47, and 86/67 mmol/L. Increasing Na/Cl concentrations from 86/67 to 106/87 mmol/L had no further effect on renin secretion. [Cl]1/2, the chloride concentration producing the half-maximal effect, was 30 mmol/L. Addition of 50 µmol/L furosemide to the luminal fluid caused renin secretion to become essentially independent of macula densa NaCl concentration. This effect was due to both an increase of renin secretion at high NaCl concentrations and a decrease of renin release at low NaCl concentrations. Verapamil added to the superfusate at a concentration of 1 µmol/L also abolished NaCl dependency of renin secretion; most of this effect was due to an increase of renin release at high luminal NaCl. These results suggest that Na-2Cl-K cotransport and calcium flux through voltage-gated channels are two mechanisms required for the expression of NaCl-dependent renin release. Identification of the cellular localizations of these two critical membrane proteins in the renin control pathway requires further study.
Key Words: kidney • juxtaglomerular apparatus • rabbit • calcium channels • glomerular mesangium
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Introduction |
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Using an isolated tubule preparation that included the juxtaglomerular apparatus (JGA), we demonstrated that renin secretion depends critically on luminal NaCl concentration.1 Increasing luminal NaCl concentration from about 25 to 80 mmol/L was noted to cause an approximately sixfold reduction in renin release.2 The addition of bumetanide to the high NaCl solution was followed by stimulation of renin secretion, suggesting that the communication pathway between macula densa (MD) and granular cells is dependent on NaCl transport.3
The present experiments were performed to further characterize MD-dependent renin secretion. Whereas our previous experiments showed that maximum inhibition of renin release was achieved in a limited concentration range,2 these studies did not resolve the profile of the NaCl dependency of renin secretion in the intermediate concentration range. In the present studies, we have developed a method that permits a stepwise increase or decrease in luminal NaCl concentration, enabling us to arrive at a more detailed identification of NaCl-dependent renin secretion.
Loop diuretics have been identified as potent inhibitors of tubuloglomerular feedback responses, the change in vasomotor tone caused by luminal NaCl concentration.4 5 Although we have seen that bumetanide did stimulate renin secretion in the presence of a high NaCl concentration,3 we were concerned that this effect was relatively modest and did not seem to be identical in magnitude to the stimulation caused by a low NaCl concentration. Therefore, in the present experiments, we have examined the effect of a loop diuretic on renin secretion over the entire NaCl concentration range.
Studies in kidney slices and in isolated juxtaglomerular cells showed that verapamil stimulates renin secretion, suggesting that calcium influx through voltage-activated calcium channels might mediate the inhibitory response to an increased luminal NaCl concentration.6 Involvement of calcium channels in MD-mediated responses is indicated by the finding that calcium channel blockers such as verapamil and nifedipine are potent inhibitors of the vascular response to changes in MD NaCl concentration.7 8 On the other hand, direct evidence that calcium influx through voltage-activated calcium channels plays a role in the renin release pathway controlled by MD is lacking. We therefore examined the effect of verapamil on the profile of NaCl-dependent renin secretion.
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Methods |
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Specimen Preparation and Perfusion
The experiments were performed on JGA specimens obtained from the kidneys of 47 female New Zealand White rabbits that weighed between 0.9 and 1.2 kg. Procedures used to harvest kidneys were in accordance with institutional guidelines as evaluated by the university's Committee on Use and Care of Animals. The specimens were dissected and perfused as previously described.2 3 9 In short, an individual JGA specimen, consisting of a short portion of the thick ascending limb of Henle (TAL), MD, and early distal convoluted tubule (DCT) with adherent glomerulus and short fragments of arterioles, was microdissected from the cortical portion of a medullary ray. The dissection medium was Dulbecco's modified Eagle's medium (DMEM, with Ham's nutrient mixture F-12; Sigma Chemical Co) containing 3% fetal calf serum (GIBCO Laboratories). Medium was aerated with 5% CO2–95% O2, and its pH was adjusted to 7.4 immediately before use. The dissected JGA specimens were transferred to a bath chamber mounted on an inverted microscope. The TAL was cannulated, and the distal end was left free. A few specimens were cannulated from the DCT and perfused in a retrograde manner. A superfusion pipette was advanced to cover the cannulated specimen.
