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Primate Research Institute, Kyoto University (S.O.), Aichi 484-8506, Japan; Laboratory of Veterinary Reproduction, Tokyo University of Agriculture and Technology (T.T.), Tokyo 183-0054, Japan; Reproductive Sciences Program (S.N., D.C.B., D.L.F.) and Departments of Physiology (D.C.B.), Obstetrics and Gynecology (D.L.F.), and Biology (D.L.F.), University of Michigan, Ann Arbor, Michigan 48109-0404; and Graduate School of Bioagricultural Sciences, Nagoya University (H.T., K.-I.M.), Nagoya 464-8601, Japan
Address all correspondence and requests for reprints to: Dr. Douglas L. Foster, Reproductive Sciences Program, University of Michigan, Ann Arbor, Michigan 48109-0404. E-mail address: dlfoster{at}umich.edu
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Introduction |
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Studies in several species have reported that reproductive activity is influenced by the availability of metabolic fuels (for review, see Ref. 16). Among those metabolic fuels, glucose plays an important role as a metabolic regulator of reproductive function. There are several lines of evidence showing that insulin-induced hypoglycemia decreases pulsatile LH secretion in rats (17, 18) and monkeys (19) as well as decreases hypothalamic multiple unit activity in monkeys (20). Pharmacological glucoprivation with 2-deoxy-D-glucose (2DG), an antimetabolic glucose analog that competitively inhibits intracellular glucose oxidation (21), interrupts estrous cyclicity in Syrian hamsters (22). Moreover, iv injection of 2DG immediately suppresses pulsatile LH secretion in rats (23). These data support the hypothesis that changes in glucose availability control reproductive function by regulating GnRH/LH release. The sheep, our experimental model, is a ruminant species in which little glucose is absorbed from the digestive tract, and plasma glucose concentrations are normally only about half those in nonruminant species. Nevertheless, ruminants have an important glucostatic mechanism that can influence reproductive neuroendocrine activity, because insulin-induced hypoglycemia in the sheep suppresses LH pulse frequency (24, 25). Of equal interest is that the replacement of insulin peripherally (26) or centrally (27) in diabetic sheep increases LH pulse frequency. Finally, 2DG administration can suppress LH secretion (28, 29).
To better understand the metabolic regulation of GnRH secretion, we need to learn which anatomical sites monitor glucose availability. Bucholtz et al. (28) found that intracerebroventricular injection of 2DG depresses pulsatile LH secretion in milk-fed, monogastric lambs, suggesting that glucose availability is detected by a central glucose-sensing mechanism. Other investigations have led to the hypothesis that an important glucose-sensing mechanism for the regulation of GnRH secretion is located in the caudal brain stem. 2DG infusion targeted to the fourth cerebral ventricle of the rat suppressed the frequency of LH pulses (30). Moreover, glucoprivic inhibition of estrous cyclicity by 2DG was abolished in the Syrian hamster when the area postrema, a circumventricular organ within the fourth ventricle, was lesioned (31).
In view of the focus on central glucose sensors, the possibility of a peripheral glucose-sensing mechanism for GnRH/LH secretion has not been thoroughly investigated. The potential existence of a peripheral glucose-sensing site has been raised by our earlier study in the rat, which found that the suppression of LH secretion by short-term fasting, during which hypoglycemia takes place, could be reversed by subdiaphragmatic vagotomy (32). Moreover, studies of ingestive behavior have revealed that peripheral afferent neural input into the brain is important and that a hepatic glucose sensor is involved in appetite control. In the rat, glucose infusion into the hepatic portal vein decreases food intake, but this does not occur when glucose is similarly infused into the jugular vein (33). In the rabbit, local infusion of 2DG into the hepatic portal circulation induces feeding behavior (34). Moreover, stimulation of feeding by a fructose analog (2,5-anhydro-D-mannitol) that does not cross the blood-brain barrier and that blocks glycogenolysis and gluconeogenesis is dependent upon the vagus nerves (35). Thus, for the regulation of feeding behavior, glucose-sensing mechanisms in the liver may monitor peripheral glucose availability and convey this information to the brain via the vagus nerve.
