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1 Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226; and 2 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The present study
determined the role of 20-hydroxyeicosatetraenoic acid [20-HETE;
produced by 
-hydroxylation of arachidonic acid via cytochrome
P-450 (CP450) 4A enzymes] in regulating myogenic activation
of skeletal muscle resistance arteries from normotensive (NT) and
hypertensive (HT) Dahl salt-sensitive (SS) rats. Gracilis arteries (GA)
were isolated from each rat and viewed via television microscopy, and
changes in vessel diameter with altered transmural pressure were
measured with a video micrometer. Under control conditions, GA from
both groups exhibited strong, endothelium-independent myogenic
activation. Treatment of GA with 17-octadecynoic acid (17-ODYA;
inhibitor of CP450 4A enzymes) did not alter myogenic activation in NT
rats, but impaired this response in HT animals. Treatment of GA from HT
rats with dibromo-dodecynyl-methylsulfimide (DDMS; inhibitor of 20-HETE
production) impaired myogenic activation, as did application of
20-hydroxyeicosa-6(Z),15(Z)-dienoic acid, an
antagonist for 20-HETE receptors. Application of iberiotoxin, a
Ca2+-activated potassium (KCa) channel
inhibitor, restored myogenic activation from HT rats treated with DDMS.
These results suggest that myogenic activation of skeletal muscle
resistance arteries from NT Dahl-SS rats does not depend on CP450,
whereas myogenic activation of these vessels in HT Dahl-SS rats is
partly a function of 20-HETE production, inhibiting KCa
channels through a receptor-mediated process.
cytochrome P-450 4A enzymes; cytochrome P-450
-hydroxylase; potassium channels; vascular smooth muscle; dibromo-dodecynyl-methylsulfimide; 17-octadecynoic acid
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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THE MYOGENIC RESPONSE of skeletal muscle resistance arteries to changes in intravascular pressure is an important contributing element underlying the autoregulation of tissue blood flow. The elucidation of the cellular mechanisms contributing to myogenic activation of these vessels is an area of active investigation, and a number of distinct signaling pathways have been identified as playing key contributing roles. Possible mechanisms include the opening of stretch-activated cation channels, causing membrane depolarization and activation of voltage-gated Ca2+ channels, a breakdown of membrane phospholipids in response to elevated stretch that may enhance intracellular Ca2+ release via inositol triphosphate production, and parallel activation of protein kinase C via diacylglycerol that may contribute to an increased Ca2+ sensitivity of the contractile machinery (5, 22).
Studies in recent years have also suggested that cytochrome
P-450 (CP450) -hydroxylase and the production of
20-hydroxyeicosatetraenoic acid (20-HETE) may play a role in myogenic
activation of small arteries and arterioles of the cerebral (12,
17) and renal (14, 16, 21) circulation. Harder et
al. (13) reported that inhibition of 20-HETE formation
abolishes the autoregulation of blood flow in response to elevated
perfusion pressure in the cerebral and renal circulation and prevents
constriction of cerebral and renal resistance arteries and arterioles
after elevations in transmural pressure. Additional studies addressing
the cellular mechanisms underlying myogenic responses of the cerebral
and renal vasculature suggest that 20-HETE may exert its effects by the following: 1) inhibiting the opening of large conductance
Ca2+-activated K+ (KCa) channels
(26), 2) activating L-type Ca2+
channels (8), or 3) activating protein kinase C
and inhibiting membrane K+ current (17).
