1 Oklahoma State University College of Osteopathic Medicine, Tulsa, Oklahoma 74107; and 2 Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil 01246
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ABSTRACT |
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PGE2 inhibits osmotic water
permeability (Pf) in the rat inner medullary
collecting duct (IMCD) via cellular events occurring after the
stimulation of cAMP, i.e., post-cAMP-dependent events. The
2-agonists also inhibit Pf in the
rat IMCD via post-cAMP-dependent events. The purpose of this study was
to determine whether PGE2 plays a role in
2-mediated inhibition of Pf,
Na+, and urea transport in the rat IMCD. Isolated terminal
IMCDs from Wistar rats were perfused to measure, in separate
experiments, Pf, lumen-to-bath
22Na+ transport (Jlb),
and urea permeability (Pu). Transport was
stimulated with 220 pM arginine vasopressin (AVP) or 0.1 mM
8-(4-chlorophenylthio)-cAMP (CPT-cAMP). Indomethacin was used to
inhibit endogenous prostaglandin synthesis, and the
2-agonists clonidine, oxymetazoline, and dexmedetomidine were used to test the role of PGE2 in the
2-mediated mechanism that inhibits transport. All agents
were added to the bath. Indomethacin at 5 µM significantly elevated
CPT-cAMP-stimulated Pf,
Jlb, and Pu, and
subsequent addition of 100 nM PGE2 reduced these transport parameters. Indomethacin reversed
2 inhibition of
CPT-cAMP-stimulated Pf,
Jlb, and Pu, and
subsequent addition of PGE2 reduced transport in each case.
Indomethacin partially reversed
2 inhibition of AVP-stimulated Pf, Jlb,
and Pu, and PGE2 reduced transport
back to the
2-inhibited level. These results indicate
that PGE2 is a second messenger involved in the mechanism
of transport inhibition mediated by
2-adrenoceptors via
post-cAMP-dependent events in the rat IMCD.
signaling pathways; second messengers; inner medullary collecting
duct; 2-adrenoceptor; osmotic water permeability
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INTRODUCTION |
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SALT, WATER,
AND UREA TRANSPORT in the inner medullary collecting duct (IMCD)
play an important role in the renal regulation of salt and water
excretion. Arginine vasopressin (AVP) stimulates these transport
properties enhancing absorption in the IMCD, and 2-agonists inhibit AVP-dependent transport
(20, 29). This inhibitory mechanism has been
associated with
2-adrenoceptors coupling to an
inhibitory G (Gi) protein that decreases adenylyl cyclase
activity, reducing cellular levels of cAMP (8,
11, 20, 34, 36).
Evidence indicates that this inhibitory mechanism occurs in the
presence of constant cellular cAMP levels. When water transport in
collecting duct nephron segments is stimulated by nonhydrolyzable analogs of cAMP in lieu of AVP, 2-agonists still produce
significant inhibition (12, 29). The
mechanism therefore appears to be more complex than just reducing
adenylyl cyclase activity and must involve other second messengers.
PGE2 has been studied extensively as a potential regulator of renal salt and water excretion and has been shown to affect these transport properties in the collecting duct (2, 14, 15). Nadler et al. (22) reported that PGE2 reduced osmotic water permeability (Pf) stimulated by a nonhydrolyzable cAMP analog in the rat IMCD, indicating that PGE2 inhibits Pf via post-cAMP-dependent events, and inhibition of protein kinase C (PKC) by staurosporine prevented the PGE2-induced inhibition. They also reported that PGE2 increased intracellular calcium concentration ([Ca2+]i) levels. These findings suggest a role for the phospholipase C metabolites in controlling water permeability.
Because both 2-agonists and PGE2 inhibit
water permeability via post-cAMP-dependent events in the IMCD, we
hypothesized that the
2-inhibitory mechanism involves
PGE2 as a second messenger. The purpose of the present
study was to test this hypothesis on water, Na+, and urea
transport in the isolated rat IMCD. Results indicate that
PGE2 indeed plays a role in the
2-inhibitory
mechanism of these transport processes in the IMCD. The specific action
of PGE2 in this mechanism remains to be determined.
