Download Control of Regional Blood Flow by Endothelium

486
Control of Regional Blood Flow by
Endothelium-Derived Nitric Oxide
Sheila M. Gardiner, Alix M. Compton, Terence Bennett,
Richard M.J. Palmer, and Salvador Moncada
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The regional hemodynamic consequences of inhibiting vascular endothelial nitric oxide
generation with JV^-monomethyl-L-arginine ( L - N M M A ) were studied in conscious Long-Evans
rats. Experiments were carried out in groups of chronically instrumented rats with intravascular catheters and pulsed Doppler probes to monitor regional blood flow. L - N M M A (0.3-300
mg/kg) caused a dose-dependent, long-lasting (5-90 minutes), and enantiomerically specific
increase in mean blood pressure and also caused bradycardia. The increase in blood pressure
was accompanied by a dose-dependent and long-lasting vasoconstriction in the internal carotid,
mesenteric, renal, and hindquarters vascular beds that could be attenuated, in a concentrationdependent manner, by L-arginine but not by D-arginine. In contrast, L-arginine did not affect
the pressor or vasoconstrictor effects of vasopressin. These results indicate that nitric oxide
production by vascular endothelial cells contributes to the maintenance of blood pressure and
to the control of the resting tone of different vascular beds in the conscious rat. (Hypertension
1990;15:486-492)
T
here is now compelling evidence that a vasodilator produced by endothelial cells is nitric
oxide (NO) (for review, see
Reference 1).
This NO is formed from L-arginine2-4 by an enzyme
that can be inhibited inGvitro in an enantiomerically
specific manner by Af -monomethyl-L-arginine (LNMMA).2"5 L - N M M A causes a dose-dependent
increase in mean systemic arterial blood pressure in
anesthetized rabbits, accompanied by a reduction in
ex vivo release of NO; these effects are not seen with
D-NMMA. Furthermore, the elevation of blood pressure and the reduction in ex vivo release of NO are
both reversed by L-arginine but not D-arginine.6
These observations indicate that, in vivo, the formation of NO by vascular endothelial cells plays an
important role in the control of blood pressure. In
the present study, we have investigated this role
further by examining the regional hemodynamic consequences of inhibiting vascular endothelial cell production of NO in conscious rats.
Methods
Male Long-Evans rats (350-400 g) were anesthetized (sodium methohexitone, 60 mg/kg i.p., suppleFrom the Department of Physiology and Pharmacology, Medical
School (S.M.G., A.M.C., T.B.), Queen's Medical Centre, Nottingham, and Wellcome Research Laboratories (R.M.J.P., S.M.),
Langley Court, Beckenham, Kent, UK.
Address for correspondence: Dr. S.M. Gardiner, Department of
Physiology and Pharmacology, Medical School, Queen's Medical
Centre, Nottingham, NG7 2UH, UK.
Received August 1, 1989; accepted in revised form January 8,
1990.
mented as required) and pulsed Doppler probes7
were sutured around the left renal and superior
mesenteric arteries and the distal abdominal aorta
below the level of the ileocecal artery (i.e., to monitor
blood flow to the hindquarters). Other rats had a
probe sutured around one common carotid artery
after the external carotid artery on the same side had
been ligated; this made it possible to monitor internal
carotid blood flow (see below). Probe wires were fed
subcutaneously and emerged at the back of the neck
where they were secured with a ligature. After 7-14
days, rats were briefly reanesthetized (sodium methohexitone, 40 mg/kg i.p.), and catheters were
implanted in the jugular vein for drug administration
and in the distal abdominal aorta (via the ventral
caudal artery) for monitoring mean arterial blood
pressure and instantaneous heart rate. The catheters
were fed subcutaneously to exit at the same point as
the probe wires. The latter were soldered into a
microconnector (Microtech Inc., Boothwyn, Pennsylvania) that was clamped to a harness worn by the rat.
The catheters ran through a flexible spring connected
to the harness. Experiments were started at least 24
hours later, when rats were conscious and unrestrained and housed in their home cages with free
access to food and water.