However, to date there has been no attempt to determine the role of
CP450 -hydroxylase in regulating myogenic activation of skeletal
muscle resistance arteries. This represents an important avenue of
investigation for two reasons. First, these vessels lie immediately
proximal to the microcirculation and play a critical role in regulating
the flow of blood through the downstream arteriolar networks. Second,
given the inherent nature of tissue-specific differences in the
regulation of vascular tone, extrapolation of previous data addressing
the role of CP450 -hydroxylase and the production of 20-HETE in
contributing to myogenic activation of resistance arteries and
arterioles from the renal and cerebral circulation to skeletal muscle
resistance arteries is problematic. The purpose of the present study
was to determine the contribution of CP450 4A -hydroxylase, and
specifically the production of 20-HETE, to myogenic activation of
extraparenchymal resistance arteries from the skeletal muscle
circulation of normotensive and hypertensive Dahl salt-sensitive (SS)
rats. The use of both normotensive and hypertensive Dahl rats
represents an important component of the present study, because
previous investigations have suggested that hypertension may be
associated with increased CP450 -hydroxylase expression
(23), elevated vascular production of 20-HETE
(4), and increased sensitivity of vessels to 20-HETE (9).
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals. The present study used two groups of 10- to 13-wk-old male Dahl SS rats (SS/Jr/Mcw). One group (normotensive) was fed a low-salt diet (0.4% NaCl) until the day of the experiment, whereas the second group was fed a high-salt diet (4.0% NaCl) for 4 wk preceding the experiment, causing the development of hypertension. All rats drank tap water ad libitum. The rats were anesthetized with an intraperitoneal injection of pentobarbital sodium (30 mg/kg), and a carotid artery was cannulated for determination of mean arterial pressure. Body weight was 287 ± 11 g in normotensive rats and 307 ± 11 g in hypertensive rats. Mean arterial pressure, measured under anesthesia, was 108 ± 5.8 mmHg in normotensive rats and 174 ± 5.9 mmHg in the hypertensive animals (P < 0.001).
Preparation of isolated vessels. The small muscular branch of the femoral artery supplying the gracilis muscle was removed from the anesthetized rat, with care taken to minimize vessel stretching and to handle the artery by its surrounding connective tissue only. The vessels were then placed in warmed physiological salt solution (PSS) equilibrated with a 21% O2-5% CO2-74% N2 mixture. The PSS used in these experiments was composed of (in mM) 119 NaCl, 4.7 KCl, 1.17 MgSO4, 1.6 CaCl2, 1.18 NaH2PO4, 24 NaHCO3, 0.026 EDTA, and 5.5 glucose.
After isolation, arteries were placed in a heated (37°C) chamber that allowed the vessel to be perfused and superfused with the PSS described above from separate individual reservoirs. Gracilis arteries were cannulated at both ends with glass micropipettes (~100 µm tip diameter) and secured to the inflow and outflow pipettes with the use of a 10-0 nylon suture. Any side branches were ligated with a single strand teased from a 6-0 silk suture. The inflow pipette was connected to a reservoir perfusion system that allowed the intraluminal pressure and luminal gas concentrations to be controlled. Vessel diameter was measured by using television microscopy and an onscreen video micrometer. Arteries were extended to their in situ length and equilibrated at 80% of the animal's mean arterial pressure to approximate the perfusion pressure encountered in vivo (18). Any vessel that did not demonstrate both a functional endothelium and active tone at rest (assessed by vasodilation in response to 1 µM acetylcholine in the vessel chamber) was not used in the study. Active tone at the equilibration pressure was calculated as (
D/Dmax) × 100, where
D is the diameter increase from rest in response to
Ca2+-free PSS and Dmax is the
maximum diameter measured at the equilibration pressure in
Ca2+-free PSS. Active tone of gracilis arteries from
normotensive rats (37.5 ± 2.4%) was significantly lower than
that for vessels from hypertensive rats (47.3 ± 2.9%;
P < 0.05).
Methods for removal of vascular endothelium. The endothelium of isolated arteries was removed via air bolus perfusion, as described previously (19), with minor modification. Briefly, five 1-ml air boli were injected into the perfusion line (each separated by 1 ml of perfusate) and were allowed to perfuse the vessel lumen. Subsequently, PSS perfusion through the lumen was restored, and the artery was allowed to reequilibrate for 30 min before proceeding with the experiment. In all experiments, the integrity of the endothelium after air bolus perfusion was assessed by determining the ability of the vessel to dilate in response to 1 µM acetylcholine. The endothelium denudation procedures were deemed successful when any dilation of the vessel in response to acetylcholine challenge was eliminated. In no experiment was it necessary to repeat the air bolus perfusion more than twice.
