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Department of Cellular and Integrative Physiology, Indiana University Medical School, Indianapolis, Indiana 46202
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Obesity is
a risk for type II diabetes mellitus and increased vascular resistance.
Disturbances of nitric oxide (NO) physiology occur in both obese
animals and humans. In obese Zucker rats, we determined whether a
protein kinase C-
II (PKC-II) mechanism may lower the resting NO
concentration ([NO]) and predispose endothelial NO abnormalities at
lower glucose concentrations than occur in lean rats. NO was measured
with microelectrodes touching in vivo intestinal arterioles. At rest,
the [NO] in obese Zucker rats was 60 nm less than normal or about a
15% decline. After local blockade of PKC-II with LY-333531, the
[NO] increased ~90 nm in obese rats but did not change in lean
rats. In lean rats, administration of 300 mg/dl D-glucose
for 45 min depressed endothelium-dependent dilation; only 200 mg/dl was
required in obese animals. These various observations indicate that
resting [NO] is depressed in obese rats by a PKC-II mechanism and
the hyperglycemic threshold for endothelial NO suppression is reduced
to 200 mg/dl D-glucose.
diabetes; hyperglycemia; LY-333531
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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OBESITY ASSOCIATED WITH INSULIN resistance is a risk factor for both type II diabetes and the elevated peripheral vascular resistance associated with hypertension (11). A number of mechanisms ranging from abnormal endothelial cell function to alterations in sympathetic nervous system activity have been proposed to explain the increased vascular resistance (1, 11). Abnormalities in endothelial cell-mediated vasodilation to insulin and muscarinic stimulation in obese humans and rats have been documented for both in vivo and in vitro conditions (23, 26, 29, 30, 34). Quite surprisingly in these studies, vasodilation to exogenous nitric oxide (NO) released from sodium nitroprusside is essentially normal in obese humans and rats (29). Therefore, most of the abnormalities of endothelium-dependent vasodilation that are documented in obese humans and animals have been endothelial rather than vascular smooth muscle in origin. Once type II diabetes mellitus has occurred, as verified by the presence of occasional or sustained hyperglycemia, there is ample evidence of even greater suppression of endothelium-dependent vasodilation in diabetic humans and animals (6, 16, 18, 21, 24).
As insulin resistance associated with obesity consistently precedes type II diabetes mellitus, we questioned whether insulin resistance predisposed the microvasculature to damage once hyperglycemia occurred. In addition, it is unknown whether insulin resistance lowers the hyperglycemic concentration, or threshold, for acute endothelial damage. This issue is important because bouts of mild to moderate hyperglycemia likely precede sustained hyperglycemia. Such periods of acute hyperglycemia may alter vascular regulation. In lean rats, 200 mg/dl D-glucose was benign, but 300 mg/dl D-glucose for ~30-60 min impaired endothelium-dependent NO vasodilation in normal cerebral, intestinal, and skeletal muscle vasculatures (5, 16, 20, 22). We found that less NO was formed after these bouts of acute hyperglycemia as determined by both bioassay and direct measurement of arteriolar wall NO concentration ([NO]) (5, 8, 16, 20). In addition, in vivo flow shear-dependent endothelial regulation, which is NO dependent in the rat intestinal arterioles, was suppressed during acute hyperglycemia (16).
Investigation into the mechanism of hyperglycemia-induced alterations
of endothelial cell function has revealed several key pathways. The
mechanism of acute endothelial cell abnormalities is known to involve
oxygen radicals formed during excessive prostaglandin formation
(31, 32) and activation of protein kinase C (PKC) by
diacylglycerol (35). PKC-II activation (12, 13,
25, 28) may be the pivotal mechanism that can both suppress
endothelial NO synthase (eNOS; Ref. 27) and increase
generation of oxygen radicals to destroy NO through increased
prostaglandin synthesis. For example, King and colleagues (14,
25) have shown that chronic treatment with LY-333531 (a specific
blocker of PKC-II) lessened neural and microvascular complications
of streptozocin-induced diabetes. In a recent study (8),
we found that pretreatment with LY-333531 to suppress PKC-II before
acute 300 mg/dl D-glucose hyperglycemia minimized NO
disturbances in the in vivo intestinal microvasculature of normal
rats. Furthermore, LY-333531 treatment after hyperglycemia
substantially restored deficits in endothelial-dependent vasodilation.