The experimental protocols ran over 2-3 days and
involved continuous measurements (between 6:30 AM
and 5:00 PM) of mean blood pressure, heart rate, and
renal, mesenteric, and hindquarters or internal
carotid Doppler shift signals. Although the Doppler
Gardiner et al
100
487
A.
50
FIGURE 1. Line graphs showing cardiovascular changes after administration of N G monomethyl-L-arginine (L-NMMA) in conscious Long-Evans rats bearing (panel A)
renal, mesenteric, and hindquarters flow probes
(n=8) and (panel B) internal carotid probes
(n=8). L-NMMA dose (mg/kg): 0.3, • - • ; 1.0,
O-o; 3.0, • - • ; 10, D-Q; and 30, A-A. Values
are mean±SEM. BP, blood pressure.
0
-50
-100
50
40
1?
Hemodynamics and Nitric Oxide
30
20
10
0
L-NMMA
L-NMMA
TIME (min)
TIME (min)
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shift signal is not a direct measure of volume flow,
percentage changes in this signal under the conditions of our experiments are a reliable indication of
changes in volume flow.7 Changes in vascular
conductance8 were calculated from mean blood pressure and the mean Doppler shift signal,7 but the
phasic Doppler shift signal was monitored continuously to ensure that it was of acceptable quality
(signal: noise >20 : 1). The Doppler shift signals were
monitored with a flowmeter (VF-1 system with
HVPD 20 modules, Crystal Biotech, Holliston, Massachusetts), and all variables were recorded on a
Gould ES1000 electrostatic recorder (Gould Electronics Ltd., Essex, UK).
(n=8) and rats with internal carotid probes (n=8)
were given increasing intravenous doses of L - N M M A
acetate (0.3, 1.0, 10, 30, 100, and 300 mg/kg), separated by at least 45 minutes. The three highest doses
of L - N M M A were given to a different group of rats
with renal, mesenteric, and hindquarters probes
(n=8). Two rats were also given D - N M M A (100
mg/kg).
Experiment 2: Dose responses to L-arginine acetate.
The rats that were given L-NMMA at a dose of 100
mg/kg in experiment 1 were given the same dose of
Experimental Protocols
Experiment 1: Dose responses to L-NMMA acetate.
Rats with renal, mesenteric, and hindquarters probes
B
Renal
Mesenteric
Hindquarters
Hindquarters
Internal Carotid
Internal carotid
t
L-NMMA
2
3
4
5
TIME (min)
FIGURE 2. Line graphs showing changes in Doppler shift
after administration of increasing doses of NG -monomethylL-arginine (L-NMMA)
in conscious Long-Evans rats with
renal, mesenteric, and hindquarters probes, or internal carotid
probes (n=8 for each group). L-NMMA dose (mg/kg): 0.3,
• - • ; 1.0, o-O; 3.0, m-m; 10, D - D ; and 30, A-A. Values are
mean±SEM.
L-NMMA
2
3
TIME (min)
FIGURE 3. Line graphs showing changes in vascular conductance after administration of increasing doses of N c monomethyl-L-arginine (L-NMMA) in conscious Long-Evans
rats with renal, mesenteric, and hindquarters probes, or internal carotid probes (n=8 for each group). L-NMMA dose
(mg/kg): 0.3, %-•; 1.0, o - o ; 3.0, M ; 10, D - D ; 30,
Values are mean ±SEM.
488
Hypertension Vol 15, No 5, May 1990
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-70 L
0.3
1.0
3.0
10.0
30.0
L-NMMA (mgkg'1)
10.0
30.0
FIGURE 4. Line graphs showing changes in mean blood
pressure (BP), Doppler shift, and vascular conductance measured 5 minutes after administration of increasing doses of
in conscious LongNc-monomethyl-L-arginine (L-NMMA)
Evans rats with renal, mesenteric, and hindquarters probes, or
internal carotid probes (n=8 for each group). Mean BP
responses: n, rats with renal, mesenteric, and hindquarters
probes; O, rats with internal carotid probes. Doppler shift or
conductance responses: • , renal; A, mesenteric; m, hindquarters; T, internal carotid. Values are mean±SEM.