Inhibition of CP450 4A enzymes.
To assess the contribution of CP450 4A enzymes in contributing to
myogenic activation of vessels with transmural pressure elevation,
these enzymes were inhibited with 17-octadecynoic acid (17-ODYA;
Sigma), as described previously (1, 3). 17-ODYA is a
suicide substrate inhibitor of CP450 4A enzymes and irreversibly inhibits the production of 20-HETE via -hydroxylation of arachidonic acid and the production of epoxyeicosatrienoic acid by arachidonic acid
epoxidation (25). Briefly, while normal PSS superfusion was interrupted, 17-ODYA was added to the vessel chamber to a final
concentration of 10 µM and was incubated with the isolated vessel for
30 min, after which superfusion with normal PSS was restored.
Inhibition of CP450 -hydroxylase.
To evaluate the role of arachidonic acid -hydroxylation and the
production of 20-HETE in contributing to myogenic activation of
gracilis arteries from these rats, this enzyme was blocked with the
selective competitive inhibitor dibromo-dodecenyl-methylsulfimide (DDMS; Ref. 25), as described previously (3).
Briefly, while normal PSS superfusion was interrupted, DDMS was added
to the vessel chamber to a final concentration of 10 µM and was
allowed to incubate with the vessel for 30 min. After the initial
treatment with DDMS, the vessel was continuously superfused with normal PSS containing 1 µM DDMS for the remainder of the experiment.
Blockade of 20-HETE receptor. A recent study (2) has suggested that the actions of 20-HETE to regulate potassium channels are receptor mediated. That study (2) also indicted that the synthetic compound 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid [6(Z),15(Z)-20-HEDE] is a highly selective antagonist of this receptor, completely abolishing vascular reactivity in response to challenge with 20-HETE. To more fully evaluate the role of 20-HETE in regulating myogenic activation of skeletal muscle arteries, the myogenic responses were tested after addition of 6(Z),15(Z)-20-HEDE to the tissue bath to achieve a final concentration of 1 µM, as described previously (2).
Inhibition of KCa channels.
Previous studies have determined that 20-HETE inhibits the opening of
large conductance KCa channels, preventing membrane hyperpolarization in the face of elevated intracellular calcium (26). To determine the extent to which KCa
channels modulate the actions of CP450 -hydroxylase and 20-HETE in
regulating arterial myogenic responses, the selective KCa
channel blocker iberiotoxin (IBTX) was added to the vessel chamber to a
final concentration of 100 nM, as previously described
(24).
Experimental protocols. Preliminary control experiments demonstrated that myogenic activation of isolated skeletal muscle resistance arteries did not decay over time courses that were similar to those that were required for the performance of the experimental perturbations and techniques described above. The initial series of experiments in the present study was performed to determine the contribution of the vascular endothelium to myogenic activation of the isolated arteries. Once vessel responses to elevated intraluminal pressure were determined under control conditions, the endothelium was removed as described above, and determination of the myogenic responses was repeated.
For the determination of myogenic responses, the perfusate outflow line was clamped and the height of the perfusion reservoir was changed to vary intraluminal pressure in 20- mmHg intervals between 20 and 160 mmHg. Vessel diameter was determined after ~10 min at each intraluminal pressure, and pressure levels were randomized for each myogenic curve. After the procedures were completed, the perfusate and superfusate were replaced with Ca2+-free PSS and the passive diameter of the fully relaxed vessel was determined over the identical pressure range used for the myogenic responses. The subsequent set of experiments determined the contribution of CP450 4A products of arachidonic acid to myogenic activation of the isolated gracilis arteries. Once myogenic responses were determined under control conditions, vessels were treated with 17-ODYA, as described above. After incubation with the CP450 4A enzyme inhibitor, the determination of myogenic responses was repeated. The third series of experiments was designed to determine the contribution 20-HETE production via CP450-hydroxylase to myogenic activation of the vessels. Once myogenic responses were determined under control conditions, vessels were treated with either DDMS (a
competitive inhibitor of the -hydroxylation reaction) to inhibit 20-HETE production or IBTX (KCa channel antagonist), as
described above. After treatment with either DDMS or IBTX, the
determination of the myogenic responses was repeated. Finally, vessels
were treated with both DDMS and IBTX, as described above, and the
procedures for determining the myogenic activation of these vessels
were repeated under conditions of combined CP450 -hydroxylase and KCa channel inhibition.
