(Hypertension. 1997;29:969-975.)
© 1997 American Heart Association, Inc.
Articles |
Role of Nitric Oxide in the Development of Vascular 
1-Adrenoreceptor Desensitization and Pressure Diuresis in Conscious Rats
From The Second Department of Internal Medicine, Tohoku University School of Medicine, Sendai, Japan.
Correspondence to Naoyoshi Minami, MD, The Second Department of Internal Medicine, Tohoku University School of Medicine, 1-1 Seiryou-cho, Aoba-ku, Sendai 980, Japan.
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Abstract |
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Abstract We evaluated whether a minor impairment of the L-arginine–nitric oxide pathway would affect the desensitization of vascular
-adrenoreceptor and
pressure diuresis induced by prolonged intravenous
infusion of phenylephrine (an
-adrenoreceptor agonist) in conscious Wistar-Kyoto
rats. We examined dose-pressor–response curves to
phenylephrine after an intravenous infusion of
phenylephrine (2.5
µg·kg-1·min-1)
or saline for 9 hours with and without concomitant infusion of
N
-L-arginine methyl ester
(L-NAME) given to partially inhibit the L-arginine–nitric
oxide pathway. In addition, to evaluate the effect of plasma volume
loss on the pressor response to phenylephrine, we evaluated
the dose-pressor–response curves to phenylephrine after
intravenous injection of furosemide (5 mg/kg) or infusion
of phenylephrine (5
µg·kg-1·min-1)
for 9 hours. The renin-angiotensin, vasopressin and
autonomic nervous systems were blocked before the examination of
dose-pressor responses. Prolonged infusion of phenylephrine
(2.5
µg·kg-1·min-1)
shifted the dose pressor–response curve to this agent rightward, with
significantly increased log ED50 (the dose needed to reach
50% of the maximal response) to a similar extent in both
L-NAME–treated (0.51±0.05 versus 0.93±0.07 µg/kg) and –untreated
(0.79±0.06 versus 1.08±0.03 µg/kg) rats. The log ED50
value after phenylephrine infusion (5
µg·kg-1·min-1)
was significantly higher than that after furosemide injection
(1.28±0.06 versus 1.02±0.01 µg/kg, respectively,
P<.01), although the two treatments induced a similar loss
of plasma volume. The slope in the linear relationship between the
average change in mean arterial pressure during the 9-hour
infusion period and the rate of urine excretion was significantly
depressed in L-NAME–treated versus control rats (L-NAME: 0.057
mL·kg-1·h-1·mm Hg-1,
control: 0.146
mL·kg-1·h-1·mm Hg-1,
P<.05). In conclusion, a minor impairment of the
L-arginine–nitric oxide pathway does not appear to
interfere with the desensitization of vascular
-adrenoreceptor but does inhibit the
pressure-diuresis response in conscious normotensive rats.
Key Words: nitric oxide • receptors, adrenergic alpha • desensitization, adrenergic • diuresis • rats
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Short-term intravenous infusion of norepinephrine increases BP in a dose-dependent manner,1 whereas prolonged intravenous infusion of a relatively low dose of this agent does not produce sustained hypertension.2 3 4 A loss in plasma volume elicited by pressure diuresis or pressure natriuresis has been proposed to explain the reduced pressor response to norepinephrine. It has also been suggested that the development of vascular
-adrenoreceptor
desensitization, which is observed in vitro,5 6
contributes to the reduction in the pressor response to an
-adrenoreceptor agonist after prolonged infusion of
catecholamine.7 However, it is not known to
what extent the two mechanisms contribute to this reduction.
It was recently demonstrated that NO, which is generated from
L-arginine and acts as an
endothelium-derived relaxing factor,8 is
important in the regulation of pressure diuresis or pressure
natriuresis in anesthetized animals.9 10 Also, it
has been shown in vitro11 that NO contributes to the
development of vascular -adrenoreceptor
desensitization. Our objectives were to determine whether prolonged
intravenous infusion of a low dose of
phenylephrine (an -adrenoreceptor
agonist) would lead to vascular -adrenoreceptor
desensitization and to examine whether a partial impairment of the
L-arginine–NO pathway, which is found in several clinical
conditions,12 13 14 affects the development of vascular
-adrenoreceptor desensitization and the
pressure-diuresis response of conscious rats.