As a major modification of the standard perfusion technique, the present studies used a method that allowed stepwise changes in perfusate NaCl concentration in the same specimen. Two perfusion solutions were made. The first solution contained (in mmol/L) NaHCO3 25, NaH2PO4 0.96, Na2HPO4 0.24, KCl 5, MgSO4 1.2, CaCl2 1, and glucose 5.5. In this solution, sodium and chloride concentrations were 26 and 7 mmol/L, respectively. The second solution was identical except that it contained an extra 80 mmol/L NaCl so that sodium and chloride were 106 and 87 mmol/L, respectively. The two different NaCl solutions were loaded into two syringes driven by two independent pumps (Razel Syringe Pump, Razel Scientific Instruments). The solutions flowing from the two syringes were mixed in a plastic capillary tube (see Fig 1) so that the NaCl concentration in the mixed solution was determined by the ratio of pump speeds. The mixing in this perfusion system was tested by loading one syringe with saline only and the other with saline and [3H]inulin. The ratio of flows from the two syringes was then changed from 9:1 to 1:9. Perfusate was collected at the tip of the superfusion pipette for 10 minutes at each step for measurement of [3H]inulin concentration. As Fig 1 shows, the observed values were close to the predicted values, indicating that the solutions from the two syringes were fully mixed. The luminal perfusion flow rate of the specimen was controlled by a hydraulic pressure head, which was constant during each experiment. The perfusion flow rate varied between 20 and 100 nL/min between different experiments. The specimens were superfused with DMEM containing 0.3% human serum albumin. Drugs were added to the superfusate by infusion upstream of the specimen through a pipette inserted through the opening of the superfusion cannula. The superfusion flow was controlled by two extra pumps at a final rate of 2 µL/min.
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The droplet of superfusate, including the perfusate, that had passed through the JGA specimen was collected at 10-minute intervals and frozen for later renin assay. During the experiment, the specimen was maintained at 38°C.
Experimental Protocols
Series 1
To test the relation between MD NaCl concentration and renin
secretion rate, the specimens were perfused with a solution in which
the concentration of Na/Cl was increased stepwise from 26/7 over 46/27,
66/47, and 86/67 mmol/L to 106/87 mmol/L. Thus, NaCl concentration was
raised by 20 mmol/L at each step change. The mixture of the perfusate
and the superfusate was collected for 10 minutes to measure renin
secretion rate.
Series 2
In these studies, each specimen was perfused twice with a
perfusate in which NaCl concentration was increased stepwise as
described above. In either the first or the second period,
5x10-5 mol/L furosemide (American Reagent Laboratories)
was present in the perfusion solution in both pumps.
Series 3
The specimens in this series also were perfused with perfusates
containing increasing concentrations of NaCl. During either the first
or the second period, 10-6 mol/L verapamil
(American Reagent Laboratories) was added to the superfusate to test
the effect of calcium channel blockade on NaCl-induced renin
secretion.
Analytical and Statistical Methods
Renin concentration in the collected droplets was measured by
radioimmunoassay of generated angiotensin I with the
antibody-trapping technique.10 Renin activity is expressed
in standard Goldblatt hog units (GU) by comparison with standard renin
obtained from the Institute for Medical Research (MRC, Holly Hill). In
agreement with earlier studies, renin secretion rate among individual
specimens was found to vary over three orders of
magnitude.1 2 3 Statistical analysis was therefore
performed on log-transformed data. The paired t test was
used to assess statistically significant differences, with a value of
P<.05 considered significant. Average values are given both
as log mean±SEM and arithmetic mean±SEM.
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Results |
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Series 1
Analysis of the NaCl dependency of renin secretion was performed in 27 specimens; Fig 2 shows the results. As Fig 2A shows, luminal perfusion with solutions in which Na/Cl concentration increased from 26/7 to 46/27, 66/47, 86/67, and 106/87 mmol/L caused a nonlinear decrease of renin secretion rate from 347.2±112.6 to 162.8±44.6 (P<.05), 68.1±22.3 (P<.02), 47.1±19.1 (P<.02), and 38.2±16.6 (P<.01) nGU/10 min, respectively. About half the total response occurred when Na/Cl concentration was increased from 26/7 to 46/27 mmol/L. Only a small decrease in renin secretion was found above a concentration of 66/47 mmol/L. Fig 2B shows the log-transformed data. The linearity down to a concentration of 86/67 mmol/L in a semilog plot indicates an exponential decrease of renin secretion rate with increasing Na/Cl concentrations over this concentration range (r2=.994). No further reduction in renin secretion was observed when Na/Cl concentration exceeded 86/67 mmol/L.
