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-hydroxylase to
altered arteriolar reactivity with high-salt diet and
hypertension
1 Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226; and 2 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75235
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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 evaluated the contribution of cytochrome P-450
-hydroxylase in modulating the reactivity of cremaster muscle arterioles in normotensive rats on high-salt (HS) and low-salt (LS)
diet and in rats with reduced renal mass hypertension (RRM-HT). Changes
in arteriolar diameter in response to ACh, sodium nitroprusside (SNP),
ANG II, and elevated O2 were measured via television
microscopy under control conditions and following cytochrome
P-450 -hydroxylase inhibition with 17-octadecynoic acid
(17-ODYA) or N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS). In normotensive rats on either LS or HS diet, resting tone was
unaffected and arteriolar reactivity to ACh or SNP was minimally
affected by cytochrome P-450 -hydroxylase inhibition. In
RRM-HT rats, cytochrome P-450 -hydroxylase inhibition
reduced resting tone and significantly enhanced arteriolar dilation to ACh and SNP. Treatment with 17-ODYA or DDMS inhibited arteriolar constriction to ANG II and O2 in all the groups, although
the degree of inhibition was greater in RRM-HT than in normotensive animals. These results suggest that metabolites of cytochrome P-450 -hydroxylase contribute to the altered reactivity of
skeletal muscle arterioles to vasoconstrictor and vasodilator stimuli
in RRM-HT.
microcirculation; skeletal muscle; 20-hydroxyeicosatetraenoic acid; 17-octadecynoic acid; N-methylsulfonyl-12,12-dibromododec-11-enamide; acetylcholine; sodium nitroprusside; angiotensin II; oxygen
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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PREVIOUS STUDIES by Lombard and colleagues (6-8, 15-17, 30) and by others (3, 27, 31) have demonstrated that high-salt diet (with no change in blood pressure) and hypertension are associated with alterations in the reactivity of skeletal muscle resistance arteries and arterioles to vasoactive stimuli. Dilator responses of skeletal muscle arterioles to agonists acting throughout the signal transduction pathways of vascular relaxation are impaired with either reduced renal mass (RRM)-hypertension or high-salt diet alone (3, 6-8, 27). Constrictor responses of skeletal muscle arteries and arterioles to ANG II are also enhanced in normotensive rats on high-salt diet (30) and in rabbits with two-kidney, one-clip renovascular hypertension (31), and arteriolar responses to elevated PO2 are enhanced in RRM-hypertensive rats (17) and spontaneously hypertensive rats (15, 16). Finally, a hallmark of developing hypertension is an increased basal arteriolar tone, requisite in the autoregulation of tissue blood flow (28). Taken together, these observations suggest that hypertension and high-salt diet may be associated with enhanced constrictor influences on skeletal muscle arteries and arterioles, which could contribute to an elevated basal tone, an enhanced response to constrictor stimuli, and an impaired relaxation in response to dilator stimuli.
Recent studies indicate that vascular smooth muscle cells metabolize
arachidonic acid via a cytochrome P-450
-hydroxylase-dependent pathway to produce 20-hydroxyeicosatetraenoic
acid (20-HETE), a potent constrictor of cerebral arteries (11), renal
arteries (20), renal arterioles (13), and skeletal muscle arterioles (12). The presence of cytochrome P-450 -hydroxylase has been demonstrated in skeletal muscle, where it appears to play an important role in regulating arteriolar diameter during changes in O2
availability by generating 20-HETE in an O2-dependent
manner (12). Finally, several studies have indicated that cytochrome
P-450 -hydroxylase expression and vascular sensitivity to
20-HETE are elevated in some tissues with hypertension (2, 9, 26). On
the basis of these prior investigations, it is important to evaluate
the role of P-450 -hydroxylase in contributing to the
alterations in the regulation of vascular tone that develop with
high-salt diet and RRM-hypertension.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Renal mass reduction. Male Sprague-Dawley rats were anesthetized with a 9:2 mixture of 100 mg/ml ketamine and 10 mg/ml acepromazine (0.1 ml/100 g body wt). As described previously (17), the rats underwent a two-stage procedure in which their total renal mass was reduced by ~75%. After recovering from the procedures, all rats with RRM were placed on a high-salt diet (4.0% NaCl; Dyets, Bethlehem, PA) for 3 days to produce RRM-hypertension.