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MATERIALS AND METHODS |
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IMCD segments were isolated and perfused by techniques previously described (4, 26, 28). Wistar rats weighing 120-125 g and fed a standard chow (184 meq Na/kg ) were killed by decapitation, and the kidneys were rapidly removed and cut into small slices that were placed in chilled dissection solution of the same composition as the bathing solution or bath described below. IMCD segments were dissected and isolated from the terminal two-thirds of the inner medulla, i.e., the terminal IMCD (19, 30).
After isolation, the IMCD was transferred to a perfusion chamber on the stage of an inverted microscope and mounted on concentric pipettes that suspended the tubule in the bath. One end of the tubule was drawn by suction into the tip of one of the outer pipettes. The tip of the inner pipette containing the luminal perfusion solution, or perfusate, was advanced into the lumen of the tubule, and perfusion was initiated via air pressure.
The opposite end of the tubule was held in the tip of another glass micropipette where the perfusate accumulated. The tip of this pipette was coated with a viscous silicone liquid (Sylgard 184, Dow Corning) to isolate the perfusate from the bath. Samples of collected perfusate were taken periodically during an experiment with a constant-volume or volumetric pipette. The bath composition was as follows (in mM): 115 NaCl, 25 NaHCO3, 10 sodium acetate, 5 KCl, 1.0 CaCl2, 1.2 MgSO4, 1.2 NaH2PO4, and 5.5 glucose, pH = 7.4. The solution was continuously bubbled with 95% O2-5% CO2. All experiments were conducted at 37°C.
Pf was determined by measuring net fluid flux
(Jv) in the presence of a lumen-to-bath osmotic
gradient (80-90 to 295-300 mosmol/kgH2O). The
perfusion solution was made hypotonic to the bath by reducing NaCl
concentration to 50 mM, and rapid perfusion rates of 20-30 nl/min
were used to avoid osmotic equilibrium. [14C]inulin at
50-100 counts/min (cpm)/nl in the luminal perfusate was used as
the volume marker. Perfusion rate (Vi) was
calculated as Vi = Vo(INo/INi), where
INi and INo are the inulin cpm per nanoliter in
the initial luminal perfusate and collected fluid, respectively, and
Vo is the collection rate.
Vo was determined directly by measuring the time
to fill the volumetric pipette, and Jv (nl
· mm1 · min
1) was then calculated
as Jv = (Vi
Vo)/l, where l is the
tubule length measured with an eyepiece micrometer. Three timed fluid samples were collected in each experimental period. The
Pf of each collection was calculated with
established methods and equations (1), and the reported
Pf for a given experimental period represents the average of the three determinations.
Lumen-to-bath 22Na+ transport
(Jlb) was determined by measuring the
disappearance rate of 22Na+ from the
lumen. Perfusion and bath solutions were identical, and the composition
was the same as the bath solution noted above. Three timed fluid
samples were collected in each experimental period, and the reported
Jlb for a given experimental period represents the average of the three determinations. Jlb
(peq · cm2 · s1) was calculated
as
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Pu was determined from the disappearance rate of
[14C]urea (50-100 cpm/nl) from the luminal
perfusate. As in the Jlb experiments, perfusion
and bath solutions were identical. Because there was no net fluid
absorption, Pu was calculated with the following equation
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Experimental protocols. Once the IMCD was mounted on concentric pipettes, perfusion was initiated and the bath temperature was raised to 37°C in 10-15 min. After an equilibration period of 30-35 min, the sampling procedure for the control period began. After three collections were taken, 220 pM AVP or 0.1 mM 8-(4-chlorophenylthio)-cAMP (CPT-cAMP) was added to the bath, followed by 15-20 min of equilibration and the sampling procedure. Other agents were added in subsequent experimental periods, followed by equilibration and the sampling procedure. The sequence of a given protocol is shown on the abscissa of Figs. 1-4 and described in their legends.
