(Hypertension. 1997;30:918-921.)
© 1997 American Heart Association, Inc.
Articles |
Decreased Vasodilator Response to Isoproterenol During Nitric Oxide Inhibition in Humans
From the Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.
Correspondence to Dr Julio A. Panza, Cardiology Branch, National Institutes of Health, Bldg 10, Room 7B-15, Bethesda, MD 20892-1650. E-mail panzaj{at}gwgate.nhlbi.nih.gov
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Abstract |
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Abstract The vasodilator effect of ß-adrenergic agonists has traditionally been ascribed solely to a direct effect on vascular smooth muscle. Experimental studies, however, have suggested a role of endothelium-derived nitric oxide (NO) in ß-adrenergic–mediated vasodilation. The purpose of this investigation was to determine whether NO contributes to the vasodilator effect of ß-adrenergic stimulation in humans. We analyzed the forearm blood flow response to increasing doses of isoproterenol (50, 100, and 200 ng/min), a ß-adrenoceptor agonist, during the concomitant infusion of saline or NG-monomethyl-L-arginine (L-NMMA; 4 µmol/min), a blocker of NO synthesis, in 23 normal subjects (9 men and 14 women, aged 48±7 years). The effect of L-NMMA was also assessed during infusion of sodium nitroprusside (0.8, 1.6, and 3.2 µg/min), an exogenous NO donor. Drugs were infused into the brachial artery, and forearm blood flow was measured by plethysmography. The vasodilator effect of isoproterenol was significantly blunted during the administration of L-NMMA compared with saline (maximum flow, 7.7±4 versus 11.2±5 mL · min-1 · dL-1, respectively; P<.001). In contrast, the vasodilator response to sodium nitroprusside was not significantly affected by the infusion of L-NMMA (maximum flow, 8.8±3.7 mL · min-1 · dL-1 during L-NMMA versus 8.9±3.2 mL · min-1 · dL-1 during saline; P=.25). These findings indicate that NO inhibition blunts the vasodilator effect of ß-adrenergic agonists in the human forearm and suggest that an abnormal response to adrenergic stimulation may occur in conditions associated with impaired NO activity.
Key Words: ß-adrenergic receptors • vasodilation • nitric oxide • endothelium • isoproterenol
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Introduction |
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The vasodilator effect of ß-adrenoceptor stimulation has classically been attributed solely to a direct action on receptors located on vascular smooth muscle cells, leading to stimulation of adenylyl cyclase, increased intracellular cyclic AMP content, and subsequent relaxation.1 However, previous experimental studies have challenged the concept that ß-adrenergic–dependent vasodilation is exclusively endothelium independent. Following the original observation that rubbing of the endothelium decreases ß-adrenergic-mediated vasodilation in canine coronary arteries,2 a number of studies using vascular preparations of rat and rabbit arteries have shown reduced vasodilator responses to ß-adrenoceptor stimulation after exposure to methylene blue and hemoglobin,3 agents known to affect the action of nitric oxide (NO), or NO synthase inhibitors.4 5 6 7 In contrast with these results, however, other studies have shown that endothelium removal does not influence ß-adrenergic–induced relaxation in hamster aortas8 ; further, in vivo studies in microvessels of feline hindquarters9 and canine large epicardial coronary arteries10 have shown that arginine analogues do not modify the vasodilation to isoproterenol.
Whether NO contributes to the vasodilator effect of ß-adrenergic stimulation in humans has not been investigated. The purpose of the present study, therefore, was to determine whether inhibition of NO synthesis modifies the vasodilator effect of ß-adrenoceptor stimulation in the forearm circulation.
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Methods |
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Study Population
Twenty-three normal volunteers (9 men and 14 women; aged 48±7 years) with no evidence of hypertension (blood pressure <140/90 mm Hg), hypercholesterolemia (total cholesterol=170±27 mg/dL, range 126 to 197), diabetes mellitus (fasting plasma glucose=92±8 mg/dL, range 80 to 109), cardiac or peripheral vascular disease, or any other systemic condition were included in the study. Participants gave written informed consent, and the protocol was approved by the National Heart, Lung, and Blood Institute Investigational Review Board.
Protocol
Each study consisted of the infusion of drugs into the brachial
artery and measurement of the forearm vascular response by means of
venous occlusion plethysmography following methodology previously
described in detail.11 Basal measurements were obtained
after a 3-minute infusion of normal saline solution at 1 mL/min.
Forearm blood flow was then measured after the infusion of
isoproterenol and sodium nitroprusside, an
endothelium-independent vasodilator with a direct
relaxant effect on smooth muscle cells.12 The sequence of
infusion of isoproterenol and sodium nitroprusside was randomized.
