Vol. 281, Issue 3, R887-R893, September 2001
Cardiovascular effects of vasopressin following
V1 receptor blockade compared to effects of
nitroglycerin
C. R.
Cooke,
B. M.
Wall,
K. M.
Huch, and
T.
Mangold
Department of Medicine, Veterans Affairs Medical Center and
University of Tennessee Health Sciences Center, Memphis, Tennessee
38104
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ABSTRACT |
Studies to more
clearly determine the mechanisms associated with arginine vasopressin
(AVP)-induced vasodilation were performed in normal subjects and in
quadriplegic subjects with impaired efferent sympathetic responses.
Studies to compare the effects of AVP with the hemodynamic effects of
nitroglycerin, an agent that primarily affects venous capacitance
vessels, were also performed in normal subjects. Incremental infusions
of AVP following V1-receptor blockade resulted in
equivalent reductions in systemic vascular resistance (SVRI) in normal
and in quadriplegic subjects. However, there were major differences in
the effect on mean arterial pressure (MAP), which was reduced in
quadriplegic subjects but did not change in normal subjects. This
difference in MAP can be attributed to a difference in the
magnitude of increase in cardiac output (CI), which was twofold greater
in normal than in quadriplegic subjects. These observations are
consistent with AVP-induced vasodilation of arterial resistance vessels
with reflex sympathetic enhancement of CI and are clearly different
from the hemodynamic effects of nitroglycerin, i.e., reductions in MAP,
CI, and indexes of cardiac preload, with only minor changes in SVRI.
vasopressin 1-receptor antagonist; hemodynamic effects
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INTRODUCTION |
IT IS NOW GENERALLY
ACCEPTED that arginine vasopressin (AVP), a potent
vasoconstrictor, is also capable of producing vasodilation. However,
the mechanisms involved in the vasodilatory response to AVP are
incompletely understood and may not be uniformly the same in all
segments of the circulation. Although there is evidence that
AVP-induced vasodilation may involve V1 receptors in some highly localized vascular beds (16, 17), a vasodilatory
effect of AVP has been most clearly demonstrated following
V1-receptor antagonist administration (13, 20, 27,
28). In early studies reported by Schwartz and Reid
(28), V1-receptor antagonist administration in
water-deprived conscious dogs was shown to produce hemodynamic changes
that were the opposite of those usually associated with increased
levels of AVP, i.e., cardiac output (CI), heart rate (HR), and plasma
renin activity (PRA) were increased. In subsequent studies by Schwartz
et al. (27), it was shown that the hemodynamic changes
produced by infusions of AVP after V1-receptor blockade in
conscious dogs were similar to those produced by administration of a
V2-receptor agonist VDAVP. Studies by Liard
(21) in which the increase in CI associated with AVP
infusion after V1-receptor blockade was prevented by prior
administration of a combined V1 + V2-receptor antagonist and studies showing the absence of
hemodynamic responses to dDAVP, a specific V2-receptor
agonist, in patients with V2-deficient congenital diabetes
insipidus (4) provided further evidence that extrarenal
V2 or V2-equivalent receptors may be involved
in the vasodilatory response to AVP.
Vasopressin infusions after V1-receptor antagonist
administration have been shown to produce marked reductions in mean
arterial pressure (MAP) in quadriplegic subjects with deficient
sympathetic efferent responses due to cervical spinal cord injury
(13). This effect on arterial pressure was attributed to
unopposed AVP-induced vasodilation of arterial resistance vessels in
quadriplegic subjects. We have extended our observations in these
studies to include other hemodynamic parameters in both quadriplegic
and normal subjects using thoracic electrical bioimpedance cardiography
to more clearly identify the cardiovascular and circulatory effects of
AVP after V1-receptor blockade with and without the
interposition of sympathetic counterregulatory responses. In additional
studies, the effects of AVP after V1-receptor blockade were
compared with those of nitroglycerin, a precursor of nitric oxide with
biological effects similar to those of endogenously generated nitric
oxide (1, 2). The purpose in this combination of studies
is to provide a more comprehensive assessment of the hemodynamic
effects of AVP-induced vasodilation after V1-receptor
blockade and to differentiate these effects from those associated with
administration of a vasodilating agent that primarily affects venous
capacitance vessels.
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METHODS |
Study subjects.