TheSource of biochemicals. AVP, CPT-cAMP, oxymetazoline, and epinephrine were purchased from Sigma Chemical (St. Louis, MO). Clonidine and dexmedetomidine were kindly provided by Boehringer Ingelheim (Ridgefield, CT), and by Dr. Riku Aantaa, Chief of Research, Orion-Farmos Pharmaceutical, Turku, Finland, respectively. [14C]inulin was purchased from New England Nuclear (Boston, MA).
Statistical analysis. Data were analyzed with a single-factor ANOVA with repeated measures, and P values between treatments were determined by using the SuperAnova statistical package. P < 0.05 was considered significant.
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RESULTS |
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Table 1 summarizes data showing that
indomethacin increased CPT-cAMP-stimulated Pf,
Jlb, and Pu and that
subsequent addition of PGE2 reversibly decreased each form
of transport.
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Figure 1 shows that
clonidine, oxymetazoline, and dexmedetomidine inhibited
CPT-cAMP-stimulated Pf by 25, 22, and 82%,
respectively. In each protocol, addition of indomethacin increased
Pf, and subsequent addition of PGE2
lowered Pf back to the
2-inhibited level in the clonidine and oxymetazoline
protocols. In the dexmedetomidine protocol, PGE2 reduced
Pf significantly, although not completely back
to the
2-inhibited level.
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Figure 2A shows that
PGE2 prevented the indomethacin-induced increase in
Pf reported in Table 1 and that the PKC
inhibitor staurosporine failed to affect Pf with
indomethacin and PGE2 in the bath. In another protocol,
staurosporine slightly although significantly increased
Pf with indomethacin, PGE2, and the
2-agonist dexmedetomidine in the bath (Fig.
2B).
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Figure 3 shows that clonidine,
oxymetazoline, and dexmedetomidine inhibited CPT-cAMP-stimulated
Jlb by 54, 56, and 77%, respectively. In each
protocol indomethacin reversed the inhibition, and subsequent addition
of PGE2 lowered Jlb back to the
2-inhibited level.
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Figure 4 shows that epinephrine at 100 nM
and 1 µM (A and B, respectively) inhibited
CPT-cAMP-stimulated Pu. In both protocols, indomethacin significantly increased Pu and
subsequent addition of PGE2 lowered
Pu. Clonidine and oxymetazoline slightly
inhibited CPT-cAMP-stimulated Pu, as shown in
Table 2.
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Table 3 summarizes data of the effect of
PGE2 on 2-mediated inhibition of
AVP-stimulated Pf, Jlb,
and Pu. The experimental protocol in these
studies was the same as that in Figs. 1, 3, and 4, except that AVP not
CPT-cAMP was used to stimulate transport. Clonidine and oxymetazoline
inhibited AVP-stimulated Pf, and indomethacin reversed the inhibition by 51 and 25%, respectively. Subsequent addition of PGE2 lowered Pf back to
the
2-inhibited level in both protocols. Clonidine and
oxymetazoline inhibited AVP-stimulated Jlb, and
indomethacin reversed inhibition by 54 and 65%, respectively. Subsequent addition of PGE2 reduced
Jlb back to the
2-inhibited level
in both protocols. Clonidine inhibited AVP-stimulated
Pu by 27%. Indomethacin reversed this
inhibition by 52%, and subsequent addition of PGE2 lowered
Pu back to the clonidine-inhibited level. The
same trend occurred with oxymetazoline, but statistical significance was not achieved.
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DISCUSSION |
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PGE2 modulates transport in the collecting duct by affecting multiple cellular signaling pathways [see review by Hébert (13)]. With regard to this modulation, it is important to note species differences, segmental differences along the collecting duct, and experimental conditions. Sonnenburg and Smith (31) reported that in purified rabbit CCD cells PGE2 elevated basal cAMP content and reduced AVP-stimulated cAMP accumulation; however, PGE2 failed to affect AVP-stimulated cAMP in cultured cells. Using different techniques, Noland et al. (23) demonstrated that PGE2 can inhibit AVP-induced cAMP accumulation in cultured rabbit CCD cells. Chabardès et al. (5) reported that PGE2 reduced AVP-stimulated cAMP in dissected rabbit CCDs but not in rat CCDs, and Chen et al. (6) provided transport data consistent with these findings in that PGE2 inhibited AVP-stimulated Pf and Jlb in the rabbit but not rat CCD.
