(Hypertension. 1997;30:1175-1182.)
© 1997 American Heart Association, Inc.
Articles |
Interactions Between Nitric Oxide and Angiotensin II on Renal Cortical and Papillary Blood Flow
From the Departamento de Fisiología y Farmacología (M.I.M., M.G.-S., J.T., F.J.R.), Facultad de Medicina, 30100-Murcia, Spain, and Novartis Ltd (M. de G.), CH-4002 Basel, Switzerland.
Correspondence to Francisco J. Fenoy, Departamento de Fisiología y Farmacología, Facultad de Medicina, 30100-Murcia, Spain. E-mail fjfenoy{at}fcu.um.es
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Abstract |
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Abstract This study examined the role of angiotensin II (Ang II) on the effects of nitric oxide (NO) synthesis blockade on renal cortical and papillary blood flow in innervated and denervated kidneys of volume-expanded Munich-Wistar rats with hormonal influences on the kidney that were held constant by intravenous infusion. Cortical (CBF) and papillary (PBF) blood flow were measured by laser-Doppler flowmetry. A low dose of N
-nitro-L-arginine methyl ester
(L-NAME, 3.7 nmol ·
kg-1 · min-1)
reduced CBF only in innervated kidneys, and this effect was
abolished by subsequent administration of valsartan (an AT1
antagonist). L-NAME 3.7 nmol ·
kg-1 · min-1
improved PBF autoregulation by lowering PBF to the range of 100 to
140 mm Hg of perfusion pressure, and this effect was attenuated
or abolished by valsartan in innervated and denervated
kidneys, respectively. These results indicate that the cortical and
medullary vasoconstriction induced by a low dose of L-NAME are caused
by potentiation of the vasoconstrictor influence of renal sympathetic
nerves and Ang II. A higher dose of L-NAME (37 nmol ·
kg-1 · min-1)
lowered CBF and PBF in both innervated and denervated
kidneys. This effect of L-NAME on the cortical circulation was
abolished by valsartan, but this AT1 antagonist
had no effect on the medullary vasoconstriction produced by NO
synthesis blockade. Therefore, a higher dose of L-NAME induces a renal
cortical vasoconstriction through potentiation of the
renin-angiotensin system, whereas the fall of PBF seen
after L-NAME 37 nmol · kg-1 ·
min-1 seems to be caused primarily by NO
suppression. This Ang II potentiation produced by L-NAME in the renal
cortex seems to be mediated by AT1 receptors, because it
was unaffected by PD123319 (an AT2 antagonist).
The results of the present study indicate that NO is an important
modulator of the vasoconstrictor influence of Ang II in the renal
cortical circulation of the rat. However, although there are some
interactions between NO and renal nerves and Ang II on the medullary
circulation, the renal medullary vasoconstriction produced by L-NAME
appears to be caused primarily by NO suppression, with little influence
of the renal vasoconstrictor systems.
Key Words: nitric oxide • kidney • renal hemodynamics • laser-Doppler flowmetry
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Nitric oxide is a humoral factor tonically secreted within the kidney, and there is increasing evidence indicating that NO is one of the most important systems controlling renal function.1 Administration of L-NAME blocks NO synthesis and lowers renal blood flow dramatically and also reduces sodium and water excretion,1 2 without affecting autoregulation of total renal blood flow and glomerular filtration rate.3 4
The changes in renal function observed after NO synthesis blockade are due, at least in part, to the fact that physiologically NO buffers the influence of endogenous vasoconstrictor systems in the kidney. Vasoconstriction may increase shear stress and NO production, which then acts as a regulation system by restraint of the constrictor action of a variety of hormones. Angiotensin AT1 receptor blockade prevents most of the acute renal hemodynamic effects of L-NAME,6 7 and it also blunts L-NAME–induced hypertension.8 9 In addition, NO potentiation by the infusion of L-arginine increases renal blood flow and reduces renal sympathetic nerve activity,10 whereas acute NO synthesis blockade produces renal vasoconstriction and increases renal sympathetic outflow.10 11 Also, it has been reported that hypertension induced by chronic NO synthesis blockade may be mediated partially by increased sympathetic tone.12 13
In the past few years, considerable advances have been made in our understanding of the role of the renal medulla in the control of sodium excretion in normal conditions and hypertension.16 Although CBF and glomerular filtration change very little within a broad range of RPPs, PBF is not autoregulated in volume-expanded rats, and it has been hypothesized that as arterial pressure rises, medullary blood flow, vasa recta capillary pressure, and renal interstitial pressure increase, leading to a fall in tubular sodium reabsorption.17 This mechanism of control of sodium excretion is believed to be nonadaptative and responsible for the long-term control of arterial pressure.16 According to this hypothesis, arterial pressure is dependent on the mechanisms that regulate the renal medullary circulation, many of which are not understood completely.
