Vol. 280, Issue 6, H2456-H2461, June 2001
SPECIAL TOPIC
Gender-specific compensation for the lack of
NO in the mediation of flow-induced arteriolar
dilation
Yuming
Wu1,
An
Huang1,
Dong
Sun1,
John R.
Falck2,
Akos
Koller1, and
Gabor
Kaley1
1 Department of Physiology, New York Medical College,
Valhalla, New York 10595; and 2 University of Texas
Southwestern Medical Center, Dallas, Texas 75235
 |
ABSTRACT |
Flow-induced dilation of
gracilis muscle arterioles was examined in both genders of control rats
and rats chronically treated with
N
-nitro-L-arginine methyl ester
(L-NAME). After L-NAME treatment (4 wk),
systolic blood pressure was significantly increased compared with
control, whereas the plasma concentration of nitrate/nitrite was
significantly reduced. Isolated and pressurized arterioles dilated
significantly in response to increases in flow (0-25 µl/min). Flow-induced dilation was comparable in arterioles of control and
L-NAME-treated rats but was significantly greater in female than in male rats. L-NAME + indomethacin, which
abolished flow-induced dilation in arterioles of male control rats,
inhibited the dilation by only ~75% in female control rats. The
residual portion of the response was eliminated by additional
administration of miconazole, an inhibitor of cytochrome
P-450. Indomethacin did not affect the dilation in female
L-NAME-treated rats but completely inhibited the response
in male L-NAME-treated rats. The indomethacin-insensitive, flow-induced dilation in female L-NAME-treated
arterioles was abolished by miconazole,
6-(2-proparglyoxyphenyl)hexanoic acid, or charybdotoxin. Thus an
augmented release of endothelial prostaglandins accounts for the
preserved flow-induced dilation in arterioles of male rats, whereas a
metabolite of cytochrome P-450 is responsible for the
maintenance of flow-induced dilation in female rats, suggesting important differences in the adaptation of the endothelium of arterioles from male and female rats to the lack of nitric oxide (NO) synthesis.
NO synthesis; hyperpolarizing factor; cytochrome P-450
metabolites; potassium channels
| |
INTRODUCTION |
THE ENDOTHELIUM PLAYS AN
IMPORTANT role in the regulation of vascular tone via release of
dilator mediators, including nitric oxide (NO), prostaglandins, and
endothelium-derived hyperpolarizing factor (EDHF), the latter generally
being characterized as a metabolite of arachidonic acid via cytochrome
P-450 (CYP) epoxygenase (6, 13, 18, 19). One of
the important local factors governing arteriolar tone is wall shear
stress, which is the primary stimulus for release of endothelial NO, as
well as prostaglandins, in vivo (14, 15).
There is but scant evidence regarding the release of EDHF in response
to increases in shear stress elicited by flow, especially because its
synthesis is believed to be inhibited by the other two endothelial
mediators released to flow (1, 24). Indeed, there is
increasing evidence suggesting a feedback inhibition on EDHF production
by NO and/or prostaglandins (2, 20, 24), as well as
potential interactions among these three endothelial mediators
(16). Upregulation of one system in response to a suppression or deficiency of the others has also been demonstrated (3, 4, 20). Our previous studies have shown that, in
skeletal muscle arterioles, flow-induced dilation in male wild-type
(WT) mice is mediated by endothelial NO and prostaglandins, whereas it
is mediated exclusively by prostaglandins in arterioles of male
endothelial NO synthase gene-deficient (eNOS-KO) mice
(22). In the same vessels isolated from female WT mice,
EDHF, together with prostaglandins, participates in the mediation of
flow-induced dilation when NO is acutely inhibited; however, EDHF is
solely responsible for the maintenance of this response in female
eNOS-KO mice (9).
The question, therefore, arose as to whether the gender-specific
compensation involving flow-induced dilation in response to NO
deficiency is a universal phenomenon or simply a species-specific response. In addition, whether the effects of a short-term adaptation to the absence of NO synthesis are any different from those caused by a
genetic lack of eNOS is of interest. Accordingly, we designed experiments to be conducted on arterioles of male and female rats that
were chronically treated with
N-nitro-L-arginine methyl ester
(L-NAME), an inhibitor of the synthesis of NO.
| |
METHODS |
Animals.