Although PGE2 modulates transport in the rabbit but not the rat CCD and the effect appears to be related to PGE2 regulation of cAMP, PGE2 plays a role in the rat IMCD by an apparent cAMP-independent mechanism. Maeda et al. (20) reported that PGE2 did not affect cAMP content in the rat IMCD with or without AVP. Nadler et al. (22) reported that 100 nM PGE2 reversibly inhibited CPT-cAMP-stimulated Pf in the isolated rat IMCD by ~40%, and the PKC inhibitor staurosporine prevented this inhibition. They concluded that in the rat IMCD PGE2 inhibits Pf via post-cAMP-dependent events that involve PKC.
Evidence regarding the effects of 2-agonists on
transport in the collecting duct also requires close attention to the
species studied. Chen et al. (6) reported that the
2-agonist clonidine inhibited AVP-stimulated
Pf and Jlb in the rat but
not the rabbit CCD. Chabardès et al. (5) reported
that clonidine reduced AVP-stimulated cAMP accumulation in the rat but
not the rabbit CCD. Maeda et al. (20) demonstrated
2-inhibition of both AVP-stimulated cAMP accumulation
and AVP-stimulated Pu in the rat IMCD. Edwards et al. (9) reported that
2-agonists
inhibited AVP-stimulated cAMP accumulation in rat but not in dog, pig,
monkey, or human IMCD.
The classic mechanistic explanation related to
2-adrenoceptors is that they couple to Gi
proteins and inhibit adenylyl cyclase activity (8,
11, 25). However, evidence indicates that
2 inhibition of AVP-stimulated transport in the IMCD
occurs via post-cAMP-dependent events. We reported that the
2-agonists dexmedetomidine, clonidine, and oxymetazoline
reduced CPT-cAMP-stimulated Pf in the rat IMCD
(17, 29). These findings indicate that the
2-inhibitory mechanism in the IMCD involves unidentified
second messengers. Because both PGE2 and
2-agonists inhibit AVP-stimulated
Pf via post-cAMP-dependent events, we
hypothesized that PGE2 is one of those messengers
associated with
2-induced inhibition.
To examine this hypothesis, we tested the ability of the cyclooxygenase
inhibitor indomethacin to reverse 2-inhibition of AVP-
and CPT-cAMP-stimulated Pf,
Jlb, and Pu in the
isolated rat IMCD. In addition, exogenous PGE2 was added to
determine whether it would decrease the indomethacin-induced reversal
of
2-inhibition. We used the
2-agonists
dexmedetomidine, clonidine, and oxymetazoline, which inhibit
AVP-stimulated Pf with dose-dependent profiles
(17, 29). Dexmedetomidine is nonselective
with respect to the
2-subtypes (
2A,
2B, and
2C) (24), clonidine
is selective to both
2- and imidazoline receptors
(3, 10) and appears to bind to
2B-adrenoceptors in the collecting duct
(16, 36), and oxymetazoline is selective to
the
2A-adrenoceptor (35). We used these
agonists because we knew of their inhibitory capability, and, because
they demonstrate different pharmacological binding characteristics, there could be distinguishing characteristics with regard to cellular signaling.
We tested the effects of indomethacin and PGE2 on CPT-cAMP-stimulated Pf, Jlb, and Pu. Table 1 summarizes these data. Indomethacin increased CPT-cAMP-stimulated transport in all three protocols, and subsequent addition of PGE2 reversibly reduced the transport properties. These results expand on the findings of Nadler et al. (22) and demonstrate that endogenous PGE2 plays a role in regulating water, sodium, and urea transport via post-cAMP-dependent events.