NO appears to be one of the key factors linking PBF to changes in sodium excretion and arterial pressure. A variety of studies have shown that NO synthesis blockade blunts sodium and water excretion,1 3 4 5 14 and this is associated with renal medullary vasoconstriction.14 15 The administration of an NO synthesis inhibitor reduces PBF only at high RPPs, thus improving the efficiency of medullary autoregulation.14 This led to the hypothesis that increases in NO synthesis as blood pressure rises may be responsible for the absence of PBF autoregulation. These observations are consistent with the fact that chronic administration of L-NAME lowers PBF18 and produces sustained sodium-dependent arterial hypertension.18 19 20 21 22 23 At present, however, little is known about the factors that regulate renal medullary circulation. In particular, the interactions among NO and the renal vasoconstrictor systems are well known in the renal cortex, but no data are available about the role of Ang II and renal nerves on the response to NO synthesis inhibition in renal medullary vessels.
The purpose of the present study was to evaluate the effect of AT1 and AT2 angiotensin receptor blockade on L-NAME–induced changes in cortical and PBF. In the preparation used in this study, neural influences on the kidney were held constant by renal denervation and maintenance of fixed high plasma levels of norepinephrine by intravenous infusion.24 However, it has been reported that fractional reabsorption of sodium is lower in this model when renal nerves are intact,24 indicating that there is some residual sympathetic tone. Therefore, to exclude any interaction between renal nerves and Ang II and NO, the role of angiotensin on the renal vascular effects of L-NAME was examined in both innervated and denervated kidneys.
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Methods |
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Experiments were performed on 39 Munich-Wistar rats (200 to 250 g) purchased from Harlan Laboratories (Madison, Wisc) and bred in our animal care facility. All procedures followed were in accordance with the recommendations from the Declaration of Helsinki and the guiding principles in the care and use of animals approved by the Council of the American Physiological Society. The rats were anesthetized with an intramuscular injection of ketamine (30 mg/kg) and an intraperitoneal injection of Inactin (thiobutabarbital, 50 mg/kg IP) and placed on a heated table to maintain body temperature at 36.5°C. Cannulas were placed in the femoral vein for infusions and in the femoral artery for measurement of arterial pressure. An aortic clamp was placed above the left renal artery, and ties were placed loosely around the mesenteric and celiac arteries so that RPP could be manipulated by the adjustment of peripheral resistance, as described previously.24 Plasma levels of norepinephrine, aldosterone, cortisol, and vasopressin were maintained at fixed levels throughout the experiment by continuous intravenous infusion of norepinephrine (333 ng · kg-1 · min-1), aldosterone (66 ng · kg-1 · min-1), cortisol (33 mg · kg-1 · min-1), and vasopressin (0.17 ng · kg-1 · min-1). With the exception of group 7, rats received an intravenous infusion of a 0.9% sodium chloride solution that contained all hormones indicated above and 1% BSA at a rate of 2 mL · 100 g-1 · h–1 throughout the experiment. The group 7 rats received the same infusion solution but with no hormones added.
The left kidney was placed with the dorsal side up in a holder positioned above the abdominal aorta. The papilla was exposed with a longitudinal incision made in the ureter from the tip to the base of the papilla. PBF (arbitrary units) was measured with a dual-channel, Pf3d laser-Doppler flowmeter (Perimed) with a fiberoptic probe (Pf 316) placed 1 mm from the tip of the papilla. CBF (arbitrary units) was measured by placement of the probe at three random locations on the dorsal surface of the kidney; the mean flow signal from these areas was reported.14 The laser-Doppler flowmeter was calibrated with a colloidal suspension of latex particles; the brownian motion of these particles (at standard temperature, 22°C) is used as a "motility standard." The probe was placed in the suspension, and the gain of the instrument was adjusted to obtain a flow signal of 250 units (±5%). The same calibration was used for CBF and PBF measurements.