The present study determined the relative importance of putative central and peripheral glucose-sensing areas in the regulation of pulsatile LH secretion in the sheep. Our approach was to monitor pulsatile LH secretion before and after local administration of 2DG into either the hepatic portal vein or the fourth cerebral ventricle.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Blood samples (2.5 ml) were collected at 10-min intervals for 8 h through indwelling jugular catheters (16 gauge; Angiocath, Becton Dickinson and Co., Mountain View, CA). Samples were placed into tubes containing 20 IU heparin and 5 mg sodium fluoride (preservative for glucose assay). After centrifugation, plasma was separated and stored at -20 C until assayed for LH, cortisol, insulin, glucose, and 2DG.
All experimental procedures were approved by the university committee for the Use and Care of Animals at the University of Michigan.
Experimental design
Exp 1: peripheral infusion of 2DG. This experiment
determined whether putative glucose-sensing mechanisms in the liver
mediate glucoprivic suppression of LH secretion in sheep. Our approach
was to compare the efficacy of 2DG infusion to suppress LH secretion
when administered locally to the liver with that when it was
administered systemically via a jugular vein. The cecal end of the
ileocolic vein was implanted with a silicon catheter (id, 1.02 mm; od,
2.16 mm; Dow Corning Corp., Auburn, MI; n = 5 sheep;
55–62 kg BW). The catheter was inserted for 10-cm so that its tip was
placed close to the hepatic portal system and was secured to the
surrounding omentum with nylon suture. The distal end of the catheter
was passed through the incision in the abdominal wall and was run sc to
the flank region, where it was exteriorized through a small incision.
The catheters were placed in a pocket made of adhesive tape and cloth
bandage, and they were maintained by daily flushing of heparinized
saline (100 IU/ml).
For full recovery of the animals, at least 10 days were allowed to elapse after the surgery before frequent blood sampling was conducted. Four hours after the beginning of a blood collection, a 25% (wt/vol) solution of 2DG (Sigma, St. Louis, MO) was infused into the hepatic portal vein for 2 h through the catheter with a peristaltic pump (Gilson, Villiers-le-Bel, France). The rate of infusion was 500 or 100 µl/min; each infusion was performed on a different experimental day. The amounts of 2DG infused were equivalent to 250 and 50 mg/kg, respectively. The higher dose (250 mg/kg) of 2DG was comparable to an effective amount that we administered peripherally as a single injection in our earlier study (28). The lower dose (50 mg/kg) was one that could have a local action, as judged from the efficacy of even lower doses to suppress LH secretion when administered centrally as a single injection (28) (also see Exp 2 below). This dose is comparable to one that was ineffective when given systemically as a single injection in our previous study (28). In the present study only the higher control dose of 2DG (250 mg/kg) was infused for 2 h through a catheter into the jugular vein contralateral to that containing the catheter used for blood collection. As an isoosmotic control, a comparable concentration of xylose (250 mg/kg; Sigma), a nonusable sugar, was infused into the hepatic portal vein for 2 h instead of 2DG. There was at least a 3-day interval between each treatment.
At the end of all treatments, the sheep were infused under general anesthesia with 50 ml 3% brilliant blue solution into the hepatic portal vein through the catheter, and they were then given an overdose of barbiturates (Beuthanasia, Schering-Plough Corp., Madison, NJ) by iv injection. The liver was removed and examined for the extent of staining to evaluate the placement of the hepatic portal catheter.
Exp 2: central infusion of 2DG. This experiment determined whether putative glucose-sensing mechanisms in the fourth ventricle mediate the glucoprivic suppression of LH secretion in sheep. Our approach was to compare the efficacy of the same dose of 2DG to suppress LH secretion when administered to the fourth ventricle (n = 5 sheep) or the lateral ventricle (n = 6 sheep). We focused on the fourth ventricle because a glucose-sensing mechanism may be located in the caudal brain stem based on lesion work in the hamster (30); our previous work in the rat had determined that LH secretion was suppressed by administration of 2DG to the fourth ventricle (30). We used the lateral ventricle because our previous work in the sheep had determined that administration of 2DG as a single injection to this site effectively suppressed LH secretion (28). Ovariectomized sheep (54–83 kg) were stereotaxically implanted under general anesthesia with a stainless-steel guide cannula (18 gauge) aimed toward either the fourth ventricle or the lateral ventricle.