These data point to rapid onset of in vivo suppression of eNOS by
activated PKC-II during acute hyperglycemia. Essentially the same
mechanism is also suspected during chronic hyperglycemia (12, 13,
25, 28).
For the current studies, we used Zucker fatty rats at ages 10-14
wk as an animal model that is both obese and insulin resistant but not
routinely hyperglycemic at this age (21, 34). Lean rats of
the Zucker strain were used as control animals. Our first hypothesis
was that the microvascular [NO] is usually depressed in
insulin-resistant animals due to increased PKC-II activation. By
obtaining direct in vivo measurement of the microvascular wall [NO]
using NO-sensitive microelectrodes and suppressing PKC-II with the
highly specific inhibitor LY-333531 (17), we were able to
provide support for this hypothesis. Our second hypothesis was that
greater endothelial cell abnormalities occur in obese insulin-resistant
rats than in lean rats during acute bouts of hyperglycemia. We found
that endothelial cell NO mechanisms were compromised in obese rats at
hyperglycemic concentrations that are considered relatively benign in
lean rats.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Surgical and support conditions. Male Zucker obese and lean rats were obtained from Harlan Industries (Indianapolis, IN) at age 8-10 wk. Rats were allowed to recover from transport for at least 1 wk and were then studied. All animals were studied with protocols approved by the Laboratory Animal Resource Center of Indiana University Medical School. Both lean and obese rats were anesthetized with subcutaneous injections of thiopental sodium (Abbott Laboratories; Chicago, IL) given at four locations over the lower back and thighs. Subcutaneous injection of the anesthetic served two purposes. First, we avoided contact of the anesthetic with the small intestine to minimize effects of the barbiturate on the bowel microvasculature. Second, although thiopental is a long-acting anesthetic in rats, subcutaneous deposition further increased the duration of surgical depth anesthesia. Lean rats received 200 mg/kg sc and obese rats routinely required 350 mg/kg sc due to their high body fat content. The anesthetic regimen maintained a remarkably stable arterial blood pressure so long as 0.4 ml of saline per 100 g of body weight was given each hour. The trachea was cannulated for mechanical ventilation and the right femoral artery was cannulated to monitor the heart rate and arterial blood pressure. The core temperature was measured in the stomach with a probe that was intubated through the mouth. A water jacket beneath the body was heated to 35°C to maintain a core temperature of 37.5 ± 0.5°C. The obese animals were prone to overheating (core temperature >38°C) and associated hypotension and had to be constantly monitored.
Because their abdominal obesity impaired the chest function that leads to hypotension, anesthetized Zucker obese animals had to be mechanically ventilated. Therefore, we ventilated both lean and obese rats. The tidal volume was based on Harvard Apparatus nomograms at a ventilation frequency of 70 breaths/min, which is the typical ventilation frequency of conscious young adult rats. The tidal volume was adjusted to maintain the highest possible mean arterial pressure (MAP), which typically occurred at an end-tidal PCO2 between 36 and 40 mmHg. Excessive tidal volume caused a decrease in both MAP and end-tidal PCO2. End-tidal PCO2 was measured with a SC-219 CO2 monitor (Pyron; Menomonee, WI) using a small fraction (3 ml/min) of expired gas taken from a side port in the endotracheal tube (minute volume > 140 ml). The instrumentation can follow both cyclic changes in end-tidal PCO2 or only report the lowest cyclic or end-tidal PCO2. The jejunal portion of the small intestine was exposed through a midline incision and the small intestine was prepared for in vivo microscopy with a standardized technique (3). The bowel was suffused with heated (37.5°C) bicarbonate-buffered physiological saline equilibrated with 5% O2-5% CO2-90% N2. The fluid was delivered by a pump at 5 ml/min and gas-protected tubing was used to avoid atmospheric contamination. The tissue-support device was also heated to 37.5°C. The microvasculature was allowed to "rest" for 30-45 min after surgery. A preparation was accepted if there were no petechial hemorrhages, and the largest arterioles would maximally dilate by >30% to topical sodium nitroprusside (10
4 M)
after bowel motility had been suppressed with a combination of
isoproterenol (10 mg/l, Sigma; St. Louis, MO) and phenytoin (20 mg/l,
Parke-Davis; Morris Plains, NJ) added to the bathing fluid. At these
concentrations, isoproterenol and phenytoin had no adverse effects on
arteriolar tone and blood flow in this vascular bed in lean or obese
animals as judged by equivalent arteriolar diameters before and after
the drugs were present.