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Methods |
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Animals and BP Measurement
Experiments were conducted in 13-week-old male Wistar-Kyoto rats (315 to 340 g) (Charles River, Yokohama, Japan). The surgical procedures and methods used for BP measurement have been previously described.15 In brief, with rats under ether anesthesia, arterial and two venous catheters were implanted into the femoral artery, femoral vein, and right jugular vein, respectively. The free ends of these catheters were brought subcutaneously to the back of the neck. The arterial catheter was connected to a hydraulic tethering system. To keep the arterial catheter patent, heparinized saline (50 U/mL) was continuously infused at a rate of 0.1 mL/h. The venous catheter was also filled with heparinized saline (50 U/mL). Rats were placed in individual plastic cages and housed at a controlled temperature (23±1°C) and 12 hour light/dark cycle, with free access to food and water. The rats were allowed to recover for 3 days after surgery. The experiments were then performed on fully conscious, unrestrained rats. BP was recorded from the femoral arterial catheter with a p23ib Statham pressure transducer (Oxford) and strain-gauge amplifier (model 1257, NEC-San-ei). Heart rate was counted from the phasic pressure wave by a cardiotachometer (model 1321, NEC-San-ei). The analog signals of phasic pressure, MAP, and heart rate were fed to an analog-to-digital converter (Mark 1, NCC). Digital signals of MAP and heart rate from this converter were fed to a microcomputer (model HP-9816, Hewlett-Packard) every 4 seconds. Mean values for these parameters were calculated every 10 minutes or 1 hour.
Protocols
Protocol 1 evaluated the effect of plasma volume loss on
the dose-pressor responses to phenylephrine. In one group
of rats (n=5), plasma volume loss was induced by
intravenous injection of furosemide (5 mg/kg) together with
deprivation of drinking water. Two hours later, plasma
volume loss was estimated by urine volume, and the dose-pressor
responses to phenylephrine were examined. In another group
of rats (n=5), a similar level of plasma volume loss as seen with
furosemide was induced via the pressure-diuresis response to
intravenous infusion of phenylephrine (5
µg·kg-1·min-1=100
µL/h) given over 9 hours. The phenylephrine infusion was
started at 10 AM and ended at 7 PM. BP and
heart rate were continuously monitored for 10 hours between 9:30
AM and 7:30 PM. One half hour after the
cessation of the phenylephrine infusion, we evaluated the
dose-pressor responses to phenylephrine. The loss in plasma
volume during the infusion was estimated in these rats as follows:
Plasma Volume Loss=Urine Volume-[Drinking Water Volume+0.9 mL
(Infusion Volume)].
We designed protocol 2 to determine whether the reduction in the dose-pressor responses to phenylephrine and the pressure-diuresis response, both of which were induced by prolonged intravenous infusion of phenylephrine, would differ between rats with an intact versus an impaired L-arginine–NO pathway. Rats were assigned to two groups. The L-arginine–NO pathway was intact in one group and impaired in the other. The latter group of rats was treated with the NO synthase inhibitor L-NAME (1 mg/kg IV followed by 0.5 mg-1·kg/h-1 IV=100 µL/h). The L-NAME used was determined to inhibit the L-arginine–NO pathway only partially.16 Each group of rats was subdivided into two groups: one group received intravenous infusion of saline (100 µL/h) for 9 hours, and the other group received intravenous infusion of phenylephrine (2.5 µg·kg-1·min-1=100 µL/h) for 9 hours. Thus, we evaluated four groups: rats with intravenous infusions of saline alone (n=6), phenylephrine alone (n=6), L-NAME alone (n=6), and concomitant infusion of L-NAME and phenylephrine (n=6). The schedules for saline or drug infusion and BP and heart rate measurements were the same as in protocol 1. The loss in plasma volume was estimated as described in protocol 1. Dose-pressor responses to phenylephrine were examined 0.5 hour after cessation of saline or drug infusion.