FIGURE 5. Line graphs showing changes in mean blood
pressure (BP) and heart rate after Na-monomethyl-L-arginine
(L-NMMA) (100 mg/kg) alone (O-o) or L-NMMA followed
by increasing doses of L-arginine acetate ( • - • ) , in the same
conscious Long-Evans rats with renal, mesenteric, and hindquarters flow probes (top panels) (n=8) or internal carotid
probes (bottom panels) (n=S). Values are mean±SEM.
The rats that had received 300 mg/kg L-arginine
acetate (experiment 2) also received 300 mg/kg Larginine hydrochloride at least 24 hours later.
L-NMMA and, starting 10 minutes later, received
increasing intravenous doses of L-arginine acetate
Experiment 5: Effects of L-arginine hydrochloride on
(35, 100, and 300 mg/kg) at 10-minute intervals. The
the responses to vasopressin. The rats that were used to
two exposures to L-NMMA were at least 24 hours
assess the effects of L-arginine acetate or hydrochloapart. These rats also received L-arginine acetate
ride (experiment 4) also received L-NMMA (100
alone at a dose of 100 mg/kg. A separate group of
mg/kg) or vasopressin (36-90 pmol/hr) on separate
rats (n=8) was given L-arginine acetate alone at 300
days followed 10 minutes later by L-arginine hydromg/kg.
chloride (300 mg/kg).
Experiment 3: Dose responses to D-arginine acetate.
The mean blood pressure and heart rate of the 40
Another group of rats with renal, mesenteric, and
rats used in this study were 103 ±2 mm Hg and 352±11
beats/min, respectively, and there were no significant
hindquarters probes («=8) was given L-NMMA (100
differences between any of the groups of rats used in
mg/kg) on two occasions (separated by 24 hours). On
one occasion, starting 10 minutes after administrathe five experiments. In all experimental protocols
drugs were dissolved in physiological saline at pH 7 (see
tion of L - N M M A , D-arginine acetate was administered intravenously (35, 100, and 300 mg/kg) at
below) and injected intravenously in volumes of 0.1 ml.
10-minute intervals. These rats also received DAll injections were given intravenously in a bolus of
arginine acetate alone at a dose of 100 mg/kg.
0.1-0.2 ml (catheter dead space 0.1 ml), flushed in with
Experiment 4: Dose response to L-arginine hydrochlo- 0.1 ml isotonic saline. Administration of vehicle alone
had no significant cardiovascular effects.
ride. The rats involved in the protocol for experiment
3 were given, on another experimental day, L-NMMA
Chemicals
at a dose of 100 mg/kg followed 10 minutes later by
increasing doses of L-arginine hydrochloride (35,100,
All compounds used (excluding vasopressin) were
and 300 mg/kg) at 10-minute intervals. These rats
obtained from Wellcome Research Laboratories
also received L-arginine hydrochloride and L-lysine
(Langley Court, Beckenham, UK) and where necesacetate alone (each at 100 mg/kg).
sary synthesized as previously described.9 Solutions
Gardiner et al Hemodynamics and Nitric Oxide
489
Renal
Mesenteric
Hindquarters
c*r^r_o.
-a-
«
-20
Hindquarters
Internal carotid
-40
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10
L-NMMA
100
L-Arg
35
20
L-Arg
100
30
10
t
20
L-Arg
or D—Arg
L-Arg
or D—Arg
100
L-Arg
300 mg kg"1
of L-arginine hydrochloride were adjusted to pH 7
with sodium hydroxide so that all solutions used had
a similar pH. Vasopressin ([Arg8] vasopressin,
Bachem, Saffron Walden, Essex, UK) was dissolved
Renal
Mesenteric
Hindquarters
Internal carotid
0
t
L-Arg
35
20
t
L-Arg
100
30
mg kg*'
40
FIGURE 6. Line graphs showing changes in Doppler shift
after administration of Nc"-monomethyl-L-arginine (LNMMA) (100 mglkg) alone ( o - o ) or L-NMMA followed by
increasing doses of L-arginine acetate (L-Arg) (*-*) in the
same groups of conscious Long-Evans rats with either renal,
mesenteric, and hindquarters probes or internal carotid probes
(n=8 for each group). Values are mean±SEM.