Measurement techniques. Video images of the microvessels were recorded and measured with Image1 image-analysis software (Universal Imaging; West Chester, PA) and referenced to a stage micrometer with 10- and 100-µm markings. A video caliper superimposed on the image was used to measure inner-vessel-wall diameter at a consistent location for each vessel during the various steps of the protocols.
The nanomolar concentration of NO was measured with NO-sensitive carbon-fiber microelectrodes based on the techniques developed by the Biocurrents Laboratory of the Woods Hole Oceanographic Institution (19). The microelectrodes were calibrated at +0.9 V with NO gas in N2 at concentrations of 0, 600, and 1,200 nM at a temperature of 37.5°C. The carbon-fiber microelectrodes, which yielded a linear current versus [NO] calibration, were >15 times more sensitive to NO than the nitrite ion and were insensitive to nitrate ion. For practical purposes, these microelectrodes were insensitive to biological concentrations of both nitrite and nitrate ions and the amino acid tyrosine. We have previously shown that NO-sensitive microelectrodes detected nothing in tissue that has been killed by freezing and rapidly rewarmed to 37.5°C (7). The typical carbon-fiber microelectrode had a current of <10 pA in N2-equilibrated saline at 37.5°C and generated 1-2 pA per 1,000 nM NO. The microelectrodes did not change average current during stirring of the calibration-cell bath fluid, although vigorous stirring increased the random electronic noise. To achieve a reference zero [NO] during in vivo experiments, we found that the microelectrode signal from 150 to 300 µm above the tissue surface in the moving suffusion fluid yielded a constant current. As the microelectrode tip approached the tissue at <100 µm, the current progressively increased as the sensor approached the tissue.Protocols. The purpose of the first protocol was to first determine whether the resting range of periarteriolar [NO] was similar in lean and obese rats, and second, at what glucose concentration we could detect impaired NO physiology. The perivascular [NO] of the largest arterioles, which are the first-order arterioles (1A), was measured by placing the tip of the NO micropipette directly against the side of the arteriole. For highest NO measurement, the NO microelectrode was positioned so that it temporarily caused a small dimple in the side of the arteriole and then was slightly withdrawn. If the microelectrode perturbed the arteriole, the [NO] was unusually high for ~2-5 min but stabilized thereafter to a lower constant concentration. We avoided applying glucose over the entire tissue because vascular responses at proximal or distal sites could have influenced vessel [NO] and reactivity in unpredictable ways within the larger arterioles. After resting measurements, a D-glucose concentration of 200 or 300 mg/dl in lactated Ringer solution (Baxter Healthcare; Deerfield, IL) was ejected (3 ml/h) from a large micropipette (100 µm) directly over the vessel for 30 min. This represents 1% of the total suffusion flow across the tissue. The fluid ejected from the 100-µm pipette tip placed just above the vessel under study displaced the bath fluid in the area with the glucose solution from the pipette. The visceral muscle layer over the vessels was ~30-40 µm thick. Given the small size and uncharged status of glucose, the small diffusion distance to the arterioles, and the fact that the glucose solution concentrations were much higher than plasma glucose concentrations in both lean and fatty rats, the tissue-glucose concentration should have been dominated by the ejected glucose concentration. This approach was successful to locally compromise the regulation of arterioles: bradykinin-induced dilation was substantially suppressed, and the local [NO] was reduced by ~30-35%. These observations indicated that glucose in sufficient concentration reached the vessel endothelium. Ejection of physiological saline at 3 ml/h alone had no influence on the vessel diameter or [NO]. After glucose application for 30 and 45 min, the [NO] and arteriolar diameter were remeasured.