An additional series of experiments was conducted to evaluate the
contribution of 20-HETE to myogenic activation of skeletal muscle
resistance arteries of the hypertensive rats. In these experiments,
myogenic responses were determined under control conditions and after
blockade of the 20-HETE receptor with
6(Z),15(Z)-20-HEDE.
Data and statistical analyses.
Throughout the present study, tension development in the vascular wall
with alterations in intraluminal pressure was calculated as described
previously (16)
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+ 
(x); where y represents arterial diameter or active tension at a specific intraluminal pressure, is an intercept term, and x is the intraluminal pressure. represents the
slope of the pressure versus diameter or the pressure versus active tension curve (i.e., the rate of change in either arterial diameter or
active tension for an incremental change in intraluminal pressure). Differences between coefficients for the curves as well as
differences in resting vessel diameter were determined by using ANOVA
with Tukey's test post hoc or Student's t-test where
appropriate. Throughout all analyses, a probability level of
P < 0.05 was considered to be statistically significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Resting vessel diameter.
Table 1 summarizes data describing the
resting diameter of isolated gracilis arteries from normotensive and
hypertensive Dahl-SS rats under the experimental conditions in the
present study. Neither removal of the vascular endothelium nor
treatment of the isolated artery with 17-ODYA significantly altered
arterial diameter in either normotensive or hypertensive animals. In
addition, treatment of isolated arteries from hypertensive Dahl rats,
either with DDMS or with the 20-HETE receptor antagonist, had no
significant effect on vessel diameter. Application of IBTX to either
control vessels or to vessels treated with DDMS tended to decrease
arterial diameter, although this effect was not significant
(P > 0.20 for both). In all cases, vessel diameter was
significantly less than that determined during superfusion with
Ca2+-free PSS, indicating the maintenance of significant
basal tone after the inhibition of the CP450 4A enzyme system.
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Effects of endothelium removal.
The effects of removing the vascular endothelium on myogenic responses
and the development of active tension in response to elevated
transmural pressure in isolated vessels of normotensive and
hypertensive rats are shown in Figs. 1
and 2, respectively. Endothelium
removal had no effect on myogenic activation or active tension
development in either the normotensive rats (P = 0.990 for myogenic responses; P = 0.964 for active tension
development) or in hypertensive animals (P = 0.993 for
myogenic responses; P = 0.418 for active tension
development).
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Effects of inhibition of CP450 4A enzymes.
The effect of 17-ODYA on pressure-induced constriction of gracilis
vessels and development of active tension in normotensive and
hypertensive rats are shown in Figs. 3 and 4, respectively. In
normotensive rats (Fig. 3), treatment of
gracilis arteries with 17-ODYA did not alter myogenic activation
(P = 0.849) or active tension development
(P = 0.828) compared with responses determined under
control conditions. In contrast, treatment of isolated vessels from
hypertensive rats with 17-ODYA (Fig. 4) impaired myogenic activation of gracilis arteries (P = 0.003) and the development of active tension (P = 0.009) after elevations in transmural pressure compared with responses
determined under control conditions. Removal of the vascular
endothelium did not affect the patterns of myogenic activation or
active tension development in normotensive and hypertensive rats after
inhibition of CP450 4A enzymes (data not shown). The slope of the
curves relating active tone versus transmural pressure in
17-ODYA-treated vessels from both normotensive and hypertensive rats
was significantly less than that of the pressure-diameter relationship
for the vessel in Ca2+-free PSS (P < 0.001 for both comparisons).