For guide cannula placement directed toward the fourth ventricle, we
first determined in a pilot study using other sheep the location of the
fourth ventricle with radioventriculographic monitoring (see Fig. 1
for a representative animal). The
sheep’s head was placed into a stereotaxic instrument (David Kopf
Instruments, Tujunga, CA) such that upon frontal view an imaginary line
drawn horizontally between the eyes was level. A sterilized 21-gauge
needle was lowered into the lateral ventricle 7 mm rostral and 5 mm
lateral to bregma until the saline in a length of Tygon tubing attached
to the needle emptied out from the tubing. X-Ray contrast medium (0.6
ml Omnipaque 240, Daiichi Pharmaceutical Company Ltd.,
Tokyo, Japan) was slowly injected through a 1-ml tuberculin syringe,
and a lateral radiograph was taken. On the x-ray film, which clearly
indicated the brain ventricular system including fourth ventricle, we
selected two landmarks on the skull: the chiasmatic sulcus and the
squamous part of the occipital bone (Fig. 1). A straight line was drawn
between the frontal edge of chiasmatic sulcus (p) and dorsal
edge of squamous part of the occipital bone (q) on the x-ray
film, and the fourth ventricle was located at a distance
0.65d from p on the line, where d was
the distance between p and q (Fig. 1). Using this
determination, the accurate placement of the outer guide cannula toward
the fourth ventricle could be calculated on the x-ray films without
radioopaque material injection during fourth ventricular cannulation.
Before cannula insertion into the brain, the 22-gauge inner cannula was
fitted into the guide cannula, and the entire assembly with an
inclination of 45° from the coronal plane was lowered into the target
region to a depth at which the gravity feed of saline occurred; this
indicated that the fluid had entered into fourth ventricle.
Confirmatory x-rays were taken, and then the outer cannula was secured
to the skull with stainless-steel screws and dental acrylic. A
protective plastic ring was placed around the guide cannula and fixed
in position using dental acrylic.
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Blood samples were collected 1 week or more after brain surgery. Four hours after the initiation of sampling, a 25% (wt/vol) solution of 2DG was infused with a peristaltic pump at a rate of 50 µl/min for 30 min into either the fourth ventricle or lateral ventricle through a 22-gauge inner cannula introduced through the outer guide cannula. The amount of 2DG infused into the ventricular system was equivalent to 5 mg/kg, a dose comparable to that we administered as a single injection into the lateral ventricle in our earlier study (28). As a control, physiological saline was infused into the fourth ventricle in the same manner; this treatment was conducted in the same animals, but on a different day.
After the final blood sample collection, all ewes were anesthetized with sodium pentobarbital and infused with 200 µl 3% brilliant blue solution into the cerebroventricular system through the cannula. They were killed to check the placement of the ventricular cannula.
Assays
The LH content in each plasma sample was measured in duplicate
50-µl determinations with a modified RIA developed by Niswender
et al. (36). Assay sensitivity averaged 0.67
ng/ml (n = 9 assays) for 200-µl plasma expressed relative to NIH
LH-S12. The intraassay coefficient of variation (CV), determined from a
serum pool that bound at 50% averaged 3.6%; the interassay CV
averaged 4.8%. For a serum pool that bound at 20%, the intraassay CV
averaged 5.0%, and the interassay CV averaged 8.7%.
Plasma cortisol concentrations were quantified in duplicate 25-µl aliquots of unextracted plasma with a solid phase RIA kit (Coat-A-Count Cortisol, Diagnostic Products Corp., Los Angeles, CA) that had been validated for use in sheep (37). Assay sensitivity averaged 0.65 ng/ml (n = 4 assays), and intra- and interassay CVs for 25-µl samples of a serum pool containing 70.2 ± 3.1 ng/ml cortisol were 6.3% and 8.8%, respectively.
Plasma insulin concentrations were determined in duplicate 100-µl aliquots of plasma with a commercial RIA kit (ICN Pharmaceuticals, Inc., Costa Mesa, CA) that had been validated for use in sheep (38). Assay sensitivity averaged 1.7 µIU/ml (n = 7 assays), and intra- and interassay CVs for 100-µl samples of a serum pool containing 46.6 ± 1.2 µIU/ml insulin were 5.0% and 6.6%, respectively.