Dose-Pressor Responses to Phenylephrine
In both protocols, the RAS and vasopressin and autonomic
nervous systems were blocked in that order before we estimated the
dose-pressor responses to phenylephrine. Each drug was
administered intravenously through a jugular vein catheter
as follows: 10 mg/kg captopril, 3 mg/kg OPC-21268 (a vasopressin
V1 receptor antagonist), 1 mg/kg methyl
atropine, 1 mg/kg, atenolol, and 10 mg/kg pentolinium. Pentolinium was
administered 10 minutes after atenolol was given. The ganglion blocker
atenolol and methyl atropine were administered to eliminate baroreflex
modulation of cardiac output and vascular tone. Captopril and the
V1 receptor antagonist were administered to
prevent restoration of BP after ganglion blockade.17
Approximately 2.5 minutes after injection of pentolinium, when BP had
reached its lower plateau, we obtained the cumulative dose-pressor
responses to 11 different phenylephrine doses in the range
of 0.125 to 128 µg/kg IV. The MAP–log dose relationship was fitted
by computer to the sigmoidal logistic equation as
follows18 :
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Drugs
L-NAME, phenylephrine, pentolinium, captopril,
methyl atropine, and atenolol were obtained from Sigma Chemical Co,
furosemide from Hoechst, and OPC-21268 from Otsuka Pharmaceutical Co,
Ltd. OPC-21268 was dissolved in dimethylformamide (Wako Pure Chemicals)
and was injected intravenously in a volume of 100 µL/kg,
followed by 100 µL saline. A dose of OPC-21268 lower than that used
in the present study, 1 mg/kg IV, has been shown to completely
antagonize the pressor effect of 30 mU/kg arginine vasopressin
IV.19 The phenylephrine used to construct the
dose-pressor response curves was dissolved in saline (0.125
mg·kg-1·mL-1).
The other drugs were dissolved in saline and injected
intravenously in a volume of 1 mL/kg.
Data Analysis
Data are expressed as mean±SEM. To investigate whether
impairment of the L-arginine–NO pathway would modulate the
effect of prolonged intravenous infusion of
phenylephrine on the ED50 value of the
phenylephrine dose-pressor–response curve, we evaluated
data statistically by factorial ANOVA with L-NAME treatment (two
levels, L-NAME or placebo) as a between-groups factor, and
phenylephrine infusion (two levels,
phenylephrine or placebo) as a within-groups factor. The
pressure-diuresis relationship was estimated by linear
regression analysis of the average change in MAP and urinary
excretion rate during the 9-hour infusion period. The average change in
MAP during the 9-hour infusion was calculated as the average MAP in the
9-hour period minus the average MAP in the control period. Other data
were analyzed by Scheffé's F test after
performance of one-way ANOVA. A level of P<.05 was
considered statistically significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Hemodynamic Changes
Fig 1a
shows the changes in MAP and heart rate in
rats receiving saline alone or two doses of phenylephrine
(2.5 and 5
µg·kg-1·min-1).
Fig 1b shows the changes in rats receiving L-NAME alone or
phenylephrine (2.5
µg·kg-1·min-1)
in addition to L-NAME. There were no significant differences among
subgroups in basal (preinfusion period) MAP and heart rate.
Phenylephrine infusion at rates of 2.5 and 5
µg·kg-1·min-1
for 1 hour increased MAP on average from 101±2 to 123±3 mm Hg
and from 100±3 to 136±5 mm Hg, respectively. This pressor
effect of phenylephrine gradually decreased with time, with
no statistically significant pressor effect being observed at 8 or 9
hours after the start of drug infusion in both groups. After cessation
of the phenylephrine infusion at 5
µg·kg-1·min-1,
MAP decreased from 108±5 to 76±2 mm Hg without reflex
tachycardia. After cessation of the
phenylephrine infusion at 2.5
µg·kg-1·min-1,
MAP fell transiently 10 mm Hg below baseline.
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), 2.5
µg·kg-1·min-1
phenylephrine (
), and 5
µg·kg-1·min-1
phenylephrine (
) infused intravenously in
conscious Wistar-Kyoto rats for 9 hours (*P<.05,
**P<.01 vs saline). b, Changes observed in response to
L-NAME (1±0.5
mg·kg-1·h-1)
(L-NAME infusion alone increased MAP slightly but significantly by 11±2 mm Hg on average during the infusion period except for the 9-hour infusion period. Infusion of phenylephrine at 2.5 µg·kg-1·min-1 in addition to L-NAME for 1 hour increased MAP from 105±1 to 142±2 mm Hg in association with marked bradycardia. The pressor effect of phenylephrine infusion in addition to L-NAME also decreased with time. However, MAP 9 hours after the start of concomitant infusion of phenylephrine and L-NAME significantly exceeded that of L-NAME alone. After cessation of concomitant infusion of L-NAME and phenylephrine, MAP decreased markedly, from 131±3 to 96±4 mm Hg. The latter value was significantly lower than that of rats treated with L-NAME alone. This decrease in MAP was not associated with reflex tachycardia. Two hours after intravenous injection of furosemide, MAP and heart rate did not change significantly.