AVP infusion studies were performed in seven quadriplegic subjects with
traumatic cervical spinal cord injury (C5-C7) that had been
present for 3 mo to 10 yr and in five normal subjects. All subjects
with spinal cord injury were accustomed to spending several hours daily
in a wheelchair. There was no evidence of heart or liver disease or
impairment of kidney function, as shown by serum creatinine
concentrations, in any subject, and no one was receiving medications
that are known to affect blood pressure, HR, or the hormonal parameters
of interest. Quadriplegic subjects were allowed to continue their usual
medications, which included multivitamins, vitamin C, acetaminophen,
and benzodiazepine used to attenuate muscle spasms.
Five normal volunteer subjects, including three who also participated
in the AVP infusion studies, received incremental infusions of
nitroglycerin. The interval between the AVP and nitroglycerin infusion
studies in these three subjects was 4-6 mo. None of the normal
subjects in either study had been taking medications. All subjects had
been eating their customary diet without NaCl or fluid restriction
before the studies, and all avoided the use of tobacco and ethanol for
at least 12 h before each study. Written informed consent was
obtained from all participants, and the studies were approved by the
Human Studies Subcommittee and the Research and Development Committee
of the Veterans Affairs Medical Center.
Study protocol.
All AVP infusion studies began at approximately 0800 after an overnight
fast. On the morning of the studies, catheters were inserted into
antecubital or forearm veins of both arms of supine subjects. After a
30-min period during which arterial blood pressure and HR were measured
every 2 min using an arm cuff and an automated recording device
(Dinamap, Critikon, Tampa, FL), blood samples were obtained for
determinations of plasma norepinephrine (PNE) concentration, PRA, cGMP, and plasma atrial natriuretic peptide (PANP) concentrations. The V1-receptor
antagonist, d(CH2)5Tyr (Me) AVP (0.5 mg in
0.9% NaCl), was then administered intravenously over 5 min.
After an additional 45-min period of observation, at the peak effect of
the V1-receptor antagonist, AVP (aqueous vasopressin, USP,
20 U/ml, American Reagent Laboratory, Shirley, NY) was infused at rates
of 400, 800, 1,600, and 3,200 µU · kg
1 · min1 in 10-min
consecutive intervals in all subjects. Observations were continued for
30 min after discontinuing the AVP infusion. The
V1-receptor antagonist has been shown to be maximally
effective within 45 min and to have a total duration of action
exceeding 3 h (9). Bussien et al. (5)
have shown that there is no effect of this antagonist on systolic or
diastolic blood pressure when administered alone in studies performed
over a period of 60 min in normally hydrated healthy subjects.
Arterial blood pressure and HR were measured every 2 min, and
electrocardiographic monitoring was continuous throughout the studies.
Blood samples were obtained immediately before the AVP infusions and at
the end of each of the incremental infusion periods for measurements of
PNE, PRA, cGMP, and PANP. Measurements of plasma AVP (PAVP) could not be obtained in the presence of
the V1-receptor antagonist because of cross-reactivity with
the antibody used in the radioimmunoassay for PAVP.
The total volume of all blood samples in each study was ~150 ml. This
volume was replaced with 0.9% NaCl after each collection of blood
samples during the studies.
The median of the last 10 measurements of arterial blood pressure and
HR before each collection of blood samples was selected as
representative of that period. For postinfusion observations, measurements were obtained during the final 15 min of the 30-min postinfusion period. The MAP was calculated from the diastolic pressure
plus (0.33 × pulse pressure). AVP infusions were well tolerated
in all subjects. There were no episodes of cardiac arrhythmia and no
electrocardiographic changes or chest pain in any subject.
Cardiovascular parameters were assessed noninvasively by thoracic
electrical bioimpedance cardiography (Bomed Medical Manufacturer, Irvine, CA). CI, stroke volume (SI), systemic vascular
resistance (SVRI), end-diastolic index (EDI), which is a measure of
preload, left cardiac work index (LCWI), ejection fraction (EF), and
thoracic fluid conductivity (TFC) were continuously recorded (7,
11, 18, 30, 38). TFC (1/ohm), the total conductivity of the thorax, is the reciprocal of the thoracic fluid index (Zo). Zo represents total impedance [resistance (ohm) to high-frequency alternating current] of the thorax. As more fluid is present
within the thorax, the thorax becomes more conductive, and its Zo will be lower and TFC higher. Previous studies have shown a close
correlation between measured right atrial pressure and TFC (7,
11). In our laboratory, we have previously demonstrated
decreasing TFC and EDI in both normal and quadriplegic subjects during
incremental upright tilting, a condition that is known to decrease
central blood volume (36). All values were indexed by body
surface area.