The second protocol, which was performed on a different set of rats, involved measuring [NO] and vessel diameter before and after LY-333531 treatment (Eli Lilly; Indianapolis, IN). LY-333531 is a selective PKC-II inhibitor that our laboratory has shown to protect
in vivo NO generation by normal arterioles during acute hyperglycemia
(8). King et al. (14) have demonstrated that LY-333531 attenuates microvascular abnormalities in chronically treated
diabetic rats. To achieve PKC-II inhibition, LY-333531 was ejected
at a concentration of 20 nM over individual arterioles for 30 min. We
assumed that if obese rats had increased PKC-II activity that
lowered the resting arteriolar [NO], then PKC inhibition would cause
an increase in [NO]. We also used these experiments to determine
whether suppression of PKC-II was associated with dilation of arterioles.
The third protocol was to determine whether endothelial-mediated
vasodilation at rest and after acute mild hyperglycemia (200 and 300 mg/dl D-glucose) was attenuated in obese Zucker rats. For
this protocol, a group of vessels in each rat was selected at random
for study at rest and after acute hyperglycemia. During rest or
hyperglycemia, vascular responses to stimulation with bradykinin (an
endothelium-dependent vasodilator) and sodium nitroprusside (a NO
donor) were tested. We suffused the drugs over the entire vasculature
at known concentrations so that we could directly compare microvascular
behaviors in lean and obese rats.
All data are expressed as means ± SE, and statistical analysis
was carried out using Sigma Stat 2.0 (Jandel Scientific; San Rafael,
CA). Two-way ANOVA for repeated measures was used (strain vs.
normoglycemia, acute hyperglycemia or strain vs. drug concentration) with subsequent Tukey's test for specific comparisons. For all tests,
significance was accepted at P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The mean weight of lean rats was 323.4 ± 11.2 g and that of obese animals was 368.7 ± 7.8 g, which was ~20% over the lean weight. Most of the excess weight in the obese rats was in the form of abdominal fat. In most obese animals, the entire mesenteric vasculature was obscured by fat cells. The intestinal wall was free of fat cells in both lean and obese rats. The mean arterial pressure was 119.3 ± 3.4 mmHg in lean rats compared to 145.3 ± 1.5 mmHg in obese rats. The mean arterial pressures were statistically different (P < 0.05). A blood sample (0.2 ml) for measurement of the plasma glucose was taken just after completion of surgery. The animals had been allowed food overnight and both the stomach and small intestine were filled with food. The postprandial glucose concentrations were 115.5 ± 5.2 mg/dl in lean rats and 147.4 ± 9.1 mg/dl in obese rats (means ± SE). We measured postprandial glucose, because obese animals ate more during the night than the day, and lean rats tended to eat primarily at night. Therefore, the postprandial glucose sample from obese rats was more likely to demonstrate hyperglycemia if it existed.
As shown in Fig. 1, the resting diameters
of large arterioles were equivalent in lean and obese rats, although
there was a trend for smaller diameters in obese than in lean animals.