Dose-Pressor Responses to Phenylephrine
Fig 2 shows the dose-pressor–response curves to
phenylephrine, which were investigated during blockade of
the RAS and vasopressin and autonomic nervous systems in rats
pretreated with vehicle, furosemide, or phenylephrine
infusion at 5
µg·kg-1·min-1.
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) in
Wistar-Kyoto rats. A similar loss in plasma volume was induced by
phenylephrine infusion and furosemide (Table 2
Pretreatment with infusion of phenylephrine (5
µg·kg-1·min-1)
and furosemide shifted the dose-pressor–response curves to
phenylephrine to the right (Fig 2
) and significantly
increased the log ED50 values (Table 1).
However, the log ED50 values in rats treated with
phenylephrine (5
µg·kg-1·min-1)
significantly exceeded those in rats treated with furosemide
(P<.01). The loss in plasma volume induced by the
phenylephrine infusion (5
µg·kg-1·min-1)
resembled that induced by furosemide (Table 2). These
results indicated that the prolonged phenylephrine infusion
shifted the dose-pressor–response curves to phenylephrine
to the right, not only because of the loss in plasma volume associated
with the pressure-diuresis response but also, probably, because
the development of vascular -adrenoreceptor
desensitization.
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Fig 3 shows the extent to which pretreatment with
phenylephrine at 2.5
µg·kg-1·min-1
shifted the dose-pressor–response curves to phenylephrine
in rats with an intact (a) and impaired (b) L-arginine–NO
pathway. In rats with the intact L-arginine–NO pathway,
phenylephrine pretreatment shifted the
dose-pressor–response curves to phenylephrine to the right
and significantly increased the log ED50 values from
0.790±0.06 to 1.08±0.03 µg/kg (P<.01) (Table 1).
Although pretreatment with L-NAME alone shifted the
dose-pressor–response curves to phenylephrine to the left
of control, pretreatment with phenylephrine in addition to
L-NAME shifted the curves to the right and significantly increased
the log ED50 values from 0.51±0.05 to 0.93±0.07 µg/kg
(P<.01). Based on the factorial ANOVA with drug
pretreatment (two levels, L-NAME or placebo) as a between-group factor
and another drug pretreatment (two levels, phenylephrine or
placebo) as a within-group factor, we observed no significant
two-factor interaction effect on the log ED50 values. This
indicated that prolonged phenylephrine infusion caused a
similar desensitization of the vascular
-adrenoreceptor in rats with an impaired
(L-NAME–treated) or intact L-arginine–NO pathway.
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) (a) as well as L-NAME (1±0.5
mg·kg-1·h-1)
alone (
Table 1 shows the parameters of the dose-pressor–response
curves to phenylephrine. The lower plateau of MAP (low BP)
after blockade of the RAS and vasopressin and autonomic nervous systems
was significantly lower in rats pretreated with
phenylephrine (2.5 and 5
µg·kg-1·min-1)
versus control. The low BP in rats pretreated with
phenylephrine in addition to L-NAME was also significantly
lower than that in rats pretreated with L-NAME alone, although the low
BP in rats pretreated with L-NAME significantly exceeded that in
control. The low BP in rats pretreated with furosemide was slightly
lower than that in control, but not to a significant extent.
Unexpectedly, the upper plateau of MAP (P1) in rats
pretreated with phenylephrine (2.5 and 5
µg·kg-1·min-1)
significantly exceeded that of control. The P1 value of
rats pretreated with phenylephrine plus L-NAME also
significantly exceeded that of rats pretreated with L-NAME alone. The
P1 in rats treated with furosemide did not differ
significantly from that in control.