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Series 2
Fig 3 shows data from the experimental series in
which we tested the effect of luminal furosemide at 50 µmol/L on the
NaCl dependency of renin secretion. Control data of this series were
similar to those of series 1. Again, renin secretion rate decreased
exponentially when MD Na/Cl concentration was increased over the
concentration range from 27/7 to 86/67 mmol/L. Application of
furosemide in the perfusate was found to block the renin secretory
response induced by changing MD NaCl concentration. None of the values
was significantly different from renin secretion at the lowest Na/Cl
concentration (Table). Furthermore, the slope of the
log linear function without furosemide (-0.0170±0.0037) was
significantly steeper than that with furosemide (-0.0024±0.0026,
P<.01; Fig 3). As Fig 3 and the Table also show, loss of
NaCl dependency in the presence of furosemide resulted from both a
decrease of renin secretion at low Na/Cl concentrations and an increase
at high Na/Cl concentrations.
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Series 3
In this experimental series, we examined the effect of 1 µmol/L
verapamil in the superfusate on NaCl-dependent renin
secretion. Fig 4 and the Table show the results.
Verapamil was found to markedly attenuate MD NaCl
concentration–induced renin secretion (Table). The slope of the log
linear function of MD NaCl–induced renin secretion in control
(-0.0200±0.0032) was significantly steeper than during
verapamil application (-0.0043±0.0058;
P<.05). This reduction in slope resulted primarily from an
increased renin secretion at high Na/Cl concentrations.
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Discussion |
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Changes in NaCl concentration in the MD segment of the nephron and NaCl-dependent transport changes act as one of the major physiological variables controlling renin secretion.11 Considerable evidence indicates that renin secretion is inversely related to changes in MD NaCl concentration and transport.11 A previous study from this laboratory made a first attempt to quantify this relation by showing that renin secretion responds to a change in NaCl concentration in a range below 80 mmol/L chloride.2 Using a modified perfusion method, we have now been able to further resolve the NaCl dependency of renin secretion. The present results demonstrate that the decrease of renin secretion in response to an increase in MD chloride concentration between 7 and 80 mmol/L followed an exponential curve. The concentration of chloride associated with the half-maximal decrease of renin secretion was about 30 mmol/L. This half-maximal concentration is remarkably similar to that previously identified for the NaCl dependency of the tubuloglomerular feedback response.4 The implications of this finding for the physiological role of the MD system for the control of renin secretion are not clear. Previous data showed that in the rat, the NaCl concentration causing half-maximal tubuloglomerular feedback responses corresponds closely to the concentration normally existing in the MD segment.4 Thus, both increases and decreases in NaCl concentration were predicted to initiate a vascular response. Unfortunately, reliable data on NaCl concentration in MD segments of rabbits are not available. Na/Cl concentration in the DCT in studies by Wong et al12 13 was found to be about 58/60.5 mmol/L. If this concentration is assumed to reflect MD concentrations under resting conditions, the operating point of MD-mediated renin release, in contrast to that of the tubuloglomerular feedback response, may not be located in the most sensitive region of the feedback curve. This finding would suggest that MD-mediated renin release may be more responsive to decrements than to increments in NaCl concentration and could explain why the renin stimulatory response to conditions such as hypotension, hemorrhage, and dehydration appears to be more powerful than renin inhibition after hypertension and volume expansion.
Results from studies in intact animals led Vander11 to suggest that the signal initiating changes in MD-dependent renin secretion is a change in NaCl transport rather than a change in NaCl concentration per se. In a previous study using the isolated JGA preparation, we found that bumetanide, an inhibitor of the Na-2Cl-K cotransporter, stimulated renin release suppressed by high NaCl concentrations when the drug was added to the perfusate but not the bath.3 Furthermore, Itoh and Carretero14 showed that furosemide stimulated renin release in isolated perfused afferent arterioles only when the MD was included in the specimen. The present finding that luminal application of 5x10-5 mol/L furosemide greatly attenuated the inhibition of renin secretion caused by increasing MD NaCl concentrations is fully consistent with the earlier evidence that Na-2Cl-K cotransport is a necessary step in MD-mediated renin release. This concept was strengthened by strong functional evidence in support of the expression of some isoform of the Na-2Cl-K cotransporter in MD cells.15 16