The resting [NO] was lower in obese than lean rats by ~60 nM or
15% below the normal range. For lean Zucker rats, 200 mg/dl
D-glucose had no measurable effect on either resting [NO]
or diameter. We tested for this possibility in three rats that were not
used for any subsequent tests. Therefore, 300 mg/dl
D-glucose was used to demonstrate that hyperglycemia can
reduce both periarteriolar [NO] and microvascular diameter in lean
rats. For the obese Zucker rats, 200 mg/dl D-glucose caused
an ~90 nM decline in [NO] compared with an ~120 nM decline in
lean animals at a glucose concentration of 300 mg/dl. Arteriolar
diameter was also decreased during 200 mg/dl D-glucose
hyperglycemia in the obese rats and during 300 mg/dl
D-glucose hyperglycemia in lean rats. 300 mg/dl
D-glucose hyperglycemia did not reduce vessel [NO] or
diameter appreciably more than 200 mg/dl D-glucose
hyperglycemia in obese rats.
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PKC inhibition of resting [NO] in obese rats.
The lower than expected resting [NO] in obese rats presented in Fig.
1 and the lower threshold for hyperglycemic impairment indicated that
the microvessels were compromised. In lean animals, blockade of
PKC-II with LY-333531 had no effect on either [NO] or vessel
diameter as shown in Fig. 2. However, in
obese rats, the blockade caused an ~90 nM increase in [NO] such
that the new concentration was equivalent to that in lean rats (Fig.
2). In addition, in obese rats, vasodilation accompanied the increased [NO] after PKC blockade such that vessel diameters were significantly (P < 0.05) larger than those in lean rats after PKC
inhibition (Fig. 2).
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Bradykinin and nitroprusside vasodilation.
Our goal was to use known concentrations of bradykinin as an
endothelium-dependent vasodilator (9) that releases NO as judged independently by a different type of NO-electrode-detection system (2). Bradykinin had the additional benefit that it
had no effect on intestinal motility. Both the large-diameter 1A and their immediate branches, the second-order arterioles (2A), exhibited slightly but significantly less dilation to bradykinin in obese than in
lean rats as shown in Fig. 3.
D-Glucose at 200 mg/dl had no effect on dilation in lean
rats, but in obese rats, this mild hyperglycemia reduced dilation to
bradykinin by about half over the dose range.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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A basic concern of this study is whether obesity in some way
compromised or enhanced the [NO] in the vessel wall. As shown in
Figs. 1 and 2, which represent data from two separate groups of lean
and obese Zucker rats, the resting [NO] was smaller by about 60 nM in
obese than lean rats. There are several reasons to believe that a
difference of 60 nM in [NO] between arterioles of lean and obese rats
would have a biological effect. First, in lean rats, we found that an
increase in NO by ~60 nM occurred during a 20% increase in
blood-flow shear rate, and arteriolar diameter dilated ~10%
(7). Second, during intestinal absorption of 300 mg/dl
D-glucose, a 60 nM increase in [NO] occurred, and arterioles dilated by ~8% (4). These observations
predict that an increase in [NO] of 60 nM in lean rats would reflect
a substantial endothelial NO response to physiological perturbations.
This prediction raised the issue of whether or not the arterioles of
obese animals are constricted due to decreased NO generation. Note in
Figs. 1, 2, and 3 that resting arteriolar diameters are quite similar in three different groups of lean and obese rats. We expected the
resting arteriolar diameter in obese rats to be larger than normal
because the bowel wall circumference was enlarged ~30%. In effect,
the arterioles of obese rats should be larger in diameter to offset the
tissue hypertrophy. We have previously shown arteriolar enlargement in
the hypertrophied bowel of both fatty diabetic Zucker (6)
and streptozotocin-diabetic (33) rats. In support of the
contention that vasoconstriction existed in obese rats, Lucas and Foy
(21) have reported a 40% increase in intestinal vascular
resistance per tissue mass in obese rats. Additional support of resting
vasoconstriction in obese rats was obtained in the present study when
PKC-II blockade dilated their arterioles and raised the [NO] but
had no effect on either diameter or NO in lean rats (see Fig. 2). Our
prior studies (4, 7) predicted that a 60 nM increase in NO
in lean rat intestinal arterioles caused an 8-10% increase in
vessel diameter. Therefore, the 17% dilation of arterioles from obese
animals for a ~90 nM increase in [NO] after PKC-II blockade is
definitely consistent with vascular behavior in lean Sprague-Dawley rats.