Animal groups and preparation.
The present studies were conducted on RRM-hypertensive rats and two
groups of normotensive Sprague-Dawley controls. In these experiments,
rats not undergoing renal mass reduction were maintained on either a
low-salt diet (0.4% NaCl) or a high-salt diet for 3 days. All rats
drank tap water ad libitum. A 3-day period for high-salt diet and
RRM-hypertension was chosen because previous studies demonstrated that
this time period allows for significant alterations to vascular
reactivity while minimizing any structural narrowing of arterioles (7,
8). Body weights of normotensive rats maintained on the low-salt and
high-salt diets were not different, whereas body weight for
RRM-hypertensive rats was significantly less than that in normotensive
rats on either diet (Table 1).
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4 M adenosine.
Inhibition of cytochrome P-450 -hydroxylase.
To assess the role of cytochrome P-450 -hydroxylase in
regulating vascular reactivity of distal arterioles, we inhibited the
enzyme with either 17-octadecynoic acid (17-ODYA) or
N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS) before
evaluating reactivity. Two inhibitors of -hydroxylation were used
because 17-ODYA also inhibits arachidonic acid epoxidation, which
inhibits not only the formation of 20-HETE but also the formation of
eicosatetraenoic acids (EETs; Ref. 33). DDMS is a more selective
inhibitor of -hydroxylation (and therefore of 20-HETE production)
and has minimal effects on EET formation via arachidonic acid
epoxidation (29). Because 17-ODYA irreversibly inhibits cytochrome
P-450 -hydroxylase and treatment with DDMS is reversible
only over an extended time frame (29), each animal in the present study
did not serve as its own control. Thus the animals were divided into
three treatment groups: 1) control (receiving no inhibition of
cytochrome P-450 -hydroxylase), 2) 17-ODYA
(receiving cytochrome P-450 -hydroxylase inhibition with
17-ODYA), and 3) DDMS (receiving cytochrome P-450
-hydroxylase inhibition with DDMS). Baseline data describing each of
the nine total experimental groups are summarized in Table 1.
-hydroxylase inhibitor, superfusion with normal PSS was restored. To
control for any time-dependent effects in control animals, we
maintained the cremaster muscle of the animals in the control group
under PSS superfusion for a period of time identical to that required
for 17-ODYA and DDMS treatment with no experimental manipulation.
Determination of vascular reactivity.
After treatment with either cytochrome P-450 -hydroxylase
inhibitor or completion of the time-control procedures, arteriolar diameter was measured before and after challenge with 1) ACh
(108-106
M), 2) sodium nitroprusside (SNP;
108-106
M), 3) ANG II
(109-107
M), and 4) elevated superfusate O2 concentration
(0, 5, 10, and 21%). Maximum arteriolar diameter was assessed by
measuring the vascular response to superfusion with
Ca2+-free PSS containing 104
M adenosine. One arteriole was selected for analysis in each rat, and
each arteriole was exposed to all challenges. In an additional group of
normotensive rats on low-salt diet (n = 5), the cremaster muscle was superfused with PSS containing a subthreshold dose of
20-HETE (1010 M; Ref. 11) such that no
constriction from baseline was identified. During this superfusion
period, arteriolar responses to topical application of ACh
(106 M) and SNP
(106 M) were evaluated.
Data and statistical analyses.
All data are expressed as means ± SE. ANOVA with Tukey's test post
hoc was used to determine differences between experimental groups for
mean arterial pressure, body weight, and resting and maximum arteriolar
diameter. Statistical evaluation of the effects of cytochrome
P-450 -hydroxylase inhibition on arteriolar responses to the
challenges in individual rat groups (i.e., normotensive rats on low- or
high-salt diet and RRM-hypertensive rats) used repeated-measures ANOVA
with Tukey's test post hoc. The statistical evaluation of the effects
of superfusion of the cremaster muscle with 20-HETE on microvessel
reactivity to ACh and SNP employed Student's t-test.