Isoproterenol (Sanofi Winthrop) was infused at 50, 100, and 200
ng/min, and sodium nitroprusside was infused at 0.8, 1.6, and
3.2 µg/min. Each dose was infused for 5 minutes, and forearm
flow was measured during the last 2 minutes. A 30-minute rest period
was allowed and another basal measurement was obtained between the
infusion of the two drugs. Then,
NG-monomethyl-L-arginine
(L-NMMA; Sigma Chemical Company) was infused at 4
µmol/min for 15 minutes and new baseline flow measurements
were obtained. This dose of L-NMMA has been previously proven effective
in blunting NO-dependent response to various pharmacological
stimuli.13 14 15 16 Subsequently, cumulative dose-response
curves for isoproterenol and sodium nitroprusside were repeated during
the concomitant infusion of L-NMMA. Blood pressure was recorded
directly from the intra-arterial catheter after each flow
measurement. Forearm vascular resistance was calculated as mean
arterial pressure divided by forearm blood flow.
Statistical Analysis
L-NMMA effects on baseline hemodynamic
variables were analyzed by paired Student's t
test. The responses to isoproterenol and sodium nitroprusside before
and after L-NMMA were assessed by analysis of variance for
repeated measures. All calculated probability values are two tailed,
and a value of P<.05 was considered to indicate statistical
significance. All group data are reported as mean±SD, except in the
figures, where values represent mean±SEM.
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Results |
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Vascular Responses to Isoproterenol and Sodium Nitroprusside
During saline administration, the infusion of isoproterenol induced a dose-dependent increase in forearm blood flow and fall in forearm vascular resistance (both P<.001 versus baseline by analysis of variance for repeated measures; Fig 1
). Similarly, the infusion of increasing
doses of sodium nitroprusside progressively raised forearm blood flow
and decreased forearm vascular resistance (both P<.001
versus baseline by analysis of variance for repeated measures;
Fig 2). There were no changes in mean
arterial pressure during infusion of isoproterenol (from
87±7 to 88±7 mm Hg; P=.97) or sodium nitroprusside
(from 88±8 to 87±7 mm Hg; P=.98).
|
) and during (
) infusion of
NG-monomethyl-L-arginine
(L-NMMA, 4 µmol/min). Values represent mean±SEM. The
probability values refer to the comparison of blood flow and vascular
resistance at the three doses of isoproterenol between the two
curves.
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Effect of L-NMMA on the Vascular Responses to Isoproterenol and
Sodium Nitroprusside
L-NMMA induced a fall in baseline forearm blood flow from 2.9±0.9
to 2.4±0.7 mL · min-1 ·
dL-1 (P<.001) and an increase in
forearm vascular resistance from 32.3±9.6 to 40.8±10.8
mm Hg/mL · min-1 ·
dL-1 (P<.001).
During coinfusion of L-NMMA, both the increase in forearm blood flow
and the decrease in forearm vascular resistance induced by
isoproterenol were significantly reduced compared with those observed
during the concurrent infusion of isoproterenol and saline (both
P<.001; Fig 1
). Because L-NMMA induced changes in baseline
forearm blood flow and vascular resistance, the responses to
isoproterenol before and during L-NMMA were also analyzed in
terms of percent changes from baseline. These comparisons confirmed
that the vasodilator effect of isoproterenol was significantly blunted
by the concomitant infusion of L-NMMA both in terms of forearm blood
flow (the increase from baseline induced by the three doses of
isoproterenol was 145±91%, 229±144%, and 307±174%, respectively,
during saline versus 103±68%, 157±104%, and 221±132%,
respectively, during L-NMMA; P<.001) and forearm vascular
resistance (the decrease from baseline was 53±18%, 64±11%, and
69±15%, respectively, during saline versus 44±21%, 52±20%, and
61±20%, respectively, during L-NMMA; P<.001).
During L-NMMA coinfusion, both the increase in forearm blood flow and
the decrease in forearm vascular resistance induced by sodium
nitroprusside were not significantly different from those observed
during the concurrent infusion of sodium nitroprusside and saline
(P=.85 and P=.94 for forearm blood flow and
vascular resistance, respectively; Fig 2).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The results of this study indicate that NO plays a contributory role in the vasodilator response to ß-adrenergic stimulation in the human forearm. This conclusion is supported by the observation that blockade of NO synthase by L-NMMA significantly reduced the forearm vascular response to isoproterenol. In contrast, L-NMMA did not blunt the vasorelaxant effect of an exogenous NO donor, sodium nitroprusside, confirming that its effect on the response to isoproterenol was specifically related to NO inhibition.