In the nitroglycerin infusion studies, nitroglycerin (200 µg/ml in
5% dextrose, Abbott Laboratories, North Chicago, IL) was infused at
rates of 25, 50, 75, 100, and 125 µg · kg1 · min1 in 10-min
consecutive intervals. Hemodynamic parameters were assessed
noninvasively by thoracic electrical bioimpendance cardiography, and
blood samples for measurements of hormonal parameters were obtained as
in the AVP infusion studies.
Analytic methods.
Blood for determinations of PNE, PRA, cGMP, and
PANP was drawn into heparinized prechilled plastic syringes
and placed in prechilled polypropylene tubes containing 10 mg EDTA/ml
blood. Aprotinin (500 KIU) was added to the samples of blood used for determinations of PANP. Samples were kept in ice until
centrifuged at 4oC, and the separated plasma was stored at
20oC until the analyses could be performed. PRA was
measured by a modification of the radioimmunoassay method of Haber
using antibody and reagents provided by Incstar (Stillwater, MN).
PNE concentrations were determined by HPLC (National
Reference Laboratory, Nashville, TN). PANP concentrations
were measured by radioimmunoassay as previously described
(13). Plasma samples adjusted to pH 3.5 are loaded onto
solid-phase extraction cartridges (Sep-Pak), eluted with 86% ethanol,
dried, and reconstituted in assay buffer for the radioimmunoassay.
Recovery of known quantities of PANP = 86 ± 2.7% (n = 10). Intra-assay and interassay coefficients
of variation are 8 and 10%, respectively. The lower limit of
sensitivity for PANP in this assay is ~10 pg/ml. Plasma
cyclic GMP was measured using an enzyme immunoassay kit (Cayman
Chemical, Ann Arbor, MI).
Statistical analysis.
Comparisons between groups (quadriplegic and normal subjects) before
and during AVP infusions were made using a t-test for unpaired variates. The effect of AVP and nitroglycerin infusions in
normal subjects was assessed using a one-factor ANOVA for repeated measures and Fisher's protected least-squares differences for within-group comparisons. In the analysis of data from the
nitroglycerin infusion studies, values for missing data for infusion
rates of 100 and 125 µg · kg1 · min1 for one
subject whose study was continued only through the 75 µg · kg1 · min1 infusion
were calculated using linear regression equations derived from
preinfusion and 25-, 50-, and
75-µg · kg1 · min1
infusion rate data. Correlation coefficients
(R2) ranged from 0.821 to 0.999 for all
variables except EF, TFC, PRA, cGMP, and PANP. Data for
these variables for all infusion rates were analyzed separately with
n = 4 (subjects with no missing data). Plasma samples
for determinations of PNE were not collected at the lower
infusion rates in the nitroglycerin infusion studies. In the analysis
of these data, a t-test for paired variates was used to
assess the significance of differences between PNE before and at maximal rates of infusion. Values of P < 0.05 were considered significant.
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RESULTS |
Baseline observations before AVP infusions.
There were no significant differences in MAP, HR, or other hemodynamic
parameters in quadriplegic subjects compared with normal subjects
before the infusion of AVP, either before or after administration of
the V1-receptor antagonist. In addition, administration of the V1-receptor antagonist in 0.9% NaCl (20 ml) before AVP
infusions did not alter these parameters in either quadriplegic or
normal subjects. These parameters in quadriplegic and normal subjects immediately before, during, and after AVP infusions are shown in Table
1.
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Table 1.
Hemodynamic parameters, including thoracic electrical bioimpedance
measurements, before, during, and after infusions of arginine
vasopressin
(µU · kg1 · min1)
in the presence of V1-receptor blockade
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Hemodynamic effects of AVP infusions in the presence of
V1-receptor antagonism.
The effects of AVP infusion (400, 800, 1,600, and 3,200 µU · kg1 · min1 in 10-min
consecutive intervals) on MAP and HR in quadriplegic (n = 7) and normal (n = 5) subjects are shown in Fig.