+ 
x, where y represents the change in arteriolar diameter from rest to challenge (expressed as %resting diameter) with
either ANG II or O2 at a specific concentration, is an intercept term, x represents the individual stimulus
concentration, and represents the rate of change in arteriolar
diameter for a change in stimulus concentration, with
y/(log [x]) for ANG II and
y/x for O2. The alteration of the
vasoconstrictor reactivity after application of either 17-ODYA or DDMS
was evaluated by determining the difference between -coefficients
(and the pooled variance surrounding that difference) describing the
dose-response data between control rats and rats receiving cytochrome
P-450 -hydroxylase inhibition in each animal group (23). The
statistical analysis of differences in -coefficients employed ANOVA
and Tukey's test post hoc. 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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Mean arterial pressure and resting and maximum arteriolar diameter.
At the time of the experiment, mean arterial pressure was significantly
higher in the RRM-hypertensive rats than in either normotensive group
(which were not different from each other). Resting diameter of
arterioles in rats not receiving cytochrome P-450
-hydroxylase inhibition was not different across the three rat
groups. Inhibition of cytochrome P-450 -hydroxylase did not alter arteriolar diameter in either normotensive rat group, although treatment with either 17-ODYA or DDMS increased arteriolar diameter in
RRM-hypertensive rats. The maximum diameter of cremasteric arterioles
was not different between the three rat groups. These data are
summarized in Table 1.
Responses to ACh.
Figure 1 presents the effects of high-salt
diet on the response of cremasteric arterioles to ACh in normotensive
and RRM-hypertensive rats. Compared with low-salt diet and normotension
in rats, both high-salt diet and RRM-hypertension exhibited reduced
microvessel dilation in response to 106
M ACh. In RRM-hypertensive rats, the arteriolar response to
106 M ACh was also significantly less
than that in normotensive rats on high-salt diet.
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-hydroxylase inhibition on
arteriolar responses to ACh. In normotensive rats on low-salt diet
(Fig. 2A), inhibition of 20-HETE production with 17-ODYA had no
significant effect on arteriolar reactivity to ACh, although treatment
with DDMS significantly increased microvessel dilation to
108 and
107 M ACh (Fig. 2A). In
normotensive rats on high-salt diet, application of 17-ODYA had no
significant effect on arteriolar responses to ACh, and cremasteric
arteriolar reactivity to ACh was significantly increased following DDMS
treatment at 106 M ACh only (Fig.
2B). However, in RRM-hypertensive rats (Fig. 2C),
treatment of the cremaster muscle with either 17-ODYA or DDMS
significantly increased arteriolar responses to ACh at each agonist
concentration.
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Responses to SNP.
Figure 3 summarizes cremasteric arteriolar
responses to SNP in normotensive rats on low- or high-salt diet and in
rats with RRM-hypertension. The response of cremasteric arterioles to
SNP was not different between the two normotensive rat groups, although vascular reactivity to SNP was significantly reduced with
RRM-hypertension.
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-hydroxylase inhibition on these
arteriolar responses to SNP in the three experimental groups. In
normotensive rats on low- (Fig. 4A) or high-salt diet (Fig.
4B), treatment of the muscle with either 17-ODYA or DDMS had no
significant effect on arteriolar dilation to SNP. In RRM-hypertensive
rats, blockade of cytochrome P-450 -hydroxylase
significantly increased vascular reactivity to all concentrations of
SNP used in the present study (Fig. 4C).
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Responses to ANG II.
Figure 5 summarizes the response of
cremasteric arterioles to ANG II in the three rat groups in the present
study. In normotensive rats on low- or high-salt diet, there were no
differences in the ANG II-induced microvessel constriction, with the
exception of the response at 107 M ANG
II, where microvessels of rats on the high-salt diet constricted significantly more than those of rats on the low-salt diet (P < 0.05). In RRM-hypertensive rats, arteriolar constriction to 108 and
107 M ANG II was significantly increased
compared with that identified for either group of normotensive rats.