Autoregulation was evaluated by the calculation of an index (AI) as follows: AI=1-{[(Fi-F)/FI]/[(Pi-P)/PI]}, where F is flow at pressure P and Fi and Pi are initial flow and pressure, respectively. Values near 1 indicate complete autoregulation.26
Experimental Protocols
After surgery and a 1-hour equilibration period, the relations
between CBF, PBF, and RPP were determined during three consecutive
periods.
Control period. RPP was first increased by 
25
mm Hg by occlusion of the mesenteric and celiac arteries.
Approximately 5 minutes later, RPP was lowered to 60 mm Hg by
tightening of the clamp on the aorta. Ten minutes later, the
laser-Doppler flow signals obtained from the renal cortex and the
papilla were recorded as the RPP was increased in steps of 20
mm Hg and 5 minutes of duration.
Experimental period. In this period, either L-NAME (groups 1 and 2, 3.7 nmol · kg-1 · min-1, n=5; groups 3, 4, 6, and 7, 37 nmol · kg-1 · min-1, n=5), valsartan (an AT1 antagonist, group 5, 92 µmol/kg, n=5), or saline (group 8, n=4) was administered intravenously. After a 30-minute equilibration period, the relationships between CBF, PBF, and RPP were again determined.
Second experimental period. In this period either valsartan (92 µmol/kg, groups 1, 2, 3, 4, and 7), L-NAME (37 nmol · kg-1 · min-1, group 5), PD123319 (an AT2 antagonist, 98 nmol · kg-1 · min-1,25 group 6), or saline (group 8) was added to the infusion solution, and 30 minutes later, the relationships between CBF, PBF, and RPP were redetermined.
The doses of L-NAME used in the present study were chosen because it has been previously shown that the low dose affects only the medullary circulation, whereas the high dose produces cortical and medullary vasoconstriction.14 The dose of valsartan used was enough to abolish the arterial pressure and renal blood flow responses to a 100-ng bolus of Ang II (+44±3 versus 0 mm Hg and -4.6±0.5 versus 0 mL/min, respectively). The kidneys were denervated in groups 2, 4, 5, and 6.
Statistical Methods
Data are presented as mean±SEM. The significance of
differences in the measured values between groups was analyzed
with a two-way ANOVA followed by a Fisher's least significant
difference (protected t test).26 A value of
P<.05 (two-tailed test) was considered statistically
significant.
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Results |
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The effects of a low dose of L-NAME (3.7 nmol · kg-1 · min-1) in innervated (group 1) and denervated (group 2) kidneys on CBF and PBF are presented in Figs 1
and 2,
respectively. L-NAME (3.7 nmol ·
kg-1 · min-1)
reduced CBF slightly in innervated kidneys only (group 1,
Fig 1), and this effect was abolished by subsequent administration of
valsartan. However, this low dose of L-NAME similarly reduced PBF in
groups 1 and 2 by 25% at 140 mm Hg of perfusion pressure.
This papillary vasoconstriction after L-NAME (3.7 nmol ·
kg-1 · min-1)
was abolished by the administration of valsartan in denervated kidneys
(group 2, Fig 2) and only reduced in innervated kidneys
(group 1, Fig 1). CBF was autoregulated in group 1 and 2 rats, and the
cortical AI was unaffected by treatment with L-NAME or valsartan (Figs 1 and 2, top right). However, control PBF was poorly autoregulated in
both groups. In innervated kidneys (group 1, Fig 1, bottom
right), NO synthesis inhibition with L-NAME (3.7 nmol ·
kg-1 · min-1)
increased the medullary AI in the range of 60 to 140 mm Hg of
RPP, and this effect was reduced by subsequent administration of
valsartan. In contrast, L-NAME improved papillary autoregulation in
denervated kidneys only at high RPP (120 to 140 mm Hg, group 2,
Fig 2, bottom right), and subsequent administration of valsartan
reversed this effect of L-NAME, lowering the medullary AI to near
control values. The changes in mean arterial pressure
observed in rats of groups 1 and 2 are presented in the
Table. L-NAME (3.7 nmol ·
kg-1 · min-1)
increased mean arterial pressure by 8% and 6% in groups 1
and 2, respectively (Table, period 2). Subsequent administration of
valsartan reversed this hypertensive effect (Table, period 3).