1. MAP in quadriplegic subjects decreased
from preinfusion MAP to a nadir of 65 ± 2 mmHg (P < 0.001) at the 800 µU · kg1 · min1 AVP
infusion rate and increased to 79 ± 3 mmHg in the postinfusion period. HR progressively increased from 68 ± 8 beats/min before AVP infusion to 86 ± 9 beats/min (P < 0.001)
with increasing AVP infusion rates and remained higher than preinfusion
HR (79 ± 9 beats/min) in the postinfusion period. In contrast to
the changes observed in the studies on quadriplegic subjects, MAP did
not significantly change with increasing AVP infusion rates in normal subjects. However, HR progressively increased from 66 ± 6 to
81 ± 8 beats/min (P < 0.001).
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Fig. 1.
Mean arterial pressure (MAP) and heart rate (HR) before
(Pre), during, and after (Post) vasopressin infusion after
V1-receptor blockade in normal (solid line) and
quadriplegic (dotted line) subjects. AVP, arginine vasopressin.
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CI progressively increased (P < 0.001), and
SVRI decreased in both normal (P < 0.01) and
quadriplegic (P < 0.001) subjects during incremental
AVP infusion (Fig. 2). LCWI, EF, EDI, and
TFC were unchanged in quadriplegic subjects. Increases in LCWI
(P < 0.001) and EF (P < 0.001) and a
slight increase in EDI (P < 0.05) were noted in the
studies in normal subjects, but there was no corresponding increase in
TFC.
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Fig. 2.
Systemic vascular resistance index (SVRI) and cardiac
index (CI) before (Pre), during, and after (Post) vasopressin infusion
after V1-receptor blockade in normal (solid line) and
quadriplegic (dotted line) subjects.
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Hormonal changes during AVP infusions.
The effects of AVP infusion on hormonal parameters in quadriplegic and
normal subjects are shown in Table 2. PRA
increased from 1.7 ± 0.4 to 5.6 ± 1.2 ng · ml1 · h1
(P < 0.001) in quadriplegic subjects but did not
change significantly in normal subjects. PNE concentrations
progressively increased during AVP infusion in normal subjects
(P < 0.001), whereas PNE increased in
quadriplegic subjects only at the highest infusion rate. No effect of
AVP infusion on PANP and plasma cGMP concentrations was
demonstrable.
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Table 2.
Hormonal parameters before and during infusions of arginine vasopressin
(µU · kg1 · min1)
in the presence of V1-receptor blockade
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Effects of nitroglycerin infusions in healthy control subjects.
The effects of incremental nitroglycerin infusions on hemodynamic and
hormonal parameters are shown in Tables 3
and 4. MAP progressively decreased from
84 ± 3 mmHg before infusion to a nadir of 69 ± 5 mmHg
(P < 0.001) at the maximal infusion rate. HR increased
from 64 ± 6 beats/min before nitroglycerin infusion to 73 ± 9 beats/min (P < 0.001) at the maximal infusion rate. CI (P < 0.001), SI (P < 0.01), LCWI
(P < 0.001), EDI (P < 0.001), and
SVRI (P < 0.04) all decreased during incremental
nitroglycerin infusions, whereas there were no significant changes in
EF or TFC.
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Table 3.
Hemodynamic parameters, including thoracic electrical bioimpedance
measurements, before, during, and after nitroglycerin infusions
(µg · kg1 · min1)
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Table 4.
Hormonal parameters before and during nitroglycerin infusions
(µg · kg1 · min1)
in 4 healthy volunteer subjects
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PNE concentrations increased from 262 ± 37 pg/ml
before nitroglycerin infusion to 407 ± 39 pg/ml
(P < 0.001) at the maximal infusion rate. No effect of
nitroglycerin infusions on PRA or plasma cGMP concentrations was
demonstrable. PANP concentrations did not significantly
change during nitroglycerin infusion; however, there was marked
between-subject variability in baseline PANP concentrations.
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DISCUSSION |
Incremental infusions of AVP in the presence of
V1-receptor blockade produced marked reductions in MAP in
quadriplegic subjects but not in normal subjects. Maintenance of MAP at
preinfusion levels in normal subjects, despite reductions in SVRI that
were similar to those noted in quadriplegic subjects, can be attributed to increased CI due to the positive inotropic and chronotropic effects
of baroreflex-mediated activation of the sympathetic nervous system and
increased PNE concentrations. Such effects are evident in
the increased SI, LCWI, and EF that were associated with the increase
in CI in normal subjects. CI also increased in quadriplegic subjects
but less so than in normal subjects. This increase in CI in
quadriplegic subjects can be attributed mainly, if not entirely, to an
increase in HR, which was presumably due to decreased parasympathetic inhibitory activity. In contrast to the changes in cardiac indexes in
normal subjects, there were no changes in SI, LCWI, or EF during AVP
infusions in quadriplegic subjects. There were no changes in EDI or TFC
during AVP infusions in either quadriplegic or normal subjects. These
observations show that AVP-induced vasodilation involving systemic
resistance vessels can result in relatively large reductions in
arterial pressure in the absence of a normal efferent sympathetic
response. When sympathetic mechanisms affecting cardiac performance are
intact, arterial pressure is maintained by an increase in CI and not by
attenuation of the dilatory effect of AVP on systemic vascular resistance.