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-hydroxylase inhibition on the
response of microvessels to ANG II. In normotensive rats on low- (Fig.
6A) or high-salt diet (Fig. 6B) and in RRM-hypertensive
rats (Fig. 6C), blockade of cytochrome P-450 with
either 17-ODYA or DDMS significantly reduced cremasteric arteriolar
responses to ANG II throughout the agonist concentration range in the
present study. In the RRM-hypertensive rats, pharmacological inhibition
of cytochrome P-450 -hydroxylase with 17-ODYA or DDMS reduced cremasteric arteriolar responses to ANG II to levels that were
not different from those determined in the normotensive controls.
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Responses to elevated superfusate O2 concentration.
Figure 7 presents the cremasteric
arteriolar response to elevated superfusate O2
concentration in the various animal groups. Arterioles of normotensive
rats on low- or high-salt diet exhibited similar constrictor responses
at all levels of superfusate O2 concentration. However, the
O2-induced constriction of arterioles in RRM-hypertensive
rats was significantly greater than that of normotensive rats on
low-salt diet at all superfusate O2 concentrations and was
significantly greater than that of normotensive rats on high-salt diet
at 10 and 21% O2.
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-hydroxylase inhibition on
arteriolar responses to elevated superfusate O2 in the
various experimental groups. In normotensive rats on either low- (Fig.
8A) or high-salt diet (Fig. 8B), inhibition of
cytochrome P-450 -hydroxylase significantly reduced the
arteriolar constriction to 21% O2 only. In
RRM-hypertensive rats, treatment of the cremaster muscle with either
cytochrome P-450 -hydroxylase inhibitor significantly
reduced arteriolar responses to each superfusate O2 level
(Fig. 8C). No significant differences were evident in the
degree of the inhibition of O2-induced constriction
following treatment with either 17-ODYA or DDMS in normotensive rats on low- and high-salt diet. However, in RRM-hypertensive rats, depression of the O2-induced vasoconstriction following inhibition of
cytochrome P-450 -hydroxylase was significantly greater than
in either normotensive rat group (assessed by comparing the difference
in -coefficients in the various groups), and arteriolar responses to
elevated PO2 in the presence of the inhibitor
were not significantly different from those measured in the
normotensive control groups.
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Effects of superfusion with 20-HETE on dilator reactivity.
To determine whether exogenous application of 20-HETE alters the
reactivity of cremasteric arterioles to ACh and SNP, we added a
subthreshold dose of 20-HETE directly to the superfusate before evaluating arteriolar reactivity to these agonists. Figure
9 presents data describing the effects of
superfusion of the cremaster muscle of normotensive rats on low-salt
diet with 1010 M 20-HETE (in PSS) on
microvessel reactivity to ACh (106 M)
and SNP (106 M). In response to
superfusion with 20-HETE, arteriolar responses to both agonists were
significantly reduced compared with responses determined during
superfusion with normal PSS.
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DISCUSSION |
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|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Previous studies indicated that the reactivity of skeletal muscle
arterioles to both dilator and constrictor stimuli is significantly altered with high-salt diet and RRM-hypertension (3, 6-8, 17, 27,
30). Other studies demonstrated that cytochrome P-450
-hydroxylase expression is elevated in many tissues with hypertension (2, 10, 26), resulting in an increased production of
20-HETE, a potent constrictor of skeletal muscle arterioles (12). On
the basis of those previous investigations, the goal of the present
study was to evaluate the potential contribution of cytochrome
P-450 -hydroxylase products (presumably 20-HETE) to the
altered reactivity of skeletal muscle arterioles in normotensive rats
on high-salt diet and in RRM-hypertensive rats.
Effects of cytochrome P-450 -hydroxylase inhibition
on basal arteriolar tone.
