(Circulation. 1995;92:1576-1581.)
© 1995 American Heart Association, Inc.
Articles |
Coronary 
1-Constrictor Tone During Renovascular Hypertension
From the Department of Physiology, University of North Texas Health Science Center at Fort Worth.
Correspondence to Patricia A. Gwirtz, Professor, Department of Physiology, University of North Texas Health Science Center at Fort Worth, 3500 Camp Bowie Blvd, Fort Worth, TX 79107-2690.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background A coronary
1-adrenergic
constrictor tone exists under conditions associated with increased
sympathetic stimulation but not during resting conditions in the normal
heart. During renovascular hypertension, elevated circulating
angiotensin II may enhance sympathetic stimulation of the
heart, even at rest. This study tested the hypothesis that an
1-adrenergic constrictor tone imposes limitations on
coronary blood flow in resting dogs after development of
renovascular hypertension, exacerbates coronary
-constrictor tone during exercise, and increases
coronary vascular adrenergic responsiveness.
Methods and Results Left circumflex blood flow velocity (CFV),
aortic pressure (AoP), and heart rate (HR) were examined in five
quietly resting dogs during control conditions and after selective
1-adrenergic blockade using an intracoronary
injection of 0.5 mg prazosin. In the normotensive state, AoP was 87±7
mm Hg (mean±SD), HR was 105±25 beats per minute, and CFV was
28±6
cm/s. These parameters were not affected by
1-adrenergic blockade. During submaximal exercise,
removal of an 1-adrenergic constrictor resulted in a
14±4% increase in CFV (P<.05). Two weeks after
development of renovascular hypertension induced by stenosis of
the left renal artery, mean AoP was 114±7 mm Hg (P<.05
versus normotensive state), HR was 111±28 beats per minute, and CFV
was 21±8 cm/s. In contrast to the normotensive state,
1-adrenergic blockade caused a 28±6% increase in CFV
at rest (P<.05) and a 27±13% increase in CFV during
exercise in the hypertensive state (P<.05 versus exercise
before blockade and versus normotensive state). This resting
coronary constrictor tone was associated with enhanced
vasoconstrictor responsiveness to norepinephrine and
phenylephrine.
Conclusions It appears that renovascular hypertension results in
a significant coronary 1-adrenergic constrictor
tone in the resting dog and an enhanced constrictor tone during
exercise.
Key Words: hypertension, renal • autonomic agents • coronary disease • exercise • receptors, adrenergic, alpha
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Although coronary blood flow is primarily regulated by local metabolic mechanisms, the autonomic nervous system exerts an important influence on flow regulation.1 2 3 4 The dominant direct sympathetic effect is an
-adrenergic receptor–mediated vasoconstriction, which
opposes and limits metabolic vasodilatory
mechanisms.1 2 The full importance and
physiological significance of sympathetic effects
in the coronary circulation are unclear at present.
However, under conditions of physiological or
pathological stress, when substantial coronary vasodilation is
required to meet metabolic demands, a functional
sympathetic constrictor tone may restrict myocardial perfusion and
oxygenation. Coronary sympathetic
vasoconstriction is negligible in the conscious resting
dog4 5 6 7 but is evident
when cardiac sympathetic drive is
increased2 4 6 7 8 9 10 11
and appears to be exacerbated by
hypertension.12 13
Hypertension appears to be a disease state in which sympathetic nervous
system activity, adrenergic receptor sensitivity, and perhaps
adrenergic receptors themselves may be altered. Increased
peripheral vascular reactivity to vasoconstrictor
substances has been observed both in clinical
hypertension14 15 and in animal models of
hypertension.16 17 18 19 The
enhanced vasoreactivity that
appears with renovascular hypertension may be due to several
mechanisms, including structural changes of the vascular
wall20 21 and/or alterations in the responsiveness of
the
vascular smooth muscle cell.19 20 22
Hypertension due to
renal dysfunction (aortic coarctation, renal artery stenosis)
is associated with elevated circulating angiotensin II.