Pressure-Diuresis Response
There was a significant correlation between the average change in
MAP and urine volume during the 9-hour infusion period in rats with an
intact or an impaired L-arginine–NO pathway (Fig 4). However, the slope of the average change in MAP
versus urine volume relationship in rats with an impaired
L-arginine–NO pathway was significantly depressed versus
that in intact rats, indicating that the pressure-diuresis
response was reduced in rats with an impaired
L-arginine–NO pathway.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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We demonstrated that intravenous infusion of phenylephrine at 2.5 or 5 µg·kg-1·min-1 for 9 hours did not produce sustained hypertension in conscious normotensive rats. This observation agrees with previous reports showing that a prolonged intravenous infusion of a relatively low dose of norepinephrine does not cause sustained hypertension.2 3 4 This phenomenon has been attributed to a loss in plasma volume associated with pressure diuresis or pressure natriuresis. This mechanism was confirmed by the present results showing that furosemide, which induced a 13% loss in plasma volume, significantly reduced the pressor response to phenylephrine, as indicated by a rightward shift of the dose-pressor–response curve (Fig 2
). However, it is unlikely that a
loss in plasma volume is the sole mechanism by which a prolonged
infusion of phenylephrine failed to cause sustained
hypertension. The phenylephrine infusion at 5
µg·kg-1·min-1
for 9 hours, which induced a loss in plasma volume similar to that
induced by furosemide (Table 2), reduced the pressor response to
phenylephrine more than did furosemide. In addition,
phenylephrine at 2.5
µg·kg-1·min-1
for 9 hours, which induced a lesser loss in plasma volume than
furosemide, reduced the pressor response to phenylephrine,
as did furosemide. These results indicate that the lessening of the
pressor response to phenylephrine after its prolonged
infusion was elicited not only by a loss in plasma volume but also,
probably, by the development of vascular
-adrenoreceptor desensitization. Although the
mechanisms responsible for such desensitization have been evaluated in
vitro,5 6 it was unclear whether the development of
vascular -adrenoreceptor desensitization occurred in
vivo. In this respect, Maze et al7 demonstrated that the
pressor response to phenylephrine is significantly reduced
by epinephrine pretreatment in conscious rabbits. However, the
effect of plasma volume loss induced by pressure diuresis was
not evaluated in that study.
The vascular responsiveness to an -adrenoreceptor
agonist is determined by the vascular smooth muscle cells and
endothelial cells. The NO released from
endothelial cells reduces the
-adrenoreceptor–mediated
vasoconstriction20 or pressor responses.21 As
expected, chronic infusion of a subpressor dose of L-NAME, an
inhibitor of NO synthesis, significantly enhanced the
pressor responses to phenylephrine in conscious rats, as
indicated by the leftward shift of the dose-pressor–response curve
(Fig 3). In addition to the acute interaction between the
-adrenoreceptor agonist and the
L-arginine–NO pathway in endothelial
cells, a chronic interaction between these two systems has also been
postulated. Hiremath et al11 demonstrated that the
development of -adrenoreceptor desensitization was
reduced in endothelium-denuded aortic rings versus
intact aortic rings, suggesting that the endothelium
promotes the development of -adrenoreceptor
desensitization in vascular smooth muscle cells. Those authors also
showed that -adrenoreceptor desensitization in
aortic rings after prolonged exposure to phenylephrine
disappeared by removing the endothelium or giving
hemoglobin, which inhibits the effect of NO.11 These
findings suggest that NO plays an important role in the development and
maintenance of vascular -adrenoreceptor
desensitization. The present study showed that prolonged
phenylephrine infusion shifted the dose-pressor–response
curve to phenylephrine to the right, similar to that
observed in rats with an intact L-arginine–NO pathway
versus those with an impaired pathway (Fig 3). Results suggest that a
minor impairment of the L-arginine–NO pathway induced
by L-NAME infusion did not significantly interfere with the development
of -adrenoreceptor desensitization. The discrepancy
between the present results and those in the previous study may be
due to the differences in the extent to which the
L-arginine–NO pathway was inhibited. In the present
study, the L-arginine–NO pathway was only partially
inhibited, whereas in the previous study, it was completely inhibited
by endothelium removal.
The lower plateau of MAP (low BP) after the elimination of the major
pressor systems and autonomic reflex was significantly higher in the
L-NAME–treated versus control rats (Table 1), indicating the tonic
vasodilator action of the endothelial NO
system.22 23 Phenylephrine infusion
significantly decreased the low BP in rats with an intact or impaired
L-arginine–NO pathway. Residual plasma
catecholamines persist even after the sympathetic nervous
system is blocked with a ganglion blocker.24 Thus, the
reduced sensitivity of the vasculature to such residual
catecholamines may be partly responsible for the relatively
lower BP in rats that were pretreated with the
phenylephrine infusion. Theoretically, the loss in plasma
volume would also reduce the low BP by reducing cardiac output.