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The effect of a higher dose of L-NAME (37 nmol ·
kg-1 · min-1)
in innervated (group 3) and denervated (group 4) kidneys on
CBF and PBF is presented in Figs 3 and 4,
respectively. L-NAME 37 nmol ·
kg-1 · min-1
reduced CBF by 12% in innervated and denervated
kidneys, and this cortical vasoconstriction was abolished by the
subsequent administration of valsartan. This high dose of
L-NAME reduced PBF at all pressures studied in innervated
kidneys, but it lowered PBF only at high RPP (100 to 140 mm Hg)
in denervated kidneys. Valsartan had no effect on the PBF responses
seen after L-NAME 37 nmol · kg-1
· min-1 in rats of groups 3 and 4. CBF was
well autoregulated in rats of groups 3 and 4, and treatments with
L-NAME or valsartan had no effect on the cortical AI (Figs 3 and 4, top
right). In contrast, PBF was not autoregulated in control conditions
(AI <0.5) in both groups. In groups 3 and 4, L-NAME 37 nmol ·
kg-1 · min-1
significantly increased the papillary AI at all RPPs studied, and this
was unaffected by the succeeding administration of valsartan (Figs 3 and 4, bottom right). The effect of L-NAME 37 nmol ·
kg-1 · min-1
and valsartan on arterial pressure in groups 3 and 4 was
similar and is presented in the Table
. L-NAME 37 nmol ·
kg-1 · min-1
increased mean arterial pressure by 12% and 15% in groups
3 and 4, respectively (Table, period 2); this increase in
arterial pressure was abolished by subsequent
administration of valsartan (Table, period 3, groups 3 and 4).
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The effect of valsartan in CBF and PBF of denervated kidneys is shown
in Fig 5 (group 5). Valsartan increased
CBF slightly at low RPP, but it had no effect on PBF. Subsequent
administration of L-NAME 37 nmol ·
kg-1 · min-1
to group 5 rats had no effect on CBF, but it lowered PBF at 120 to
140 mm Hg of RPP in valsartan-pretreated rats. Valsartan had no
significant effects on arterial pressure (Table, group 5,
period 2); however, subsequent infusion of L-NAME 37 nmol ·
kg-1 · min-1 produced a
significant increase in arterial pressure of approximately
9% (Table, group 5, period 3)
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The effect of PD123319 (AT2 antagonist, 98
nmol · kg-1 ·
min-1) on the L-NAME–induced changes in CBF
and PBF of denervated kidneys is presented in Fig 6 (group 6). L-NAME 37 nmol ·
kg-1 · min-1
lowered CBF and PBF; subsequent administration of PD123319 had
no effect on those L-NAME–induced changes. PD123319 had no effect
on arterial pressure in L-NAME–pretreated rats
(Table, group 6, period 3).
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The effect of L-NAME 37 nmol ·
kg-1 · min-1
and valsartan on CBF and PBF in rats with no hormones added to the
infusion solution is presented in the Fig 7. Because sympathetic tone was not
clamped by the administration of norepinephrine,
arterial pressure did not increase after the occlusion of
the mesenteric and celiac arteries (probably caused by the buffering of
baroreflexes), and the range of RPP studied was 60 to 120 mm Hg.
CBF decreased after the infusion of L-NAME, and subsequent
administration of valsartan restored it to near control values. PBF
decreased at all RPPs studied after L-NAME, and subsequent valsartan
had no further effect on PBF.
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A time-control group is presented in Fig 8. The relationships between CBF and PBF
and RPP were not affected during the span of the experiment.
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Discussion |
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Previous studies have shown that blockade of NO reduces renal blood flow and sodium and water excretion.1 2 3 4 5 This effect seems to be due, at least in part, to the potentiation of the renal vasoconstrictor systems.6 7 10 11 In addition, this potentiation of the renin-angiotensin and sympathetic systems seems to be an important factor in the pathogenesis of hypertension induced by chronic NO synthesis blockade.8 9 12 13 The renal medulla plays an important role in sodium and water homeostasis and in long-term control of arterial pressure.16 However, at present no data are available about the interactions between NO and the renal vasoconstrictor systems in the control of renal medullary blood flow.