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0.001).
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-hydroxylase with 17-ODYA or
DDMS, although the reduction in the development of active tension with
elevated transmural pressure after treatment of the vessels with
6(Z),15(Z)-20-HEDE failed to reach significance
(P = 0.152).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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It has recently been suggested that -hydroxylation of
arachidonic acid via CP450 4A enzymes, and the resulting production of
20-HETE, plays a central role in regulating the pressure-induced constriction of arteries and arterioles in the cerebral and renal circulation that can play an important role in the autoregulation of
renal and cerebral blood flow (11, 13). To date, however, there has been little attempt to determine a comparable role for CP450
-hydroxylase and the production of 20-HETE in regulating myogenic
responses of the skeletal muscle vasculature under either normal
physiological conditions or with the development of pathological alterations impacting the vasculature (e.g., SS hypertension). The
present study begins to address these questions by evaluating the
contribution of CP450 -hydroxylase and the production of 20-HETE to
the regulation of myogenic response in isolated skeletal muscle
resistance arteries from normotensive and hypertensive Dahl SS rats.
The results of the present study clearly indicate that endothelium removal has no effect on pressure-induced constriction of isolated skeletal muscle arteries or the increase in tone with elevations in transmural pressure of either normotensive and hypertensive Dahl-SS rats. Whereas these results contrast with previous investigations (10, 15), which suggested a role for the vascular endothelium in regulating myogenic responses in other vascular beds, they are in agreement with the majority of the existing literature (5-7, 19, 22), indicating that myogenic activation of skeletal muscle vessels is independent of the endothelium. As such, the results of the present study indicate that production of endothelium-derived products does not play a significant role in mediating the myogenic activation of skeletal muscle resistance arteries of either normotensive or hypertensive Dahl-SS rats in response to increased intraluminal pressure.
In the present study, the inhibition of CP450 4A enzymes had no effect
on myogenic activation and active tension development of isolated
arteries from normotensive Dahl-SS rats on a low-salt diet. This
suggests that production of 20-HETE via the -hydroxylation of
arachidonic acid does not contribute to pressure-induced constriction or myogenic tone in this strain of rats under normotensive conditions. The lack of an effect of inhibiting CP450 4A enzymes on the myogenic responses of skeletal muscle resistance arteries from normotensive rats
is in contrast to results from recent studies indicating a significant
contribution of 20-HETE production in mediating pressure-induced
activation of renal and cerebral arteries and arterioles of
Sprague-Dawley and spontaneously hypertensive rats fed a normal salt
diet (13). When integrated, these results suggest that the
role of 20-HETE production in contributing to myogenic activation may
differ substantially in resistance vessels from different tissues and
from different animal strains.
However, the results of the present study indicate that the production
of 20-HETE via CP450 pathways is an important mediator of the
pressure-induced constriction of skeletal muscle resistance arteries
from hypertensive Dahl-SS rats. Specifically, treatment of isolated
arteries from hypertensive Dahl-SS with either 17-ODYA or DDMS blocks
constriction of the vessels and attenuates the active tension
development of the arteries in response to elevations in intraluminal
pressure. Furthermore, application of the selective receptor antagonist
for 20-HETE, 6(Z),15(Z)-20-HEDE mimicked the effects of CP450 -hydroxylase inhibition on myogenic reactivity and
active tension development in these vessels. These results provide
additional support for the previous study of Alonso-Galicia et al.