Figure 1 contains results from three separate protocols showing that
indomethacin reversed 2-induced inhibition caused by clonidine, oxymetazoline, and dexmedetomidine (Fig. 1, A,
B, and C, respectively) of CPT-cAMP-stimulated
Pf. PGE2 added in the final period
reduced Pf back to the
2-inhibited level in (Fig. 1, A and
B but not in C) although PGE2 still
significantly reduced Pf. These results indicate
a role for PGE2 in
2-mediated inhibition of
Pf.
In the Pf experiments we tested the effect of
the PKC inhibitor staurosporine. Figure 2A shows that
PGE2 added to the bath with indomethacin did not affect
CPT-cAMP-stimulated Pf. PGE2 prevented the indomethacin-induced increase in CPT-cAMP-stimulated Pf (see Table 1). Subsequent addition of 10 nM
staurosporine, the same concentration shown to block
PGE2-induced inhibition of CPT-cAMP-stimulated
Pf reported by Nadler et al., did not affect Pf. Figure 2B, however, shows that
dexmedetomidine added with indomethacin and PGE2 reduced
CPT-cAMP-stimulated Pf by 60% and the addition
of staurosporine reversibly increased Pf by
22%. This suggests a role for PKC in the 2-mediated
inhibition of Pf.
The three 2-agonists inhibited CPT-cAMP-stimulated
Jlb (Fig. 3, A, B, and
C). In all three cases, indomethacin reversed
2-inhibition and the subsequent addition of
PGE2 reduced Jlb back to the
2-inhibited level. Dexmedetomidine inhibited
Jlb (77%) more than clonidine (56%) or
oxymetazoline (56%). PGE2 accounted for the major portion of the clonidine- and oxymetazoline-induced inhibition (70 and 79%,
respectively), whereas it accounted for only 42% in the
dexmedetomidine-induced inhibition. Rocha and Koda (27)
reported that PGE2 did not affect bath-to-lumen
Na+ flux.
In the Pu experiments we used the nonselective adrenergic agonist epinephrine because of our earlier study, which showed that dexmedetomidine is not an effective Pu inhibitor (29). Indomethacin reversed epinephrine-induced inhibition of CPT-cAMP-stimulated Pu, and PGE2 reduced this effect (Fig. 4). These results demonstrate that urea transport can be inhibited via post-cAMP-dependent events and PGE2 plays a role in modulating urea transport. Further data summarized in Table 2 show that clonidine and oxymetazoline significantly lowered CPT-cAMP-stimulated Pu. Indomethacin and PGE2 produced small effects that were significant in the oxymetazoline but not the clonidine experiments.
In addition to our results on CPT-cAMP-stimulated transport, we also
tested the effect of PGE2 on 2-mediated
inhibition of AVP-stimulated Pf,
Jlb, and Pu. These
results are summarized in Table 3. Indomethacin reversed clonidine- and
oxymetazoline-induced inhibition of AVP-stimulated
Pf, and PGE2 reduced
Pf back to the
2-inhibited level.
The same pattern was observed with clonidine- and oxymetazoline-induced
inhibition of AVP-stimulated Jlb. Indomethacin reversed clonidine-induced inhibition of AVP-stimulated
Pu, and PGE2 reduced
Pu back to the clonidine-inhibited level.
Oxymetazoline did not reduce AVP-stimulated Pu
with statistical significance. Again, results with
2-mediated inhibition of Pu are
not as consistent as with Pf and
Jlb, but it still appears that
2-adrenoceptors are involved in the modulation of
AVP-stimulated Pu.
Reversal of 2-induced inhibition of transport by
indomethacin was observed regardless of the method of transport
stimulation (AVP or CPT-cAMP) and of the
2-agonist used.