The reduction in arterial pressure in quadriplegic subjects was not
prevented by stimulation of the renin-angiotensin system as shown by
the increase in PRA, which was negatively correlated with the reduction
in MAP (R2 = 0.921, P < 0.01). Whether or not increased levels of ANG II may have played a role
in the lack of reduction in EDI, TFC, and PANP in
quadriplegic subjects is uncertain. There were also no significant
changes in plasma cyclic GMP concentrations, which is consistent with
the absence of changes in PANP in both quadriplegic and
normal subjects. A close correlation between plasma cyclic GMP and
atrial natriuretic peptide concentrations has been shown in previous
studies (3, 12, 33) and reflects the direct effect of
PANP on particulate guanylate cyclase, an intermediate step
in the production of cyclic GMP. Cyclic GMP is also generated by nitric
oxide via a mechanism involving soluble guanylate cyclase, which has
not been clearly associated with changes in plasma cyclic GMP
concentrations (14, 23, 31). Furthermore, plasma cyclic GMP concentrations in forearm venous blood did not increase during intra-arterial infusions of AVP, which produced vasodilation at high
rates of infusion in studies reported by Suzuki et al.
(31). These investigators also found in forearm blood flow
studies that plasma cyclic GMP concentrations did not change during
intra-arterial infusions of sodium nitroprusside (31).
The hemodynamic responses to nitroglycerin were substantially different
from those observed in the AVP infusion studies in normal subjects,
three of whom also participated in the nitroglycerin infusion studies.
In the AVP infusion studies in normal subjects, HR, CI, SI, LCWI, and
EF increased, SVRI decreased, and other measured parameters were
unchanged. In contrast, during the nitroglycerin infusion studies, MAP,
CI, SI, LCWI, and EDI all decreased, and reductions in SVRI were
relatively small (Fig. 3). There was an 18% decline in SVRI during vasopressin infusions, compared with a 2%
decline in SVRI during nitroglycerin infusions. These responses to
nitroglycerin infusions are consistent with a predominant vasodilatory effect on venous capacitance vessels, leading to a reduction in right
atrial filling and to decreased CI and SI.
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Fig. 3.
Maximal changes in hemodynamic parameters during
vasopressin infusion after V1-receptor blockade
(A) and during nitroglycerin infusion (B) in
normal subjects are shown as %changes from baseline observations. SI,
stroke volume; LCWI, left cardiac work index; EF, ejection fraction;
EDI, end-diastolic index.
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Variable hemodynamic effects of nitroglycerin have been reported,
depending on route of administration (sublingual or intravenous), dosage, and cardiac status of study subjects. At low sublingual doses,
dilation of systemic veins is the principal action of nitroglycerin (15, 22, 24, 29). Any effect on peripheral arterioles is
relatively small and is associated with little or no change in total
systemic vascular resistance (22, 24). Left ventricular end-diastolic pressure and volume are reduced (22, 24,
29), and reductions in CI, SI, and systemic arterial pressure
have been reported (37, 39) but are not consistently
observed. In cardiac catheterization studies, Robin et al.
(26) noted reductions in systolic arterial and left
ventricular end-diastolic pressures and increases in HR, SI, and EF
after 0.6-mg sublingual doses of nitroglycerin. CI was not
significantly reduced in normal subjects but was reduced in patients
with atherosclerotic heart disease. In studies reported by Christensson
et al. (6), intravenous nitroglycerin infusions at a rate
lower than that used in our studies (0.17 mg/min) also decreased
systolic arterial pressure and SI in supine normal subjects but with
negligible effects on CI.
Despite reductions in MAP and CI, there was no increase in PRA in our
nitroglycerin infusion studies. However, few studies of the effect of
nitroglycerin on renal vasculature have been reported. Vatner et al.