Angiotensin II has a direct
vasoconstrictive action on blood vessels, promotes the
retention of salt and water by the kidneys, and appears to enhance
sympathetic stimulation of the cardiovascular
system,23 which may play an important role in the
pathogenesis of hypertension. The effect of renovascular hypertension
on the coronary circulation needs to be examined, especially
during exercise stress. Because hypertension is associated with limited
cardiac function and exercise tolerance and with congestive heart
failure clinically, this study examined the effect of renovascular
hypertension on the coronary circulation of conscious dogs at
rest and during exercise. Studies were designed to test the hypothesis
that an 1-adrenergic constrictor tone imposes
limitations on coronary blood flow in resting dogs after
development of renovascular hypertension, exacerbates a
coronary -constrictor tone during exercise, and
increases coronary vascular adrenergic responsiveness.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Animal Selection
Five adult dogs (weight, 25 to 30 kg) of either sex were selected on the basis of being free of heartworms, in good health before surgery, and willing to run on a motor-driven treadmill.
Surgical Preparation and Methods of Measurement
All dogs were
premedicated with acepromazine maleate (0.03 mg/kg
SC), anesthetized with sodium thiamylal (0.44 mg/kg IV), and
intubated. Anesthesia was maintained with isoflurane gas
(1% to 3%) and nitrous oxide (0.6 L) with an equal offset of oxygen
(1.0 L). The chest was opened through the left fifth intercostal space,
and the heart was instrumented.
Global function (left ventricular pressure [LVP], dP/dt, and heart rate [HR]) was measured by implanting a Konigsberg P 6.5 transducer in the apex of the left ventricle. A 10-MHz Doppler flow probe was implanted around the base of the circumflex artery for measurement of coronary flow velocity (CFV). Catheters were implanted in the ascending aorta for measurement of aortic blood pressure (AoP) and in the circumflex artery24 for measurement of coronary blood pressure (CBP) and for intracoronary (IC) administration of solutions. The Konigsberg pressure transducer was calibrated before implantation and routinely checked and adjusted by simultaneously measuring pressure through an implanted, heparin-filled Tygon catheter (1.27-mm OD) connected to an external Isotec pressure transducer, which was calibrated with a mercury manometer. When surgical preparation was completed, the catheters and lead wires were tunneled under the skin to exit between the scapulae. The ribs were approximated, the incision was closed in layers, and the thoracic cavity was evacuated.
After instrumentation of the heart was completed, a midline laparotomy was performed. The left renal artery was isolated, and a 10-MHz Doppler flow probe and a hydraulic occluder were placed around the vessel. The incision was closed in layers. Antibiotics and painkillers were given by the veterinarian for 5 days or as needed. At least 10 to 14 days was allowed to elapse before we began the experiments. During this time, we familiarized the dogs with the laboratory setting.
Model of Renovascular Hypertension
Hypertension was induced
by the unilateral renal artery
stenosis method (two-kidney, one-clip Goldblatt
hypertension model) described by Anderson et al.25 This
model is more appropriate for the study of renovascular hypertension
than the one-kidney models, which are more appropriate for the
study of renal parenchymal hypertension.26 27 After
prestenosis or normotensive studies were completed, the
left renal artery was stenosed by inflating the hydraulic occluder
until renal flow was reduced by 60%.28 Verification of
stenosis or sham stenosis was performed several times
daily. Studies were repeated 2 weeks after development of hypertension.
In all dogs, venous blood samples were taken before and during the
development of hypertension for measurement of plasma renin activity by
Smith Kline Laboratories. Plasma renin modestly increased after 2 weeks
of stable hypertension from 1.0±0.2 to 1.9±0.1
ng · mL-1 · h-1.