(2), which demonstrated the effectiveness of
6(Z),15(Z)-20-HEDE in preventing the effects of
20-HETE on vascular tone, presumably by impairing its ability to
inhibit the opening of KCa channels. These data suggest
that production of 20-HETE via CP450 -hydroxylase plays a central
role in contributing to myogenic responses of skeletal muscle
resistance arteries subsequent to the development of hypertension in
Dahl-SS rats. Taken together, the results of the present study suggest
that hypertension leads to an increased role of CP450 enzymes and
20-HETE in contributing to myogenic activation of skeletal muscle
resistance arteries. This enhanced contribution of 20-HETE to myogenic
responses may be important in allowing the vessels to constrict at
higher pressures in hypertensive animals. This constriction may be a
crucial factor contributing to the well-known shift of the
autoregulatory curve to a higher pressure range in hypertensive
subjects, possibly protecting the downstream microcirculation from the
detrimental effects of an elevated arterial pressure.
One key observation from the present study was that, after inhibition of 20-HETE production, isolated arteries from hypertensive rats lost their ability to decrease their diameter in response to elevated intraluminal pressure, although the ability to keep their diameter constant over a wide range of transmural pressures was maintained. By losing their ability to decrease their diameter with elevated intraluminal pressure, the ability of the vessels to fully contribute to the myogenic component underlying blood flow autoregulation may be impaired. The results from the present study support those from previous investigations indicating that the production of 20-HETE has an important role in the autoregulation of flow in the renal and cerebral vascular beds (13).
The results of the present study indicate that application of IBTX, a
highly selective inhibitor of KCa channels, to control vessels from hypertensive rats tends to increase the basal tone of
isolated arteries, with no impairment of myogenic activation in
response to elevated intraluminal pressure. Our results indicate that
application of IBTX to arteries that have also been treated with DDMS
restores myogenic reactivity and active tension development to levels
that are not different from those determined in arteries in which
20-HETE formation is not inhibited with DDMS. When integrated, the
results of this study suggest that myogenic reactivity of isolated
skeletal muscle resistance arteries from hypertensive Dahl-SS rats is
partially dependent on the activation of CP450 -hydroxylase, which
results in an increased production of 20-HETE. Consistent with earlier
hypotheses of 20-HETE action (26), the 20-HETE produced in
response to transmural pressure elevation in hypertensive animals may
then reduce the open-state probability of vascular smooth muscle
membrane KCa channels through a receptor-mediated mechanism. The loss of either the production (through 17-ODYA or DDMS)
or the action [through 6(Z),15(Z)-20-HEDE] of
20-HETE in response to elevated intraluminal pressure would impair full myogenic activation of these vessels, because the efflux of
K+ through KCa channels in the absence of any
inhibitory effects of 20-HETE on these channels could attenuate the
myogenic depolarization of the vascular smooth muscle membrane and the
resulting influx of calcium into the cell through voltage-activated
(L-type) calcium channels.
In conclusion, our results suggest that myogenic activation of isolated
skeletal muscle resistance arteries from normotensive Dahl-SS rats is
independent of both endothelium-derived vasoconstrictor substances and
the production of vasoactive metabolites via CP450 4A enzymes. In
contrast, the myogenic response in arteries from hypertensive Dahl-SS
rats, while still independent of the vascular endothelium, is partially
dependent on 20-HETE production via CP450 -hydroxylase working
through a receptor-mediated process to inhibit the open-state
probability of KCa channels. Although the production of
20-HETE in response to elevated intraluminal pressure is not necessary
for development of myogenic activation, this process does appear to be
critical for the ability of the isolated artery of hypertensive rats to
decrease its diameter with elevated intraluminal pressure.
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ACKNOWLEDGEMENTS |
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This work was supported by National Institutes of Health Grants HL-65289, HL-29587, HL-37374, and GM-31278 and Postdoctoral Fellowship F32 HL-09994.
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. H. Lombard, Dept. of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226 (E-mail: jlombard{at}mcw.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.
Received 27 June 2000; accepted in final form 9 October 2000.
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TOP
ABSTRACT
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MATERIALS AND METHODS
RESULTS
DISCUSSION
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P < 0.05 vs. endothelium removal.
P < 0.05 vs. treatment of the
vessel with DDMS. §P < 0.05 vs. treatment of the
vessel with DDMS and IBTX.