Inhibition of cytochrome P-450 -hydroxylase with either
17-ODYA or DDMS had no effect on the resting diameter of cremasteric arterioles in normotensive rats on low- or high-salt diet, although cytochrome P-450 inhibition significantly increased arteriolar diameter, i.e., decreased basal tone, in RRM-hypertensive rats. The
lack of an effect on active tone in skeletal muscle arterioles of
normotensive rats with 17-ODYA is consistent with the results of
previous studies (12, 18). However, the lack of an effect on basal tone
in normotensive rats on high-salt diet and the significant reduction of
active tone in arterioles of RRM-hypertensive rats was not identified previously.
-hydroxylase inhibition suggests that the effects of 20-HETE
production on these channels may not be of primary importance in
regulating resting tone of the vascular smooth muscle in these vessels.
However, in RRM-hypertensive rats, the increased arteriolar diameter
following inhibition of P-450 -hydroxylase suggests that
enhanced 20-HETE production or an increased sensitivity of the
arteriolar smooth muscle cells to this compound may contribute to the
commonly identified increases in vascular tone with developing hypertension (28). An increase in resting tone was proposed to be an
essential step in the transition from the high cardiac output stage of
RRM-hypertension to the established stage of hypertension, where
peripheral vascular resistance is elevated via local autoregulatory mechanisms (17). The present study suggests that metabolites of the
cytochrome P-450 system may contribute to this transition to a
maintained elevation in vascular resistance in this volume-expanded form of hypertension.
Effects of cytochrome P-450 -hydroxylase inhibition
on ACh- and SNP-induced vasodilation.
The results of the present study are consistent with previous
observations that cremasteric arterioles of normotensive rats on
high-salt diet and RRM-hypertensive rats rapidly develop an impaired
reactivity to ACh and SNP (within 3 days following exposure to
high-salt diet) compared with responses of arterioles in normotensive rats on low-salt diet (7, 8). The present study demonstrates that
treatment of the cremaster muscle with the cytochrome P-450 -hydroxylase inhibitors 17-ODYA or DDMS had disparate effects on
ACh- and SNP-induced arteriolar dilation across the three rat groups.
In normotensive rats on low- or high-salt diet, cytochrome P-450 -hydroxylase inhibition had little effect on
cremasteric arteriolar reactivity to ACh and SNP. These observations
for ACh are comparable to previous observations in which
pharmacological inhibition of cytochrome P-450 -hydroxylase
in normotensive rats fed standard rat chow had no significant effect on
cremasteric arteriolar reactivity to ACh (18). However, in
RRM-hypertensive rats, cytochrome P-450 -hydroxylase
inhibition significantly enhanced arteriolar reactivity to ACh and SNP
such that the responses to these agonists were similar to those in
normotensive rats on low-salt diet. These findings represent previously
unidentified relationships and suggest that the reduced vascular
reactivity to ACh and SNP with RRM-hypertension may be partially a
function of elevated 20-HETE production or an increased vascular
sensitivity to 20-HETE. Because 20-HETE inhibits KCa
channels (32) in vascular smooth muscle, blocking the production of
this compound could alleviate its influence on KCa channels
of microvessels and restore the reduced ACh- and SNP-induced dilator
responses in the RRM-hypertensive rats to normal levels. This
speculation is supported by the results of the studies summarized in
Fig. 9 showing that superfusion of the cremaster muscle with a
subthreshold dose of 20-HETE blunted the dilation of the arterioles in
response to ACh and SNP in a manner similar to that observed during
high-salt diet (for ACh) and RRM-hypertension (for both agonists).
Clearly, additional investigation is warranted to further delineate the
role of 20-HETE in the depressed vascular reactivity to ACh and SNP
that develops under these conditions.
Effects of cytochrome P-450 -hydroxylase inhibition
on ANG II-induced vasoconstriction.
The present study indicates that both RRM-hypertension and high-salt
diet alone increase the responsiveness of cremasteric arterioles to ANG
II. These observations are in agreement with the previous study
demonstrating an increased reactivity to ANG II in skeletal muscle
resistance arteries of normotensive rats on high-salt diet (30). In the
present study, treatment of the cremaster muscle with either 17-ODYA or
DDMS reduced the vasoconstriction to ANG II in all rats, suggesting
that some portion of the ANG II effect on vascular smooth muscle cells
may be mediated via the cytochrome P-450 system and 20-HETE.