Data Acquisition
Data were recorded on a Coulbourn
eight-channel strip
recorder and on magnetic tape (eight-channel tape,
Hewlett-Packard Co) in analog fashion for subsequent analysis
with an IBM-compatible personal computer and a Data Flow software
program (Crystal Biotech). The variables obtained from the
recorded data and analyzed included peak systolic LVP
(LVSP), end-diastolic LVP (LVEDP), maximum rate of LVP
generation (dP/dtmax), HR, CFV, and AoP. An
index of coronary vascular resistance was calculated by
dividing mean CFV by mean AoP.
Experimental Protocols
All protocols were reviewed and
approved by the institutional
Animal Care and Use Committee.
Series 1
Experiments were
performed 2 weeks after surgery to examine
whether a coronary 1-constrictor tone was
present at rest and whether adrenergic sensitivity was altered by
hypertension. After resting control measurements were obtained, 0.3
µg norepinephrine IC and 20 µg
phenylephrine IC were administered. After returning to
steady state, 0.5 mg prazosin IC was administered to antagonize
1-adrenergic receptors. Adequate
1-antagonism was verified by the absence of a
vasoconstrictor response to norepinephrine and
phenylephrine. Studies were repeated 2 weeks after
induction of renovascular hypertension.
Series 2
The presence of a coronary 1-adrenergic
constrictor tone during submaximal exercise was evaluated in the same
five dogs. After control measurements, each dog was exercised on a
motor-driven treadmill at speeds up to 6.4 km/h at a 16% incline,
and data were collected. Prazosin (0.5 mg IC) was administered while
the dog was running. Data were obtained 2 to 3 minutes after prazosin
administration. Studies were repeated 2 weeks after induction of
renovascular hypertension.
Series 3
Studies were
performed in a second group of five dogs to examine
whether an -constrictor tone at rest in the hypertensive dogs
was due to increasing circulating levels of angiotensin II.
After control measurements were obtained, angiotensin II
(diluted in normal saline) was infused at a dose of 0.05
µg · kg-1 · min-1 IV for
30
minutes. Measurements were again obtained, and prazosin (0.5 mg IC) was
administered. While angiotensin II was still being infused,
data were collected 5 minutes after IC administration of prazosin.
Statistical Analysis
For all comparisons, data within and
among the protocols were
analyzed with two-way ANOVA. In this analysis,
factor A was with or without drug (prazosin,
norepinephrine, or phenylephrine) and factor B
was normotensive or hypertensive. If the ANOVA detected significant
differences within factor means, then these differences were identified
with Student's paired t test for factor A and with the
Student-Newman-Keuls test for factor B. A value of P<.05
was considered significant. All data collected in a given animal were
compared at rest or during submaximal exercise and after each drug
intervention. The responses with each agent were compared with their
respective responses before blockade, as well as with the responses to
the other agents. Data were compared in all animals before and after
development of renovascular hypertension. In this study, each dog was
used as its own control. All values are presented as
mean±SD.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Series 1
This study was performed to test the hypothesis that an
-adrenergic constrictor tone imposes limitations on
coronary blood flow in resting dogs after induction of
renovascular hypertension. LVP, dP/dtmax,
CFV, AoP, and HR were examined in five quietly resting dogs during
control conditions and after selective 1-adrenergic
blockade with IC injection of 0.5 mg prazosin. A typical tracing from
one dog is shown in Fig 1
; data from all dogs are
presented in Table 1. In the normotensive state,
none of the measured variables were affected by IC administration
of prazosin, indicating the absence of a coronary
1-adrenergic constrictor tone at rest. Two weeks after
induction of renovascular hypertension, mean AoP was significantly
increased by 24±3 mm Hg (P<.05), with no change in
resting HR, and CFV, LVSP, and dP/dtmax were also
significantly increased (P<.05). In contrast to the
normotensive state, prazosin administered at rest now caused a
significant 28±6% increase in CFV in the hypertensive state. Thus,
unlike the normotensive condition, it appears that renovascular
hypertension resulted in a significant 1-adrenergic
coronary constriction in the resting dog.