However, in the present study, the low BP in rats treated with
furosemide was not significantly lower than that in control.
Another interesting finding was that the maximal pressor response to
phenylephrine, P1, was significantly higher in
phenylephrine-pretreated rats regardless of the presence or
absence of L-NAME (Table 1). This was unexpected because in an in vitro
study,11 the sensitivity and maximal contraction observed
in response to phenylephrine were significantly reduced in
aortic rings that were chronically exposed to phenylephrine
compared with control aortic rings that had not been exposed to
phenylephrine. In the present study, we estimated the
changes in vascular resistance induced by phenylephrine from the
changes induced in BP by phenylephrine in rats with
autonomic blockade. In this condition, the maximal pressor response
would reflect the maximal vascular constriction only when the cardiac
output is constant. This was not confirmed in the present study. It
is possible that the cardiac output was not constant under conditions
of extremely high systemic vascular resistance. A pressure overload to
the heart for 9 hours may induce a greater cardiac
contractility against high systemic vascular
resistance, resulting in a higher maximal pressor response versus
control. It has been shown that the adaptational event in cardiac
myocytes, such as myosin heavy chain isoform transition in response to
a pressure overload, occurs very quickly.25
In the present study, the diuretic response to an increase
in systemic arterial pressure, which was induced by
prolonged (9 hours) intravenous infusion of
phenylephrine, was significantly reduced in rats with an
impaired L-arginine–NO pathway, as indicated by the
depression in the slope for the MAP–urine volume relationship (Fig 4).
This has been well documented in perfusion studies performed in
vivo.9 10 These previous studies show that intrarenal NO
synthesis plays a key role in mediating the diuretic and
natriuretic responses to acute elevations in renal
perfusion pressure. Thus, the present result obtained in
chronically instrumented, conscious rats corroborates the earlier
results.9 10 Since NO was systemically inhibited in the
present study, it is possible that the inhibition of NO in organs
except the kidney also modulates the pressure-diuresis
response. It has been demonstrated that central NO tonically inhibits
the activity of the renal sympathetic nerves.26 27 Thus,
intravenous infusion of L-NAME may alter renal function by
activating renal sympathetic nerve activity,28 29 leading
to a reduction in pressure diuresis. However, this seems
unlikely because systemic inhibition of NO elevated
arterial pressure and activates the baroreflex
mechanism, which in turn offsets the activation of renal sympathetic
nerve activity elicited by inhibition of central NO.30
In humans the sympathetic nervous system is activated in
accelerated hypertension31 or congestive heart
failure.32 In these conditions, it can be assumed that the
development of vascular -adrenoreceptor
desensitization occurs as an adaptational event to decrease
peripheral vascular resistance or cardiac afterload.
However, this has not been proved. Apart from these pathological
conditions, there is a possibility that vascular
-adrenoreceptor desensitization develops in healthy
subjects during the daytime in response to activation of the
sympathetic nervous system elicited by physical activities or mental
stress. Basal -sympathetic vasoconstrictor activity is increased in
the morning and decreased in the afternoon,33 whereas
directly recorded sympathetic nerve activity in the morning is not
different from that in the afternoon.34 It has been
hypothesized that a circadian variation of -sympathetic
vasoconstrictor activity33 is related to the
well-documented morning increase in cardiovascular
events.35 The present results suggest that vascular
-adrenoreceptor desensitization develops in
pathophysiological conditions13 in
which the endothelial L-arginine–NO
pathway is impaired as well as in healthy subjects.
In conclusion, the results of the present study suggest that a
decrease in the pressor responsiveness to phenylephrine
after prolonged infusion of this agent is not only due to the reduction
of plasma volume associated with the pressure-diuresis response
but also probably due to the development of vascular
-adrenoreceptor desensitization. A minor impairment
of the L-arginine–NO pathway did not seem to interfere
with the development of vascular -adrenoreceptor
desensitization, whereas it contributed to significantly elevated basal
vascular tone, increased vascular reactivity, and depressed
pressure-diuresis response.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by Research Grants for Scientific Research (07670746 and 07670420) from the Ministry of Education, Science and Culture of Japan.
Received July 15, 1996; first decision September 10, 1996; accepted October 17, 1996.
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