Although further investigation is necessary to more fully establish the
contribution of 20-HETE in mediating vasoconstrictor responses to ANG
II, this speculation is supported by previous studies demonstrating a
role for products of cytochrome P-450 -hydroxylase,
including 20-HETE, in regulating renal (4) and placental (14) vascular
tone and renal tubular transport (1, 4, 19) following challenge with
ANG II.
Effects of cytochrome P-450 -hydroxylase inhibition
on O2-induced vasoconstriction.
The present study indicates that O2-induced constriction of
cremasteric muscle arterioles of normotensive rats is not altered by
high-salt diet alone. However, development of RRM-hypertension is
associated with a significantly increased microvessel constrictor sensitivity to elevated O2 levels. This latter observation
is in agreement with previous studies by Lombard et al. (15-17)
and by Rafi and Boegehold (25), in which the O2-induced
constriction of skeletal muscle microvessels in RRM-hypertensive rats,
spontaneously hypertensive rats, and hypertensive Dahl salt-sensitive
rats was increased compared with that observed in their normotensive
controls. Taken together, the results of these studies and the present
experiments clearly indicate that the development of hypertension is
associated with a significant increase in microvascular sensitivity to
increased O2 availability.
-hydroxylase as an important mediator of
O2-induced constriction of arterioles in rat and hamster
skeletal muscle, respectively. Harder et al. (12) demonstrated that
20-HETE production from renal microsomes was highly O2
dependent and that 20-HETE production is accelerated as ambient
O2 levels increase (0-150 mmHg). In the studies of
both Harder et al. (12) and Lombard et al. (18), treatment of skeletal
muscle arterioles with cytochrome P-450 -hydroxylase
inhibitors blunted vasoconstriction to elevated O2 tension.
The results of those studies, when integrated with the present
experiments, suggest that endogenous production of 20-HETE plays a
significant role in mediating O2-induced constriction of
arterioles in skeletal muscle.
Inhibition of vasoconstrictor responses between animal groups with
17-ODYA and DDMS.
The major goal of the present study was to determine the role of
endogenously produced 20-HETE in regulating vascular reactivity in
skeletal muscle microvessels of normotensive animals on high-salt diet
and of RRM-hypertensive rats. Inhibition of 20-HETE production reduced
the arteriolar constriction to ANG II in all rats, although this effect
was exacerbated with RRM-hypertension, as indicated by a significant
difference in the -coefficient in the RRM-hypertensive rats versus
the normotensive control groups. These results suggest that cytochrome
P-450 and the production of 20-HETE may play a more significant
role in mediating arteriolar responses to ANG II in RRM-hypertensive
rats than in normotensive animals.
-hydroxylase may play a major role in contributing to the enhanced
response of arterioles to elevated O2 tension in
hypertensive rats compared with normotensive controls.
In conclusion, results from the present study suggest that 20-HETE
production via cytochrome P-450 -hydroxylase may play a
central role in regulating 1) resting microvascular tone in RRM-hypertensive rats, 2) enhanced arteriolar constrictor
responses to ANG II and O2, and 3) reduced dilator
responses with RRM-hypertension and, to a lesser extent, high-salt diet
alone. Addressing the role of cytochrome P-450 metabolites of
arachidonic acid in regulating vascular reactivity under normal
physiological conditions and during the development of different
pathological conditions represents an exciting area for future investigation.
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ACKNOWLEDGEMENTS |
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This work was supported by National Institutes of Health Grants HL-29587, HL-37374, HL-52211, and GM-31278.
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FOOTNOTES |
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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.
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).
Received 5 August 1999; accepted in final form 3 November 1999.
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REFERENCES |
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|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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vessel diameter) determined during superfusion with
Ca2+-free physiological salt solution (PSS) containing
10
Significant decrease
(P < 0.05) in dilation compared with that determined for
normotensive rats on high-salt diet.
Significant increase (P < 0.05) in
response to ACh compared with that determined under control
conditions.