Plasma 2DG concentrations were measured by colorimetric assay, based on a quinaldine reaction (39) and modified from a method developed by Blecher (40). Briefly, 200-µl aliquots of plasma were diluted with 350 µl distilled water and then mixed with 200 µl 20% trichloroacetic acid (Sigma) for deproteinization. After centrifugation, 500 µl supernatant were transferred to glass tubes and 500 µl of a 0.01-M solution of 3,5-diaminobenzoic acid dihydrochloride (Sigma) in 5.0 M H3PO4 were added. Mixtures were heated in a boiling water bath for 15 min and were then cooled in a cold water bath (15-17 C) for 20 min. After the addition of 200 µl 2.5 M H3PO4, mixtures were centrifuged, and the optical densities of the solution were determined with a spectrophotometer at 420 nm wave length. A standard curve was obtained simultaneously in each run. In this assay, the cross-reactivity with glucose was very low (1%; data not shown). The recovery of added 2DG to normal sheep plasma averaged 70.18% (n = 6) after deproteinization of the mixtures with trichloroacetic acid, and the results were corrected with the recovery rate to obtain actual concentration in each sample. Assay sensitivity, defined as 2 SD from the normal plasma control, averaged 3.84 mg/dl (n = 9 assays), and the intra- and interassay CVs for 200-µl samples of a serum pool containing 34.7 ± 0.6 mg/dl 2DG were 4.9% and 4.8%, respectively.
Plasma glucose levels were measured in a single determination by a glucose oxidase method with an assay kit supplied by Sigma. The intra- and interassay CV averaged 1.6% and 2.8%, respectively. In our glucose assay, the cross-reactivity between 2DG and glucose averaged 91.79% (n = 18 in graded doses). Therefore, the glucose concentration in each sample was calculated by subtracting the value of 91.79% of the 2DG concentration from the glucose value obtained in the assay.
Data analysis
For the identification of LH pulses from samples collected at
10-min intervals, the Cluster Analysis Program developed by Veldhuis
and Johnson (41) was used. Cluster sizes for nadir and
peak were 1/1 points; the t statistics for significant
increases and decreases were 2.05/1.0. Because the effect of 2DG on
pulsatile LH secretion was transient in both experiments, the number of
identified LH pulses per unit time (frequency) and mean LH
concentrations were calculated for 3 h (Exp 1) or 2 h (Exp 2)
before and after treatments for the purpose of analysis. Significant
differences were analyzed using two-way ANOVA for repeated measures
(between = treatment, within = time), followed by contrast
test for multiple comparisons.
The time courses of glucose, cortisol, insulin, and 2DG concentrations were compared between treatments using two-way ANOVA for repeated measures (between = treatment, within = time), followed by contrast test for multiple comparisons.
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Results |
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Exp 1: peripheral infusion of 2DG
Infusion of 250 mg/kg 2DG into either hepatic portal or jugular
vein suppressed pulsatile LH secretion in all animals; infusion of the
lower test dose (50 mg/kg) locally into the hepatic portal vein did not
alter plasma LH profiles (Fig. 2).
Infusion of 2DG (250 mg/kg) into either hepatic portal or jugular vein
decreased both LH pulse frequency as well as mean LH concentrations
(P < 0.05 vs. pretreated values; Fig. 3). Moreover, the suppressive effect of
2DG on pulsatile LH secretion during 2DG (250 mg/kg) infusion into
either site was equipotent, because the hepatic portal 2DG treatment
did not enhance the glucoprivic inhibition of LH pulses beyond that in
the jugular-treated group (Fig. 3). In xylose-infused animals, LH
secretion was diminished in two of five sheep during infusion (Fig. 2);
there was no effect of xylose infusion on plasma LH profiles in the
other three animals, resulting in no overall significant difference
between pre- and posttreatment values of LH pulse frequency and mean LH
concentrations (Fig. 3).
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. The 250 mg/kg 2DG infusion increased
plasma 2DG levels significantly (P < 0.05) compared
with pretreatment values. Significantly (P < 0.05)
lower 2DG concentrations were detected during the latter half of the
infusion period in the hepatic portal vein-treated group than in the
jugular vein-treated group (Fig. 4a). By contrast, infusion of
the low test dose of 2DG (50 mg/kg) locally into the liver did not
result in increased plasma levels of the glucose antagonist (Fig. 4a).