No major distinguishing differences between clonidine- and
oxymetazoline-induced inhibition were observed other than clonidine
inhibited AVP-stimulated Pu whereas those
results with oxymetazoline failed to produce statistical significance
(Table 3). One observation worth noting is that indomethacin partially
reversed clonidine- and oxymetazoline-induced inhibition of
AVP-stimulated Pf and
Jlb; i.e., the AVP period was significantly
higher than the AVP+
2-agonist+indomethacin period
whereas it completely reversed clonidine- and oxymetazoline-induced inhibition of CPT-cAMP-stimulated Pf and
Jlb and the CPT-cAMP period was not
significantly different from the
CPT-cAMP+
2-agonist+indomethacin period. Endogenous
production of cAMP via AVP likely provided a more effective transport
stimulus that indomethacin at 5 µM did not block completely. AVP
increases [Ca2+]i levels in the rat IMCD
(32); thus it is also possible
[Ca2+]i plays a role in
2-inhibitory mechanism. We did not measure [Ca2+]i levels, but a zero-calcium bath did
not reduce
2-mediated inhibition of AVP-stimulated
Pf in the rat IMCD (results not shown). We are
unaware of any results with regard to the effect of
2-agonists on phosphoinositide hydrolysis in the
collecting duct; however,
2-adrenoceptors have been
shown to activate multiple signal transduction pathways, including
those associated with arachidonic acid and the phosphoinositide system
(7, 18, 21, 33).
Indomethacin partially reversed dexmedetomidine-induced inhibition of
CPT-cAMP-stimulated Pf and
Jlb (Figs. 1C and 3C).
Dexmedetomidine, which as stated earlier is nonselective for the
2-adrenoceptor subtypes, produces greater inhibition of
AVP-stimulated transport than either clonidine or oxymetazoline. This
could be due to higher potency, efficacy, or both. Evidence has been
conflicting as to which
2-adrenoceptor subtypes exist in
the IMCD. Some results demonstrate the
2B over the
2A whereas other results suggest the opposite
(34, 36). Our results could suggest that
multiple adrenoceptors are responsible for the higher inhibition
produced by dexmedetomidine. Because PGE2 accounts for a
smaller portion of the inhibition produced by dexmedetomidine compared
with clonidine and oxymetazoline, other second messengers could be
involved in dexmedetomidine-induced inhibition. Future studies are
required to determine these other messengers as well as
2-adrenoceptor subtypes.
Finally, it is recognized that indomethacin can influence other
cellular events besides cyclooxygenase inhibition, and thus it is
conceivable that another indomethacin-induced event occurred in our
experiments. We used indomethacin because it has been the most commonly
used agent in these kinds of experiments. In addition to indomethacin
we have tested naproxen and ketorolac, two other potent inhibitors of
cyclooxygenase, on dexmedetomidine-induced inhibition of
CPT-cAMP-stimulated Pf by using the same
protocol as in Fig. 1C (i.e., replacing indomethacin with
naproxen or ketorolac). Both agents reversed 2-mediated
inhibition to the same degree as indomethacin, and subsequent addition
of PGE2 significantly reduced Pf
(these data are not shown). Thus we think it is unlikely that
endogenous prostaglandins were not the major cellular messengers being
affected in this study.
In summary, results of this study indicate that
2-adrenoceptors in the rat IMCD play a role in
regulating water, sodium, and urea transport via a cellular mechanism
that involves post-cAMP dependent events, which involve, among other
second messengers, PGE2. PKC appears to be involved as
well. This mechanism could involve multiple
2-adrenoceptors and signaling pathways.
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ACKNOWLEDGEMENTS |
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This study was supported by National Science Foundation Career Award IBN-9507444 and CNPq-grant 303259 from Brazil (L. H. Kudo). Portions of this study have been published previously in abstract form (FASEB J 13: A728, 1999).
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FOOTNOTES |
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Address for reprint requests and other correspondence: A. J. Rouch, Oklahoma State Univ. College of Osteopathic Medicine, 1111 W. 17th St., Tulsa, OK 74107 (E-mail: rouch{at}osu-com.okstate.edu).
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.
Received 28 September 1999; accepted in final form 16 March 2000.
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