0
t
L-NMMA
35
0
L-NMMA
100
0
4C
L-Arg
300 rngkg"1
FIGURE 7. Line graphs showing changes in vascular conductances after administration of NG-monomethyl-L-arginine
(L-NMMA) (100 mglkg) alone ( O - o ) or L-NMMA followed
by increasing doses of L-arginine acetate (L-Arg) ( • - • ) in the
same groups of conscious Long-Evans rats with either renal,
mesenteric, and hindquarters probes or internal carotid probes
(n=8for each group). Values are mean±SEM.
FIGURE 8. Line graphs showing changes in vascular conductance after administration of Nc'-monomethyl-L-arginine
(L-NMMA) (100 mglkg) followed by D-arginine acetate (DArg) (o—o) or followed by L-arginine hydrochloride (L-Arg)
(•-•) in the same conscious Long-Evans rats (n=8) with
renal, mesenteric, and hindquarters probes. Values are
mean±SEM.
in physiological saline containing 1% bovine serum
albumin and was infused in 0.3 ml/hr.
Statistics
Data were subjected to Friedman's test, Wilcoxon's rank sum test, or the Mann-Whitney U test as
appropriate, and p<0.05 was taken as indicating
statistical significance.
Results
Dose Responses to L-NMMA
L-NMMA (0.3-30 mg/kg) induced a dosedependent increase in mean blood pressure and a
decrease in heart rate that were maximal within 2
minutes and had generally stabilized by 5 minutes.
The effects were not significantly different between
those rats with renal, mesenteric, and hindquarters
probes and those with internal carotid probes (Figure
1). L-NMMA (0.3-30 mg/kg) also induced, within 2
minutes, a dose-dependent decrease in blood flow
(Figure 2) and in vascular conductance (Figure 3) in
the renal, mesenteric, and internal carotid vascular
beds that was significant at doses of 1 mg/kg and
above at this time.
There were some differences in the initial response
of the vascular beds. There was a significant vasoconstriction in the mesenteric vascular bed 1 minute after
administration of 0.3 mg/kg L-NMMA. In the hindquarters, there was an early (1-2 minute), significant
vasodilatation induced by 0.3 and 1 mg/kg L-NMMA,
although at later times and with higher doses there
was only vasoconstriction (Figures 2 and 3).
Five minutes after administration of L-NMMA
(0.3-300 mg/kg), all vascular beds showed similar
490
Hypertension
Vol 15, No 5, May 1990
TABLE 1. Cardiovascular Changes 1 Minute After Administration of Bolus Doses of Arginine or Lysine in Conscious
Long-Evans Rats
Compound
L-Arginine acetate
(100 mg/kg) (n=7)
L-Arginine acetate
(300 mg/kg) (n=8)
L-Arginine hydrochloride
(100 mg/kg) («=7)
L-Arginine hydrochloride
(300 mg/kg) (n=8)
D-Arginine acetate
(100 mg/kg) (n =9)
L-Lysine acetate
(100 mg/kg) (n=9)
A Flow (%)
A Conductance (%)
A Heart rate A MBP
(beats/min) (mm Hg) Renal Mesenteric Hindquarters Renal Mesenteric Hindquarters
33±11*
12+3*
9±3*
44±4*
-15±5*
-3±5
29±5*
-24±6*
29±4*
7±2*
13±3*
73+4*
-7+6
7±3
63+5*
-12±6
23±7*
2+1
5±1*
7+3
14+7
3±1*
5+3
12±7
1±8
2±2
6±1*
8+3
9±6
4±3
5±3
6±6
24±3*
14±1*
3±4
49+6*
-2+7
-9+4
32+6*
-13±6
28±8*
10±3
10±2*
41±6*
-7+3
0+2
28±5*
-15±3*
Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017
Values are mean±SEM.