Plasma cortisol concentrations increased significantly
(P < 0.05 vs. pretreated values) during 250
mg/kg 2DG infusion by either route, with peak values being similarly
attained by the end of 2DG infusions (Fig. 4b). During infusion of the
high 2DG dose (250 mg/kg) into the hepatic portal and jugular
vein-infused groups, plasma glucose levels gradually increased by
halfway through the infusion and remained higher (P <
0.05) than those in the 50 mg/kg 2DG- or xylose-treated groups (Fig. 4c). After infusion of the high dose of 2DG (250 mg/kg), there was no
significant difference in blood glucose levels between hepatic portal
and jugular vein-infused groups, except for a single point at 1.5
h after the start of infusion. Plasma insulin levels increased
significantly (P < 0.05 vs. pretreated
values) after the infusion of 250 mg/kg 2DG into the jugular vein,
although great variability was evident in this group (Fig. 4d). The
infusion of 2DG into the hepatic portal vein with either high or low
doses was without stimulatory effect in this regard.
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). LH pulse frequency
2 h after 2DG infusion into either the fourth or lateral
ventricles decreased significantly (Fig. 6; P < 0.05
vs. pretreated values). This was not the case for mean LH
concentrations, for which a significant difference was only detected
after 2DG infusion into the lateral ventricle (Fig. 6;
P < 0.05 vs. pretreated value). The
suppressive effect of 2DG on LH secretion after 2DG infusion into
either site was equipotent, as there were no significant differences in
LH pulse frequency and mean LH concentrations between the routes of
administration (Fig. 6).
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. Plasma 2DG concentrations were
not detectable after either fourth or lateral ventricle infusion of the
glucose antagonist (Fig. 7a). Plasma cortisol concentrations increased
significantly (P < 0.05 vs. pretreated
value) after 2DG infusion into either the fourth or lateral ventricle;
the levels were greater in animals infused into the fourth ventricle
(Fig. 7b). Plasma glucose concentrations increased significantly
(P < 0.05 vs. pretreated value) only when
2DG was infused into the fourth ventricle (Fig. 7c). 2DG infusion into
the fourth or lateral ventricle comparably decreased (P
< 0.05) plasma insulin levels (Fig. 7d).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Plasma 2DG levels were elevated during the peripheral infusion of only the high dose (250 mg/kg) of the glucose antagonist. The finding that peripheral 2DG concentrations were lower during hepatic portal infusion compared with those during jugular infusion may simply reflect some uptake by the liver. Importantly, however, the efficacy of the high 2DG dose was not enhanced by its local infusion into the hepatic portal system. Of equal significance, local administration of the low 2DG dose (50 mg/kg) into the hepatic portal system did not suppress pulsatile LH secretion, whereas an even lower dose (5 mg/kg) of 2DG was effective when administered centrally. We did not test a 50 mg/kg dose of 2DG infusion into the jugular vein, because our earlier study revealed that even a higher dose (120 mg/kg) of 2DG had no effect on LH pulsatility when administered as bolus iv injection in milk-fed lambs (28). This bolus treatment would be much stronger than the slow infusion that we used in the present study; thus, one could assume that a 50 mg/kg jugular infusion was ineffective. As a consequence, we were not able to find a difference in the efficacy on pulsatile LH secretion between hepatic and jugular 2DG treatments. These comparative results lead us to conclude that glucose-sensing mechanisms in the liver are not crucial to mediate suppression of LH pulses by glucoprivation.