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A question relevant to the
pathogenesis of renovascular
hypertension is whether enhanced vascular sensitivity plays a role in
the development of the hypertension. To examine coronary
vascular reactivity, norepinephrine (0.3 µg IC) and
phenylephrine (20 µg IC) were administered to these five
dogs before and 2 weeks after left renal artery stenosis. Data
are presented in Fig 2 and Table 2. IC
administration of these -agonists did not
alter LVSP, mean AoP, or HR. In the normotensive state,
norepinephrine caused a biphasic coronary flow
response, ie, CFV initially increased by 88±15%, which was followed
by an 11±6% decrease. After development of hypertension,
norepinephrine caused a 137±32% increase, followed by a
25±4% decrease. Phenylephrine caused a 13±5% decrease
in the normotensive state. After hypertension was induced, CFV
decreased by 21±4% in response to phenylephrine. These
coronary flow responses to norepinephrine and
phenylephrine were significantly greater in the
hypertensive state compared with the normotensive state. The greater
functional hyperemic response to norepinephrine may
indicate an altered myocardial ß1-receptor responsiveness
after hypertension. The greater vasoconstrictor responses indicate an
enhanced coronary -receptor sensitivity or density.
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Series 2
The presence of a coronary -constrictor tone
during
exercise was also examined in four of these dogs before and after
development of hypertension. Data presented in Table 3
demonstrate that while dogs were in a
normotensive state, CFV increased 15±4% after IC
administration of prazosin to remove an -constrictor tone during
exercise. In the hypertensive state, CFV increased 27±10%. These data
suggest that a coronary 1-adrenergic constrictor
tone was significantly greater during exercise after hypertension was
induced.
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Series 3
To examine whether this -constrictor tone at
rest was due
to increasing circulating levels of angiotensin II, which
stimulates the autonomic nervous system, another study examined whether
an acute IV infusion of angiotensin II would stimulate the
sympathetic nervous system, thereby eliciting an -adrenergic
coronary constriction. Five additional conscious, chronically
instrumented dogs were studied. Angiotensin II was infused
systemically, after which 0.5 mg prazosin was administered IC. Data
given in Table 4 indicate that angiotensin
II infusion resulted in a significant increase in LVSP, mean AoP,
HR, and CFV. Intracoronary 1-blockade with
prazosin resulted in no further change in measured
parameters. Calculated coronary resistance did not
change significantly before or during angiotensin II
infusion or after prazosin. These data suggest that an
-adrenergic constrictor tone is not present during acute IV
angiotensin II infusion. However, it is unknown whether
chronic exposure to angiotensin II (which occurs during
renovascular hypertension) would sufficiently enhance sympathetic tone
to the heart and explain the resting -constrictor tone in
hypertensive dogs. This possibility requires further study.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The most important finding of this study is that renovascular hypertension causes enhanced coronary vascular reactivity, a resting
1-adrenergic vasoconstrictor tone, and an
enhanced -constrictor tone during exercise in chronically
instrumented dogs. These findings, along with those from other
laboratories, confirm our hypothesis that renovascular hypertension
results in greater sympathetic outflow to the heart, even during
resting conditions. Hypertension appears to be a disease state in which
sympathetic nervous system activity, adrenergic receptor sensitivity,
and perhaps adrenergic receptors themselves are altered. Our data
support the hypothesis that cardiac sympathetic tone and
coronary vascular reactivity are enhanced in the hypertensive