*p<0.05 vs. baseline (Wilcoxon's rank sum test). A, Change from baseline; MBP, mean blood pressure; n, number
of rats in each group.
degrees of vasoconstriction, apart from a slightly
reduced maximum response to the higher doses of
L-NMMA in the renal vascular bed (Figure 4). The
duration of the effects of L - N M M A (0.3-300 mg/kg)
on mean blood pressure, heart rate, and regional
vascular conductances was also dose-dependent, lasting between 5 and 90 minutes. D-NMMA acetate
(100 mg/kg) caused no pressor or regional vasoconstrictor effects; there was a transient mesenteric
vasodilatation that was probably attributable to the
acetate moiety (see below).
Attenuation by L-Arginine Acetate of
Effects of L-NMMA
Administration of L-NMMA (100 mg/kg) caused a
sustained increase in mean blood pressure, decrease
in heart rate, and regional vasoconstrictions (Figures
5-7) that returned slowly toward control levels over a
period of 90 minutes.
L-Arginine acetate (35-300 mg/kg) caused a significant dose-dependent attenuation of the effects of
L-NMMA on mean blood pressure and heart rate,
although mean blood pressure was still significantly
elevated 10 minutes after administration of 300 mg/
kg (Figure 5). L-Arginine acetate also attenuated the
vasoconstrictor effects of L-NMMA. There were,
however, some differences in the degree of attenuation that was achieved (Figures 6 and 7). Thus, 10
minutes after administration of L-arginine acetate
(300 mg/kg), the renal vascular conductance was not
significantly different from the basal level, whereas
mesenteric, internal carotid, and hindquarters vascular conductances were still 10±3, 31±4, and 33±4%
below baseline, respectively (/?<0.05 for all).
Immediately after administration of L-arginine
acetate, the mesenteric vascular bed showed a significant, dose-dependent hyperemia and vasodilatation
(Figures 6 and 7) that rapidly waned, although flow
and conductance remained higher than before
administration of L-arginine acetate. D-Arginine acetate did not attenuate the cardiovascular effects of
L-NMMA, although a transient mesenteric vasodilatation was observed (Figure 8). A similar mesenteric
response at 1 minute was seen when L-arginine
acetate, L-lysine acetate, and D-arginine acetate, but
not L-arginine hydrochloride, were administered
alone at doses of 100 mg/kg (Table 1). The mesenteric vasodilator effects of L-arginine acetate
increased with dose, but even at a dose of 300 mg/kg,
L-arginine hydrochloride did not affect mesenteric
TABLE 2. Effects of L-Arginine Hydrochloride on Cardiovascular Responses to /VG-Monomethyl-L-arginine or
Vasopressin in the Same Conscious Long-Evans Rats (n=8).
Hemodynamic measurements
A Heart rate (beats/min)
A Mean blood pressure (mm Hg)
A Renal conductance (%)
A Mesenteric conductance (%)
A Hindquarters conductance (%)
L-NMMA
L-NMMA +
L-arginine
hydrochloride
Vasopressin
Vasopressin
+ L-arginine
hydrochloride
-88±8*
43±3*
-38±4*
-53±2*
-51+3*
-38±5*t
23±3*t
-19±3*t
-32±3*t
-39±5*t
-86±9*
34 ±2*
-24±3*
-57±2*
-51±4*
-71±12*
34±2*
-21±5*
-56±2*
-46+5*
Values are mean±SEM. L-Arginine hydrochloride (300 mg/kg) was given 10 minutes after injection of N°monomethyl-L-arginine (L-NMMA) or 10-15 minutes after onset of vasopressin infusion. Measurements were made 5
minutes after L-arginine hydrochloride administration. A, change from baseline; n, number of rats in the group.
*/><0.05 vs. baseline; t£><0.05 vs. L-NMMA alone (Friedman's test).
Gardiner et al
vascular conductance (Table 1). However, L-arginine
hydrochloride (100 mg/kg) attenuated the vasoconstrictor effects of L - N M M A (Figure 8) causing transient rises in mesenteric and hindquarters vascular
conductances that rapidly fell but to levels higher
than those before its administration. Ten minutes
after administration of L-arginine hydrochloride (100
mg/kg), the renal vascular conductance had returned
to the basal level, but mesenteric and hindquarters
vascular conductances were still reduced 18 ±6 and
32±5% below basal levels, respectively (p<0.05).