Twelve-week-old Wistar rats (Charles River Laboratories, Wilmington,
MA) were divided into four groups: control untreated male,
L-NAME-treated male, untreated female, and
L-NAME-treated female rats. Rats
received L-NAME in the drinking water (50 mg/100 ml) for 4 wk. Age-matched normal male and female rats drinking tap
water alone were studied concomitantly. All protocols were approved by
the Institutional Animal Care and Use Committee of New York Medical
College and conform to the guidelines of the National Institutes of
Health and the American Physiological Society for the use and care of
laboratory animals.
Experimental procedures.
Systolic blood pressure (SBP) and heart rate were monitored every 3 days after the start of treatment by using the tail-cuff method. Rats
were anesthetized with pentobarbital sodium (Nembutal, 50 mg/kg ip).
Experiments were conducted on isolated gracilis muscle arterioles of
all rats. The dissection of muscle and isolation of vessels have been
described previously (10, 14). Changes in the diameter of
arterioles in response to increases in flow were studied at 80 mmHg
perfusion pressure. Perfusate flow was increased from 0 to 25 µl/min
in 5 µl/min steps. After control experiments, inhibitors were
administered in the perfusate for 30 min before and during the
experimental protocols.
In the first series of experiments, the role of NO or prostaglandins in
the mediation of flow-induced dilation was assessed by using
L-NAME (10
4 M) and indomethacin (Indo,
105 M), inhibitors of NO synthase and cyclooxygenase,
respectively. After control flow-diameter curves were obtained, an
inhibitor was administered alone or in combination with the other
before the flow-diameter relationships were once more assessed.
In the second series of experiments, the role and interaction of
metabolites of cytochrome P-450 (CYP) and eNOS on
flow-induced dilations were assessed by using miconazole (MCZ, 2 × 106 M), an inhibitor of CYP epoxygenase, and
L-NAME. After control experiments, MCZ or
L-NAME was administered before the experiments were
repeated. Then flow-induced responses were studied once more in the
additional presence of the other inhibitor. In a separate group of
experiments, the effect of metabolites of CYP on flow-induced dilation
in arterioles of L-NAME-treated female rats was confirmed further by using 6-(2-proparglyoxyphenyl)hexanoic acid (PPOH, 105 M), which is thought to be a more specific inhibitor
of CYP epoxygenase (23).
In the third series of experiments, the contribution of EDHF to
flow-induced responses was again evaluated by performing the experiments before and after abluminal administration of charybdotoxin (ChTX, 2 × 108 M), a blocker of
Ca2+-dependent K+ channels. These channels are
thought to be activated by EDHF, causing hyperpolarization of vascular
smooth muscle and vessel dilation.
Passive diameter.
At the conclusion of each experiment, the suffusion solution was
changed to a Ca2+-free solution containing 1 mM EGTA.
Vessels were incubated for 10 min to reach maximal diameter at 80 mmHg
perfusion pressure.
Measurement of plasma nitrate/nitrite.
After the muscle had been excised, blood (5 ml) was withdrawn from the
abdominal aorta with a 10-ml syringe containing 0.1 ml of heparin
sodium (1,000 U/ml). The blood sample was centrifuged immediately
(3,000 rpm at 4°C for 20 min) to obtain the plasma, which was then
filtered through a 10,000-mol wt cutoff filter (NANOSEP, Fisher) to
remove Hb. The plasma was kept at 
80°C for later measurement of
plasma nitrite/nitrate (NO2/NO3) concentration (25) by fluorometric assay.
Chemicals.
All chemicals were obtained from Sigma (St. Louis, MO). PPOH was
dissolved in ethanol at 102 M and further diluted with
physiological salt solution (PSS). L-NAME and ChTX were
dissolved in saline. Indo and MCZ were dissolved in DMSO at
101 and 102 M for Indo and MCZ,
respectively, and further diluted with PSS. The highest concentration
of DMSO in the chamber was 0.1% (vol/vol), which had no effect on
vessel tone.