PKC-II activity in obese rats.
We propose that a component of the relative vasoconstriction in obese
rats is related to increased PKC-II activity that reduced resting
[NO]. We have previously shown that the LY-333531 blocker has minor
effects on resting vascular tone and [NO] in normal Sprague-Dawley
rats (8) just as we found in lean Zucker rats (see Fig.
2). Therefore, unless endothelial PKC was activated in obese rats,
there was no reason for the [NO] to increase in obese rats after the
PKC-II blocker LY-333531 was exposed to individual arterioles. As
shown in Fig. 2, arterioles in obese Zucker rats dilated ~17% and
the [NO] increased ~90 nM. In fact, after PKC-II blockade, the
[NO] in obese rats exceeded that at rest in lean rats both for
resting and blockade conditions. The exact reason or stimulus for
endothelial PKC activation in obesity has yet to be elucidated.
However, in other tissue types (9, 15) where large volumes
of cells are available for study, the excessive availability of lipids
during obesity is proposed to provide a large supply of diacylglycerol
that activates the PKC enzyme.
Acute hyperglycemia abnormalities.
We questioned whether some aspect of obesity predisposed the
microvasculature to greater injury during hyperglycemia or whether endothelial abnormalities developed at a lower hyperglycemic threshold. One of the major risks of obesity is that severe insulin resistance can
allow occasional or sustained hyperglycemia, which are the hallmarks of
type II or insulin-independent diabetes mellitus. In vivo studies in
normal rats indicate that acute, 
300 mg/dl D-glucose
hyperglycemia was detrimental to the NO function of normal endothelial
cells in intestinal, cerebral, and skeletal muscle vasculatures
(5, 16, 20, 22). In the present study, we found the same
result in lean Zucker rats (see Figs. 1 and 3). By comparison, in
Zucker obese rats, 200 mg/dl D-glucose hyperglycemia caused
decreased [NO] (see Fig. 1) and suppressed bradykinin dilation (see
Fig. 3) greater than that in lean rats at 300 mg/dl
D-glucose. In neither case was dilation to nitroprusside
impaired (Fig. 4). We could detect abnormalities in Zucker fatty rats
within 30 min after 200 mg/dl D-glucose hyperglycemia
began. Acute bouts of hyperglycemia, particularly mild hyperglycemia,
are relevant to human insulin resistance. It is entirely predictable
that as insulin resistance secondary to obesity progresses, acute
episodes of mild to moderate hyperglycemia occur before the
disease process evolves to chronic hyperglycemia. We have previously
shown (8) that hyperglycemia suppressed
endothelium-dependent dilation in the intestinal microvasculature
secondary to excessive activation of PKC-II. The current data (see
Fig. 2) predicted that the arterioles of the Zucker obese rat have an
elevated PKC-II system and this may have exacerbated endothelial NO
abnormalities once mild hyperglycemia occurred. If a similar process
exists in obese humans, brief periods of mild to moderate hyperglycemia
may have the potential to compromise endothelial function of the NO
system long before the sustained hyperglycemia of insulin-independent
diabetes is present.
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ACKNOWLEDGEMENTS |
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The authors thank the Eli Lilly Company for providing LY-333531 and Mary Ann Neill for technical assistance.
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FOOTNOTES |
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This study was supported by National Heart, Lung, and Blood Institute Grant HL-25824.
Address for reprint requests and other correspondence: H. G. Bohlen, Dept. of Cellular and Integrative Physiology, Indiana Univ. Medical School, 635 Barnhill Dr., Indianapolis, IN 46202 (E-mail: gbohlen{at}iupui.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. Section 1734 solely to indicate this fact.
10.1152/ajpheart.00019.2002
Received 11 January 2002; accepted in final form 14 March 2002.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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