dog. The enhanced vasoreactivity with renovascular hypertension may be due to several mechanisms. Some studies indicate that structural changes in the vascular wall occur.20 21 There is greater evidence suggesting alterations in vasomotor responsiveness of the vascular smooth muscle cell to adrenergic and humoral stimuli.19 20 22 Hypertension due to aortic coarctation or renal artery stenosis is associated with elevated levels of circulating angiotensin II, which has been shown to enhance sympathetic stimulation of the cardiovascular system.29 This can occur via several actions of angiotensin II. Angiotensin II can act on the central nervous system to increase sympathetic outflow,15 27 29 30 increase prejunctional release of norepinephrine,31 increase postjunctional responsiveness to the sympathetic neurotransmitter,12 32 33 34 and inhibit neuronal uptake of norepinephrine.20 31 However, it appears that acute systemic infusion of angiotensin II sufficient to substantially raise mean arterial pressure, as performed in this study, did not enhance sympathetic stimulation of the heart or of the coronary vasculature. In this setting, the increase in arterial pressure was primarily due to a direct vasoconstrictor effect of angiotensin II. Considering the pathogenesis of renovascular hypertension, it is more likely that chronic elevation of angiotensin is the stimulus to enhance sympathetic tone and alter vascular reactivity. The results from this study indicate that altered postjunctional sensitivity to adrenergic receptor stimulation in the heart and vascular smooth muscle contributes to the enhanced sympathoadrenal activity and maintenance of hypertension.17 20 21 31
As mentioned above, another mechanism whereby vasoconstrictor effects could be augmented during renovascular hypertension is by attenuation of compensatory vasodilatory influences. Impaired release of vasodilator substances could increase the vasoconstrictor effects of sympathetic stimulation and angiotensin II and the endothelial release of the vasoconstrictor endothelin. Angiotensin II appears to increase endothelial release of endothelin.35 There are several reports of diminished endothelium-dependent relaxation in various models of experimental hypertension, which led to the idea that nitric oxide–mediated vasodilation is impaired.36 37 In contrast, others report that nitric oxide–mediated vasodilation and pressor and constrictor responses are similar in normotensive and spontaneously hypertensive rats, and the disorder is associated with production of vasoconstrictor prostenoids.38 Pucci et al39 showed that pressor and aortic constrictor responses to nitric oxide synthase inhibition are increased after aortic coarctation in rats (with renin-dependent hypertension) and suggested that a combination of endothelium-dependent (via nitric oxide) and -independent mechanisms are involved in the enhanced constrictor response. Similar conclusions were reached by Hoshino et al22 in rats in the early stages of one-kidney, one-clip hypertension. We will examine this effect in future studies.
In normal dogs and in those with renovascular hypertension, exercise
activates the sympathetic nervous system. Our data suggest that
the degree of activation is greater in dogs with renovascular
hypertension. Both norepinephrine and
angiotensin II are potent vasoconstrictors of arterioles,
which can limit coronary blood flow to the heart. Renovascular
hypertension appears to produce vascular changes that augment these
vasoconstrictor effects. Increased peripheral vascular
responsiveness (pressor response) to -agonists has been
described.17 19 We observed that in contrast to
normotensive dogs, there is a significant 1-constrictor
tone in the resting conscious dog with renovascular hypertension. In
addition, we observed an exacerbated coronary
1-constrictor tone during exercise in the hypertensive
dog. The effect of renovascular hypertension on the coronary
circulation needs further examination, especially during exercise
stress, because hypertension is associated with limited cardiac
function and exercise tolerance and with congestive heart failure
clinically.
In summary, there appear to be enhanced vasoconstrictor influences, altered vascular responsiveness to vasoactive agents, and perhaps impaired vasodilatory influences that may contribute to altered coronary blood flow and its regulation at rest and during exercise during renovascular hypertension. Results of these studies provide important new information regarding regulation of coronary blood flow in the normotensive state and mechanisms involved in the alterations of the regulation of coronary flow and cardiac contractile function during renovascular hypertension.
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Acknowledgments |
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This research was funded by NIH grants HL-34172 and HL-29232 and a grant from the Texas Affiliate of the American Heart Association. The author wishes to thank Linda Howard and Abraham Heymann for their excellent technical assistance and Charlene Ghaedi for her secretarial assistance in preparing this manuscript.
Received February 14, 1995; accepted March 27, 1995.
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