An extensive sympathetic innervation of the efferent arteriolar vessels of the juxtamedullary glomeruli, which eventually divide to form the afferent vasa recta, has been described.29 However, at present, its functional importance remains obscure. It has been reported that NO synthesis blockade lowers PBF at high RPPs only, restoring PBF autoregulation.14 In the present study, the relationship between PBF and RPP is not affected by renal denervation. This is not surprising, because in this model, plasma levels of norepinephrine are maintained at high levels by intravenous infusion, and endogenous sympathetic tone should be low. This may also explain why the presence or absence of renal nerves has no effect on the PBF response to L-NAME.
The role of the renin-angiotensin system in the control of the renal medullary circulation remains controversial. PBF has been reported to increase (measured by laser-Doppler flowmetry30 ), decrease (measured by the albumin accumulation technique31 ), or remain unaltered (measured by videomicroscopy32 ) during the infusion of Ang II in rats. These differences may be related to the different techniques used to measure blood flow in the renal medulla. Although it has been shown that the administration of captopril increases PBF,32 33 this effect seems to be caused by increased levels of kinins instead of the suppression of Ang II because it is abolished by kinin receptor blockade.33 This point of view is compatible with the cortical vasodilatation that the administration of losartan produced, but it had no effect on PBF in euvolemic rats.33 Taken together, these studies indicate that Ang II is not an important factor in the control of medullary blood flow. In the present study, the administration of a low dose of L-NAME (3.7 nmol · kg-1 · min-1) lowered PBF at high RPPs in innervated or denervated kidneys. However, subsequent treatment with valsartan restored PBF to near control values only in denervated kidneys; in innervated kidneys, AT1 receptor blockade failed to abolish the effects of L-NAME on PBF. This indicates that there is some residual endogenous renal sympathetic tone in this preparation and also that there are some interactions among NO, renin- angiotensin, and sympathetic systems modulating the relationship between arterial pressure and PBF.
The renal medullary circulation is a pressure-dependent vascular bed that is not able to autoregulate blood flow with changes in RPP in volume-expanded rats.14 16 It has been hypothesized that the lack of PBF autoregulation is the key phenomenon that couples the rise in arterial pressure with increases in renal interstitial pressure and sodium excretion. This pressure-dependent vascular bed has been implicated in long-term control of arterial pressure.16 There is evidence that indicates the lack of medullary blood flow autoregulation may be caused by increased NO synthesis,14 which probably originated by elevations of endothelial shear stress as blood pressure rises. This is in accord with data from the present study, showing that NO synthesis inhibition causes an improvement in PBF autoregulation. This effect of L-NAME can cause hypertension, as shown by Nakanishi et al,18 who demonstrated that during chronic L-NAME–induced hypertension, sodium retention is associated with renal medullary vasoconstriction, with no changes in renal CBF. In the present study, a low dose of L-NAME (3.7 nmol · kg-1 · min-1) improved PBF autoregulation in all groups of rats, but this effect was more pronounced in innervated kidneys. This effect of L-NAME improving PBF autoregulation is abolished by subsequent administration of valsartan only in denervated kidneys. These results indicate that, although denervation or AT1 receptor blockade alone does not affect the relation between arterial pressure and PBF, renal nerves and Ang II have a slight tonic influence on the renal medullary vessels that is detectable only when NO synthesis is inhibited. In this regard, Romero et al36 postulated that at low RPP, the low flow and shear stress should reduce NO production, and this might contribute to the increase in renin secretion; at high RPP, shear stress and NO increase within the kidney, inhibiting renin secretion. Therefore, the reduction in PBF observed with the low dose of L-NAME at high RPP (which reverts with valsartan) may be due, at least in part, to the lack of inhibition of NO on renin release.
A higher dose of L-NAME (37 nmol · kg-1 · min-1) increased the papillary AI and lowered PBF between 100 and 140 mm Hg of RPP, and these effects were unaffected by renal denervation. In addition, subsequent administration of valsartan or PD123319 to L-NAME–treated rats had no further effects on PBF. Also, valsartan alone had no effect on PBF when administered to a different group of untreated rats, and subsequent administration of this high dose of L-NAME after valsartan lowered PBF, demonstrating that a higher dose of L-NAME overrides any other influence and produces an important renal medullary vasoconstriction. It has recently been reported that NOS activity is approximately 10 times higher in the renal medulla than in the renal cortex and other organs34 ; therefore, NO should be expected to be a dominant factor in the control of PBF. In addition, it has been reported by Mattson et al35 that only endothelial NOS is present in the renal cortex, whereas three isoforms of NOS (endothelial, neuronal, and inducible) exist in the renal medulla. An alternative explanation for the different effects of a low versus a high dose of L-NAME on PBF may be that L-NAME may not inhibit the three isoforms with equal potency, and as the dose of L-NAME increases, more isoforms of NOS may be blocked. On the other hand, it appears that Ang II is not an important factor in the control of renal medullary circulation in this preparation.