Lorenz et al3 previously noted that bumetanide added to the high NaCl solution caused an approximately threefold increase of renin secretion, whereas a decrease in NaCl concentration in this preparation is associated with an increase of renin secretion by a factor of about 6.2 3 Thus, blockade of transport by bumetanide appeared to be a less powerful stimulator of renin release than a decrease in NaCl concentration. The present data confirm this observation: furosemide in the presence of high NaCl concentrations caused an approximately threefold increase in renin secretion, whereas a reduction in NaCl concentration increased renin secretion by a factor of about 10. In fact, when furosemide was added to the low NaCl concentration, it inhibited rather than stimulated renin secretion. Because it is unlikely that furosemide stimulates NaCl transport in the presence of a low NaCl concentration, it appears that furosemide exerts an effect that is independent of its blockade of the luminal Na-2Cl-K cotransporter. Further studies are needed to clarify the mechanism of this MD transport–unrelated effect of furosemide and to identify the cells involved in it. It is of note that furosemide-sensitive transporters are present on both mesangial and vascular smooth muscle cells, so it is feasible that the effect seen at low luminal NaCl concentrations is mediated by an interaction of furosemide with cells in the JGA other than MD cells.17 18 19 It is also of note that furosemide in the present studies does not appear to fully mimic its in vivo effects. As Fig 3 shows, renin secretion rates at NaCl concentrations that may be considered normal in vivo were not different from those at the elevated levels caused by the presence of furosemide. One explanation may be that, under in vivo conditions, renin release is under other influences in addition to MD NaCl concentration and that these factors exert a suppressing effect that is not seen in the isolated preparation. For example, the arterioles in the isolated preparation are not perfused. Thus, differences in arteriolar wall tension and/or the release of endothelial factors may be responsible for lower renin secretory rates at normal NaCl concentrations in vivo than in vitro. It is conceivable that because of lower baseline renin secretions, the stimulatory effect of furosemide is more easily detectable in vivo. Another difference is that in vivo furosemide is present in the vessel lumen, the interstitium, and tubular fluid, whereas it is present only in tubular fluid in our preparation. If furosemide had other effects, eg, direct vascular effects, these could contribute to the stimulatory effect in vivo.
There is substantial support for the notion that a change in [Ca2+]o is a common response of the effector cells controlled by the MD signals.20 21 Intracellular calcium is directly related to smooth muscle tension, and calcium influx through voltage-activated calcium channels is an important mechanism in the activation of afferent arteriolar vascular smooth muscle cells.22 23 That calcium channel blockers such as verapamil and nifedipine are effective blockers of MD-initiated vasoconstriction is consistent with this notion.7 8 Similarly, there is convincing evidence that renin secretion from granular cells is inversely related to intracellular calcium.6 21 Furthermore, studies in kidney slices suggest that an increased calcium flux through voltage-activated calcium channels makes an important contribution to the inhibition of renin secretion caused, for example, by potassium depolarization.24 25 The attenuation of the renin inhibitory effect of increasing MD NaCl concentrations by verapamil in the present study is compatible with the possibility that an increase in MD NaCl concentration causes an increase of cytosolic calcium not only in vascular smooth muscle cells but also in granular cells and that this increase is at least in part the result of an activation of voltage-dependent calcium channels. The cause of this change in granular cell calcium permeability under physiological conditions is not known with certainty but could be related to the NaCl-dependent generation of adenosine or other local mediators with membrane-depolarizing actions.26 This interpretation would have to be reevaluated if recent evidence confirms that granular cells do not express voltage-activated calcium channels.27 28 29
Some experimental evidence supports the concept that adenosine participates in the transmission mechanism of NaCl-dependent renin secretion.26 30 In the context of this theory, it is pertinent to recall that both in vivo and in a kidney slice preparation, verapamil has been found to be without effect on the renin inhibitory action of exogenous adenosine.31 32 The verapamil inhibitability of NaCl-dependent renin secretion in the current studies suggests that adenosine is not a major participant in MD-regulated renin release but that increases in luminal NaCl induce the release of other locally active agents that affect renin release by a mechanism that includes a verapamil-blockable component. Alternatively, it is possible that adenosine generated by MD cells interacts with granular cells indirectly through participation of an intermediary cell and that this indirect interaction is verapamil-sensitive.
In summary, the present experiments demonstrate an inverse exponential relation between renin secretion and MD NaCl concentration in an Na/Cl concentration range between 26/7 and 86/67 mmol/L. [Cl]1/2, the chloride concentration at which the change in renin secretion was half-maximal, was 30 mmol/L. Both furosemide and verapamil greatly attenuated the dependency of renin secretion on MD NaCl concentration, suggesting that in addition to an operative Na-2Cl-K cotransporter, voltage-activated calcium channels are necessary constituents of MD control of renin release. Identification of the cellular localizations of these two critical membrane proteins in this mechanism requires further study.
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Acknowledgments |
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Dr Greenberg is the recipient of Individual National Research Service Award DK-08579. Work performed in this laboratory is funded by National Institutes of Health grants DK-37448, DK-39255, and DK-40042. We wish to thank Ann Smart for expert technical assistance in the renin microassay.
Received November 21, 1994; first decision December 15, 1994; accepted April 13, 1995.
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References |
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