Calculations and statistics.
Passive diameter (PD) was used to assess the active tone (%PD)
generated by arterioles in response to intravascular pressure and to
normalize the changes in diameter in response to increases in flow in
each vessel. Values are means ± SE; n is the number of
rats. Statistical significance was calculated by repeated-measures of
ANOVA followed by the Tukey-Kramer multiple-comparison test. Student's
t-test was also used, as appropriate. Significance level was
taken at P < 0.05.
| |
RESULTS |
Table 1 shows the changes in SBP,
heart rate, and plasma concentrations of
NO2/NO3 in four groups of rats. SBP was
significantly increased and heart rate was correspondingly reduced in
L-NAME-treated rats compared with untreated rats
(P < 0.05). Also, plasma concentration of
NO2/NO3 was significantly reduced after
L-NAME treatment (P < 0.05).
Characteristics of arterioles of gracilis muscle from the four groups
of rats studied are summarized in Table
2. PDs were significantly smaller in
arterioles of L-NAME-treated than untreated rats, whereas
active diameters and basal tone, expressed as percentage of PD, were
comparable in vessels from rats of the same gender. On the other hand,
basal arteriolar tone in female rats was significantly attenuated
compared with that in male rats (P < 0.05).
Increasing flow from 0 to 25 µl/min elicited significant increases in
diameter of arterioles from all four groups of rats (Fig.
1). The magnitude of flow-induced
dilation of arterioles was comparable in untreated and treated rats of
the same gender but was significantly greater in female than in male
rats (~89.8 ± 1.3 vs. 73.9 ± 1.3% at 25 µl/min),
confirming our previous findings (11).
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Fig. 1.
Normalized diameter of gracilis muscle arterioles, as a
function of perfusate flow, in male control (untreated,
n = 5) and
N-nitro-L-arginine methyl ester
(L-NAME)-treated (n = 6; A) and
female untreated (n = 15) and
L-NAME-treated (n = 16; B)
rats.
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|
Arterioles of male rats.
The endothelial mediators responsible for the mediation of flow-induced
dilation in arterioles of male rats are summarized in Fig.
2, showing that in untreated rats
(A), Indo or L-NAME alone inhibited flow-induced
dilation by ~50%. Combined administration of both inhibitors
abolished the responses. In rats treated chronically with
L-NAME (Fig. 2B), Indo eliminated the dilator
responses to flow, revealing a solely prostaglandin-mediated
flow-induced dilation as a consequence of L-NAME treatment.
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Fig. 2.
Normalized diameter of gracilis muscle arterioles, as a
function of perfusate flow, of male untreated (n = 5;
A) and L-NAME-treated rats (n = 6; B) in the control condition and in the presence of
indomethacin (Indo, 105 M), L-NAME
(104 M), or Indo + L-NAME. PD, passive
diameter. *Significant difference between the 2 curves.
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Arterioles of female rats.
The endothelial mediators responsible for the mediation of flow-induced
dilation in arterioles of female rats are summarized in Figs.
3 and 4. A
prostaglandin-mediated portion of flow-induced dilation in arterioles
of untreated female rats was demonstrated by the fact that Indo
inhibited the responses by ~50% whether Indo was administered first
or last among the inhibitors used (Fig. 3). The roles of NO and
metabolites of CYP in the mediation of flow-induced dilation in vessels
of untreated female rats were also assessed by using L-NAME
and MCZ. The Indo-resistant portion of the response was partially
inhibited by L-NAME or MCZ after L-NAME (Fig.
3, top and middle). On the other hand, unlike
L-NAME, MCZ alone did not affect the Indo-resistant portion
of the response, which, however, was eliminated by additional
administration of L-NAME (Fig. 3, bottom),
suggesting an interaction between NO and metabolites of CYP.
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Fig. 3.
Normalized diameter of gracilis muscle arterioles of
untreated female rats (n = 5 for each group), as a
function of perfusate flow, in the control condition and after
administration of L-NAME, Indo, or miconazole (MCZ, 2 × 106 M) in different sequence, alone and in
combination. *Significant difference between the 2 curves.
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Fig. 4.