In the present study, a low dose of L-NAME (3.7 nmol · kg-1 · min-1) lowered CBF only in innervated kidneys, without affecting renal cortical autoregulation. This is in agreement with previous studies showing NO synthesis blockade increases renal sympathetic nerve activity.10 11 This low dose of L-NAME reduces CBF at low RPP in innervated kidneys probably because the tonic effect of renal nerves is more evident during the autoregulatory vasodilation in the renal cortex. However, a higher dose of L-NAME (37 nmol · kg-1 · min-1) lowered CBF in both innervated and denervated kidneys. This may be due to the low endogenous sympathetic tone in norepinephrine-infused rats, as discussed above. In any case, it seems clear that basal NO generation within the kidney is an important factor regulating renal perfusion. However, subsequent blockade of AT1 receptors with valsartan in L-NAME–treated rats increased CBF near control values, regardless of the dose of L-NAME used. These results are in accord with those of other authors who have found that AT1 receptor blockade reduced6 or even abolished7 the renal vasoconstriction that follows the administration of L-NAME. On the other hand, AT2 receptor blockade with PD123319 had no effect on the cortical vasoconstriction induced by L-NAME. It is known that subtype 2 of angiotensin receptors are sparse in the adult rat kidney.28 Although AT2 antagonists seem to affect renal function in angiotensin-infused rats to some extent, the meaning of these changes is still unclear.25 28
The administration of valsartan to untreated rats increased CBF slightly at low RPP, indicating that renin secretion is not totally suppressed in this volume- expanded preparation. Similar results were obtained in a previous study after the administration of losartan to euvolemic rats.33 In the original description of this experimental model, Roman and Cowley24 reported that plasma renin activity was 2.7±0.4 ng Ang I · mL-1 · h-1, very similar to the values measured in conscious rats. Because the effect of valsartan on CBF is observed only at low RPP, this may indicate that renin secretion increases as RPP is reduced. In addition, the infusion of L-NAME into these valsartan-pretreated rats had no effect on CBF. Thus, the presence of an intact renin- angiotensin system appears to be a very important factor for the full expression of the renal cortical vascular effects of NO synthesis blockade, suggesting that NO is normally buffering the vasoconstrictor effects of the renin-angiotensin system in the kidney cortex.
The experimental model used in the present study was described originally by Roman and Cowley,24 who characterized the acute relation between sodium and water excretion and RPP, while the hormonal influences on the kidney were maintained constant by intravenous infusion of vasopressin, aldosterone, cortisol, and norepinephrine. To evaluate the effect of these hormones on the renal hemodynamic responses to NO or angiotensin inhibition, a study was performed with a group of rats (group 7) with no hormones added to the infusion solution. It was found that the effects of L-NAME and valsartan in these rats were essentially the same as in rats with hormonal influences on the kidney clamped by intravenous infusion; therefore, it appears that this model is useful to study hormonal interactions with renal hemodynamics. One of the problems caused by the absence of hormones in the infusion solution is the difficulty in raising and holding constant arterial pressure by the manipulation of peripheral resistances, since sympathetic outflow is not clamped by norepinephrine infusion and baroreflexes efficaciously buffer the occlusion of mesenteric and celiac arteries.
In conclusion, the results of the present study indicate that renal CBF is modulated by interactions between NO and Ang II. However, although there are some interactions between NO and renal nerves and Ang II on the medullary circulation, renal PBF appears to be regulated primarily by NO, with little influence of the renal vasoconstrictor systems.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by a grant from the Fondo de Investigaciones Sanitarias de la Seguridad Social (FIS 94/0798) and by a grant from the Comisión Interministerial de Ciencia y Tecnología (PB94-1131).
Received December 13, 1996; first decision January 17, 1997; accepted April 15, 1997.
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