We reported that central glucoprivation by 2DG injection into the lateral ventricle suppresses pulsatile LH secretion in milk-fed lambs, indicating a central site of action of 2DG (28). That study, however, was not designed to determine where within the central nervous system such glucose-sensing mechanisms might exist. In our present study, 2DG infusion into either the fourth or lateral ventricles equally suppressed LH pulses. However, the stimulatory effects of central 2DG on plasma cortisol and glucose were greater in animals infused into the fourth ventricle. The stimulation of the hypothalamo-pituitary-adrenal axis seems to be a hallmark of glucoprivation by peripheral administration of 2DG, as indicated by elevated plasma glucocorticoid concentrations in 2DG-treated rats (43) and sheep (this study). Moreover, because we found that a CRH antagonist blocks the suppressive effect of 2DG on LH pulses in estradiol-treated ovariectomized rats (44), CRH release is stimulated during glucoprivation in this animal model. Considering those reports along with our cortisol data, it is reasonable to suppose that an important site of action of 2DG is in the hindbrain, and that lesser amounts of 2DG infused into the lateral ventricle are transported caudally by the flow of cerebrospinal fluid to act on the area surrounding the fourth ventricle. This possibility accords with the study by Ritter et al. (45), in which obstructing the flow of cerebrospinal fluid into the fourth ventricle in rats prevents both the feeding behavior and the peripheral hyperglycemia found after lateral ventricular administration of 5-thioglucose, another inhibitor of glucose metabolism. Moreover, the retrograde diffusion of 2DG is unlikely because the rate of infusion into the fourth ventricle was slower than the cerebrospinal fluid flow. Our earlier studies in rodents have led to the consideration that the lower brain stem around the fourth ventricle contains an important glucose-sensing mechanism that modulates GnRH/LH secretion. We found that local delivery of 2DG, but not xylose as a control, into the fourth ventricle suppresses pulsatile LH secretion in rats (30), providing direct evidence for the location of hindbrain glucodetectors. This finding accords well with that of Schneider et al. (31), who found that lesioning a circumventricular organ of the lower brainstem, the area postrema, abolishes 2DG-induced impairment of ovarian cyclicity in hamsters.
On the other hand, in addition to central glucose-sensing mechanisms around the fourth ventricle, other similar sensors may exist that are important to the regulation of gonadotropin secretion. In the present study, the glucoprivic suppression of pulsatile LH secretion after 2DG infusion into the lateral ventricle was comparable to that after fourth ventricular infusion. If this does not simply reflect the transport of 2DG by the flow of cerebrospinal fluid as discussed above, then it is possible that glucosensors important to the control of gonadotropin secretion are also located more rostral to the fourth ventricle. Recently, we have found in cells of the cerebroventricular walls in the rat, immunoreactivity for the pancreatic-type glucokinase (46), an enzyme that is considered an essential component of the glucose-sensing mechanism in pancreatic islets (47, 48). This pancreatic glucokinase-like immunoreactivity was distributed widely in the ventricular system, including the central canal, aqueduct, and lateral, third, and fourth ventricles. According to such morphological evidence, multiple glucose-sensing sites could be present in the circumventricular system. The function of such multiple glucodetectors might be very different or might be overlapping. In this respect there were equipotent effects of 2DG infusion into either fourth or lateral ventricle on suppression of LH and insulin secretion, but not on the induction of cortisol secretion and hyperglycemia. Clearly, further experiments will be required to investigate this multiple glucose-sensing hypothesis.
From the results of the present study, any glucose-sensing mechanism in the liver does not seem to be important for the regulation of GnRH/LH secretion. However, it is likely that the liver has detectors for other nutrients that could potentially serve as metabolic signals for the control of gonadotropin secretion. In sheep, infusion of short-chain fatty acids into the hepatic portal vein caused a dose-dependent depression of food intake, and this response was blocked by the section of the hepatic afferent fibers (49). In rats, induction of feeding (50) and Fos-like immunoreactivity in the nucleus of the solitary tract (51) by 2-mercaptoacetate, an inhibitor of fatty acid oxidation, are totally abolished by subdiaphragmatic vagotomy. In contrast, 2DG-induced feeding and Fos-like immunoreactivity in this nucleus are not blocked by vagotomy. These results suggest that vagal sensory inputs from the abdominal viscera are required for lipoprivic, but not glucoprivic, feeding. Perhaps the liver detects changes in fatty acid metabolism and transmits this information to the GnRH neurosecretory systems in the brain via vagal afferent pathways. Indeed, in the mature ram, pulsatile LH secretion was stimulated by the dietary supplementation of short-chain fatty acids, which are the major energy-yielding substrates absorbed from the ruminant digestive tract (52).
In summary, the findings of the present study suggest that central, but not peripheral, glucose-sensing mechanisms play an important role in detecting decreased glucose availability to suppress pulsatile LH secretion in sheep. We believe that at least one glucose-sensing site to regulate GnRH release is located around the fourth ventricle of the hindbrain; whether other central sites exist remains to be determined.
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Acknowledgments |
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Footnotes |
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Received May 17, 2000.
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,
H2DG/50; #, J2DG/250 [P < 0.05 vs.
pretreated values (time zero)]. §, H2DG/250 vs.
J2DG/250 (P < 0.05).