Normalized diameter of gracilis muscle arterioles of
female L-NAME-treated rats (n = 6 for each
group), as a function of perfusate flow, in the control condition, in
the presence of Indo, MCZ, or PPOH (A), and in the presence
of charybdotoxin (ChTX, 2 × 108 M; B).
*Significant difference from control and from the presence of Indo.
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Figure 4 shows that, in female rats treated chronically with
L-NAME, flow-induced dilation was independent of
prostaglandins, since Indo had no effect on the response. Dilation,
however, was eliminated by MCZ or PPOH (Fig. 4A), revealing
the involvement of the CYP pathway in the mediation of the responses,
as a consequence of chronic L-NAME treatment. When these
arterioles were treated with ChTX, flow-induced dilation was abolished
(Fig. 4B).
| |
DISCUSSION |
The present study demonstrates a gender-specific adaptation to the
lack of NO in the mediation of endothelium-dependent flow-induced dilations in rat gracilis muscle arterioles. It also shows that although NO and prostaglandins participate equally in the mediation of
flow-dependent responses in control rats of both genders, after chronic
treatment with L-NAME, prostaglandins account solely for this response in vessels of male rats and EDHF in vessels of female rats. Also, EDHF contributes partially to the mediation of flow-induced dilation when NO synthesis is acutely inhibited in female control rats.
These findings are consistent with our previous studies in WT and
eNOS-KO mice (9, 22). The congruence between the present
and our previous studies reveals that a deficiency of eNOS-derived NO
activates gender-specific signal transduction pathways.
It was reported previously that the cardiovascular system adapts to an
acute inhibition of NO synthesis in a manner that is different from
that observed with a chronic lack of NO (5). Also our
previous studies demonstrated that, in skeletal muscle arterioles of
eNOS-KO mice, endothelial cells adapt to the chronic lack of NO and
maintain a normal or close-to-normal response to shear stress by
upregulation of the synthesis of other mediators, which, however,
operate in a heterogeneous fashion dependent on gender (9,
22). Given that compensatory mechanisms may play an important
role in the maintenance of cardiovascular function and that sex
hormones may participate in the control of this compensation, it was of
interest to define the nature of the mechanisms by which vessels are
capable of responding normally to flow/shear stress in the absence of
NO. To this end, flow-induced dilation and the nature of the
endothelial factors mediating this response were investigated in
gracilis muscle arterioles of rats of both genders treated chronically
with L-NAME.
SBP was significantly enhanced, resulting in a reflex attenuation of
heart rate in L-NAME-treated rats. Also, plasma
concentrations of NO2/NO3 were significantly
reduced after chronic L-NAME treatment (Table 1). The PD of
arterioles of L-NAME-treated rats was significantly smaller
than that of untreated littermates, a finding similar to that in
eNOS-KO mice (9, 22), whereas the active diameters and the
basal tone of vessels were comparable in the vessels of the two groups
(Table 2). In addition, the results showing attenuated basal tone
(Table 2) and enhanced flow-induced dilation (Fig. 1) in arterioles of
female compared with male rats are consistent with our previous
findings (10-12) showing that the greater basal and
stimulated release of endothelial NO, triggered by the presence of
estrogen, is responsible for these differences. Interestingly, in the
present study, the reduced basal tone and greater flow-induced dilation
in female than in male rats seem not to be purely NO dependent, since
they are also present in L-NAME-treated littermates. On the
other hand, the similar magnitude of flow-induced dilation in treated
and untreated rats of the same gender (Fig. 1) further supports our
hypothesis that arterioles of skeletal muscle are able to compensate
for the absence of NO to maintain dilator responses to shear stress.
Adaptation of arterioles of male rats.