Different potential mechanisms may explain the role of NO in the
vasodilator effect of isoproterenol observed in our study. One
possibility is that ß-adrenoceptor stimulation with isoproterenol
increases NO synthesis from vascular endothelium. This
concept is supported by the identification of functional
ß-adrenoceptors on the surface of cultured human
endothelial cells,17 the reduction of
ß-adrenoceptor–mediated vasodilation after
endothelium removal,2 and the blunted
vasodilator response to ß-adrenergic agonists after NO inhibition
observed in experimental studies.4 5 6 7 Also, it has been
demonstrated that stimulated ß-adrenoceptors activate
adenylyl cyclase by a guanine nucleotide binding protein
(G
s) and increase intracellular cyclic AMP
levels.7 This activity leads to protein kinase A
stimulation,18 which in turn may either activate
endothelial constitutive NO synthase by increasing
intracellular calcium19 or directly
phosphorylate constitutive NO synthase and thereby induce
changes in its activity.20 These findings suggest that
endothelial production of NO may take place
with the involvement of a signal-transduction pathway that is different
from the activation of phosphoinositol-specific
phospholipase C that mediates the effect of other
endothelial agonists, such as acetylcholine,
serotonin, substance P, and bradykinin.21
However, because the results of the present investigation do not
provide direct evidence of increased NO synthesis in response to
ß-adrenoceptor stimulation, other possibilities must be considered
that may also account for our study findings. For example, because
isoproterenol has a direct vasorelaxant effect on vascular smooth
muscle cells, it may potentially trigger endogenous release
of NO simply by increasing blood flow and the shear stress to which
endothelial cells are exposed. The existence of such a
mechanism has been demonstrated in dog epicardial coronary
arteries in vivo, where the presence of endothelium
reinforces the vasodilator response to isoproterenol through an
indirect, flow-dependent mechanism.22 In our study,
however, the vasodilator response to sodium nitroprusside was not
modified by L-NMMA. Although the inhibitory effect that
exogenous NO donors exert on endogenous generation of
NO23 may have contributed to this phenomenon, this
observation seems to argue against a flow-dependent response as the
primary mechanism of NO involvement in the vasodilator effect of
isoproterenol. Moreover, the concept of a more specific interaction
between NO and ß-adrenoceptor–mediated vasodilation in the
microcirculation is supported by the results of experimental studies.
In fact, it has been shown in conscious dogs that changes in
coronary vascular conductance after intracoronary bolus
of isoproterenol were attenuated by L-NMMA, even when increases in
blood flow were prevented by a hydraulic constrictor,24
thus suggesting that ß-adrenoceptor–mediated NO formation was
related to a receptor-operated mechanism independent of induced changes
in blood flow. Finally, another potential mechanism by which blockade
of NO formation may blunt ß-adrenoceptor–mediated vasodilation is
related to the interactions between cyclic nucleotides
within vascular smooth muscle cells. Thus, it is possible that the
reduction in cyclic GMP content in vascular smooth muscle cells after
NO inhibition enhances the activity of the cyclic GMP–inhibited
phosphodiesterase III25 ; this in turn may lead to
increased breakdown of cyclic AMP and blunted vasodilator effect of
ß-adrenoceptor stimulation. This hypothesis is suggested by data
showing that, in rat aortic smooth muscle rings, cyclic GMP levels
modulate cyclic AMP–mediated vasodilation through regulation of
phosphodiesterase activity.26 27 However, recent studies
using human vessels in vitro have shown that the vasodilator effect of
phosphodiesterase inhibitors (which, like ß-adrenoceptor
agonists, increase cyclic AMP content in vascular smooth muscle) is
largely independent of NO release.28 29 Similarly, a
preliminary report 30 has shown that in the human forearm
circulation, NO inhibition by L-NMMA blunts the effect of
ß-adrenoceptor agonists but not that of prostacyclin, another
vasodilator increasing cyclic AMP content in vascular smooth
muscle.31 Moreover, direct measurements of cyclic
nucleotides in rabbit aortic preparations7
have indicated that ß-adrenoceptor stimulation by isoprenaline causes
a concomitant increase in both cyclic GMP and cyclic AMP; NO blockade
by NG-nitro-L-arginine abolishes the
increase in cyclic GMP but does not affect cyclic AMP content, implying
that isoprenaline directly activates NO production.
In our study, NO inhibition by L-NMMA determined only a partial reduction of the vasodilator effect of isoproterenol, suggesting that the major portion of the isoproterenol-induced vasodilation stems from its direct vasorelaxant effect on vascular smooth muscle cells. However, because a single dose of L-NMMA was used in this study, we cannot ascertain that blockade of NO activity was complete. Thus, our findings may actually underestimate the true physiological contribution of NO to forearm vasodilation during ß-adrenoceptor stimulation. Nevertheless, even a partial contribution of NO to the vasoactive effect of ß-adrenoceptor stimulation, as observed in our study, may be of clinical importance. For example, in addition to its effect on vascular tone, NO has other important physiological roles, such as inhibition of platelet aggregation32 and norepinephrine release.33 Therefore, an increased vascular availability of NO in response to ß-adrenoceptor stimulation may exert a protective action against the unwanted proaggregatory34 and vasoconstrictor35 effects of endogenous catecholamines released during physiological stimuli such as mental stress and exercise. An abnormality in this mechanism could result in adverse cardiovascular effects of catecholamines in conditions with impaired NO activity.
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Footnotes |
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Presented in part at the 69th Scientific Sessions of the American Heart Association, New Orleans, La, November 10-13, 1996, and published in abstract form (Circulation. 1996;94[suppl I]:I-6).
Received December 17, 1996; first decision January 15, 1997; accepted April 4, 1997.
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C. Cardillo, C. M. Kilcoyne, A. A. Quyyumi, R. O. Cannon III, and J. A. Panza Selective Defect in Nitric Oxide Synthesis May Explain the Impaired Endothelium-Dependent Vasodilation in Patients With Essential Hypertension Circulation, March 10, 1998; 97(9): 851 - 856. [Abstract] [Full Text] [PDF]
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