L-Arginine hydrochloride (300 mg/kg) significantly
attenuated all the cardiovascular effects of L-NMMA,
without affecting those of vasopressin (Table 2).
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Discussion
Recent studies have shown that L-NMMA induces
an elevation in blood pressure in the anesthetized
rabbit6 and the guinea pig.10 This hypertensive
response was associated with an inhibition of
endothelium-dependent vasodilatation induced by
acetylcholine and was accompanied by inhibition of
the release of NO from the aorta of the treated
animals.6 These observations clearly implicate the
formation of NO from L-arginine in the maintenance
of blood pressure and pose the question as to the role
of NO in the regulation of regional blood flow in
conscious animals.
We have now shown that L-NMMA causes dosedependent increases in mean blood pressure in conscious rats. These effects are associated with renal,
mesenteric, hindquarters, and internal carotid vasoconstriction, which is similar in all vascular beds
studied. All these effects are accompanied by bradycardia that, as shown in the rabbit6 and the guinea
pig,10 is probably reflex in nature.
The hypertensive response to L-NMMA, as well as
its regional vasoconstrictor actions, are rapid in onset
and both are attenuated by L-arginine. Furthermore,
L-arginine has no sustained influence on the cardiovascular actions of vasopressin. These findings are
consistent with inhibition by L-NMMA of the production of NO by vascular endothelial cells, rather than
an effect mediated by an action on the arginine: NO
pathway in other cells.11
The ability of L-arginine to reverse the vasoconstriction induced by L - N M M A varied between vascular beds; although the responses in the renal and
mesenteric vasculatures, respectively, were totally or
almost totally reversed, the conductances in the
internal carotid and hindquarters were only partially
restored to pretreatment levels. The reasons for
these findings are not clear at present but, as all
vascular beds respond similarly to L-NMMA after 5
minutes, it is unlikely that the differences in the
responses to L-arginine are due to regional differences in the activity of the L-arginine: NO pathway,
or in the sensitivity to the NO formed. Whether
variation in the reflex control of the different vascular
beds, in the uptake of L-arginine, or its ability to
displace L-NMMA account for the differences
Hemodynamics and Nitric Oxide
491
observed remains to be established. The mechanisms
underlying the differences observed between vascular
beds in the first 5 minutes after administration of
L-NMMA also require investigation.
Under basal conditions, L-arginine acetate, Darginine acetate, and L-lysine acetate all caused
transient mesenteric vasodilatations. These effects
are probably due to the acetate moiety (a known
vasodilator)12 as D-arginine and L-lysine are not
substrates for the NO-forming enzyme,5 and mesenteric vasodilatation is not seen with L-arginine hydrochloride alone. Because none of these effects can be
attributed to the conversion of L-arginine to NO, it is
likely that substrate availability is not rate limiting
under resting conditions, confirming previous observations in vitro and in vivo.4-6-10
The present observations clearly indicate that the
overall conductance of all the vascular beds studied is
regulated by NO generated from L-arginine. The
mechanisms that control the activation of this pathway remain to be established, but could involve
mechanical stimulation of endothelial cells due to
shear stress resulting from pulsatile flow or other
physical factors. This would be consistent with recent
observations in intact vascular networks in vitro.13
This and our previous results show that in the
vasculature there is a substantial and functionally
significant NO-mediated vasodilator tone that may
be the main determinant of blood flow and on which
local or systemic vasoconstrictor influences act.
Acknowledgment
We are grateful to Philip A. Kemp for his technical
assistance.
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492
Hypertension
Vol 15, No 5, May 1990
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KEY WORDS • nitric oxide
vasopressin • hemodynamics
endothelium
Long Evans rats
arginine
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Control of regional blood flow by endothelium-derived nitric oxide.
S M Gardiner, A M Compton, T Bennett, R M Palmer and S Moncada
Hypertension. 1990;15:486-492
doi: 10.1161/01.HYP.15.5.486
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