Our present findings are similar to those we reported previously
(14) showing that endothelium-derived NO and
prostaglandins are coreleased in gracilis muscle arterioles of
untreated male rats in response to increases in flow, that
endothelium-derived NO and prostaglandins are responsible for the
ensuing vasodilation, and that inhibition of NO or prostaglandin
synthesis reduces the dilation by ~50%. Combination of both
inhibitors eliminated the responses (Fig. 2A). In contrast,
in arterioles of male rats treated chronically with L-NAME,
Indo completely eliminated flow-induced dilation, indicating that the
response is solely mediated by enhanced release of dilator
prostaglandins (Fig. 2B), a finding that corresponds to that
observed in the same vessels of male eNOS-KO mice (22). Recently, we demonstrated that this compensatory upregulation of
prostaglandin synthesis most likely involves inducible cyclooxygenase (unpublished observations). In keeping with the present findings, an
upregulation of cyclooxygenase activity, as a consequence of chronic NO
deficiency, has also been demonstrated in the dog coronary (3,
21) and rat mesenteric circulations (8).
Adaptation of arterioles of female rats.
As for the endothelial factors responsible for the mediation of
flow-induced responses in arterioles of female mice, results shown in
Fig. 3 indicate that in untreated rats, apart from the coparticipation
of NO and prostaglandins, CYP metabolites contribute, in part, to the
mediation of the responses, as indicated by the inhibitory effect of
MCZ on the dilations. However, such a role for CYP metabolites was
observed only in the presence of L-NAME, since MCZ alone
did not affect the responses (Fig. 3, bottom). Unlike MCZ,
either L-NAME or Indo alone significantly inhibited flow-induced dilation (Fig. 3, top and middle),
indicating that NO and prostaglandins are the primary mediators of this
response in normal conditions. The absence of NO after the acute
administration of L-NAME activates CYP, eliciting EDHF
formation, which then contributes to the mediation of flow-dependent
dilation. A similar effect of a NO donor on agonist-induced EDHF
release from porcine (1, 2) and canine coronary arteries
(20) was also reported.
In female rats treated chronically with L-NAME (Fig. 4),
MCZ or PPOH alone abolished flow-induced dilation, indicating a solely CYP metabolite-dependent response, unaffected by inhibition of cyclooxygenase (Fig. 4A). Furthermore, the dilation is
completely inhibited by ChTX (Fig. 4B), suggesting further
that the CYP-mediated dilation to flow is indeed dependent on
hyperpolarization of vascular smooth muscle, via activation of
Ca2+-sensitive K+ channels (6).
These results, together with those observed in eNOS-KO mice, may well
form the basis of the gender-dependent mechanisms by which compensation
for the lack of endothelial NO occurs in resistance vessels. Regarding
the relationships between EDHF and female hormones, previous studies
have provided some evidence suggesting that estrogen enhances the
contribution of EDHF in the mediation of agonist-induced vasodilation
(17) and smooth muscle membrane hyperpolarization (7). Further studies are necessary to establish the
possible role(s) of specific hormones that are responsible for the
activation of endothelial pathways leading to the synthesis of NO,
prostaglandins, and EDHF in the two genders.
In conclusion, we demonstrated that, in skeletal muscle arterioles of
male and female rats, NO and prostaglandins are the primary mediators
of flow-induced dilation in control conditions. When NO synthesis is
blocked acutely, EDHF participates in the responses of vessels of
female rats. In arterioles of male rats chronically treated with
L-NAME, prostaglandins are solely responsible for the
preserved flow-induced dilation, whereas in vessels of L-NAME-treated female rats, this response is exclusively
mediated by EDHF. These data, together with our previous findings in
eNOS-KO mice, support our hypothesis that compensatory mechanisms in
arterioles evoked by the absence of NO are indeed gender dependent in
nature, through which enhanced contribution of endothelial mediators
other than NO contribute to the maintenance of shear stress-sensitive regulation of skeletal muscle arterioles and, consequently, peripheral resistance.
| |
ACKNOWLEDGEMENTS |
We appreciate the excellent secretarial assistance of Miriam Nunez
and Dana M. Spencer.
| |
FOOTNOTES |
This study was supported by National Heart, Lung, and Blood Institute
Grants HL-43023 and HL-46813, and American Heart Association Grant 9930244N.
Address for reprint requests and other correspondence: G. Kaley, Dept. of Physiology, New York Medical College, Valhalla, NY
10595 (E-mail: Gabor_Kaley{at}NYMC.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 7 December 2000; accepted in final form 10 January 2001.
| |
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ABSTRACT
INTRODUCTION