(34), in studies in conscious dogs, noted an early
increase in renal blood flow associated with a reduction in renal
vascular resistance during both intravenous and sublingual
nitroglycerin administration. Dilation of renal vasculature after
intra-arterial administration of nitroglycerin in dogs was reported by
Frohlich et al. (8). In studies of the central and
regional hemodynamic effects of nitroglycerin in patients with
congestive heart failure, Leier et al. (19) found that
renal vascular resistance did not change and that renal blood flow
decreased only slightly as systemic arterial pressure was reduced.
These studies show a clear differentiation of the hemodynamic effects
of nitroglycerin from those associated with AVP-induced vasodilation
after V1-receptor blockade. The primary vascular effect of
AVP, which was unmasked by V1-receptor blockade, was a
reduction in SVRI in both quadriplegic and normal subjects. The
magnitude of reduction in SVRI was not affected by whether or not the
sympathetic nervous system was intact. However, this did have an effect
on the response of CI, which was twofold greater in normal subjects
than in quadriplegic subjects. This increase in CI, due to reflex
sympathetic stimulation in normal subjects, was sufficient to maintain
systemic arterial pressure despite the reduction in SVRI. Whereas the
relevance of these observations to normal cardiovascular homeostatic
mechanisms is presently uncertain, this combination of primary and
secondary hemodynamic responses may serve to maintain or increase
peripheral blood flow in areas of the circulation where the
vasodilatory effect of vasopressin is not normally countered by
V1 receptor-mediated vasoconstriction. Studies reported by
Naitoh et al. (25) have suggested that vasodilation is the
predominant effect of AVP on renal resistance vessels. Increases in
renal blood flow produced by intravenous infusions of AVP in conscious
dogs in these studies were further increased by prior administration of
a V1-receptor antagonist and completely inhibited by
administration of a V2-receptor antagonist. In studies showing biphasic changes in forearm vascular resistance during intra-arterial infusions of AVP, vasodilation produced by high rates of
AVP infusion was augmented by L-arginine and inhibited by
NG-monomethyl-L-arginine
(L-NMMA), an inhibitor of nitric oxide generation by nitric
oxide synthase, suggesting that the vasodilatory effect of AVP may be
mediated by nitric oxide (32). Although the hemodynamic
responses to nitroglycerin, a known precursor of nitric oxide, were
markedly different from those noted during AVP infusions in the
presence of V1-receptor blockade in normal subjects, the
possibility that nitric oxide might be involved in the vasodilatory
effect of vasopressin is not excluded by these studies.
Perspectives
These studies provide further evidence that AVP may play a major
role in complex homeostatic mechanisms that affect blood flow
distribution through its vasodilatory as well as vasoconstrictive effects on resistance vessels. The vasodilatory effect, which is
readily demonstrable after V1-receptor blockade in human
subjects, is capable of inducing large changes in hemodynamic
parameters and is closely associated with increasing plasma vasopressin
concentrations. This latter association suggests that vasopressin may
be involved in a mechanism that contributes to the preservation or
enhancement of blood flow to organs or tissues that could be adversely
affected by dehydration or volume depletion due to blood loss or other causes. The possibility that vasopressin-induced vasodilation may be
mediated by V2 or V2-equivalent receptors in
blood vessels also suggests a unifying concept in which the
antidiuretic action of vasopressin, which is known to be mediated by
V2 receptors on renal tubules, and its vasodilatory effect
may function in concert to maintain essential blood flow during periods
of actual or threatened volume deficiency.
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ACKNOWLEDGEMENTS |
We thank the staff and patients of the Spinal Cord Injury Unit,
Veterans Affairs Medical Center, Memphis, TN for continued support and
cooperation in the performance of these studies. We also thank M. A. Bobal for excellent technical assistance. The V1-receptor antagonist used in these studies was provided
by Dr. Haralambos Gavras, Boston Univ. School of Medicine.
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FOOTNOTES |
This study was supported by a grant from the Spinal Cord Research
Foundation, Paralyzed Veterans of America.
Address for reprint requests and other correspondence: C. R. Cooke, VAMC Nephrology Section (111 B), 1030 Jefferson Ave., Memphis, TN 38104 (E-mail: Charles.Cooke{at}med.va.gov).
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 23 July 2000; accepted in final form 10 May 2001.
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Am J Physiol Regul Integr Comp Physiol 281(3):R887-R893
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