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Circulation. 1995;92:1576-1581

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(Circulation. 1995;92:1576-1581.)
© 1995 American Heart Association, Inc.

Articles

Coronary {alpha}1-Constrictor Tone During Renovascular Hypertension

Patricia A. Gwirtz, PhD

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.


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowMethods
down arrowResults
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Background A coronary {alpha}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 {alpha}1-adrenergic constrictor tone imposes limitations on coronary blood flow in resting dogs after development of renovascular hypertension, exacerbates coronary {alpha}-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 {alpha}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 {alpha}1-adrenergic blockade. During submaximal exercise, removal of an {alpha}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, {alpha}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 {alpha}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


*    Introduction
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 *Introduction
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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 {alpha}-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 {alpha}1-adrenergic constrictor tone imposes limitations on coronary blood flow in resting dogs after development of renovascular hypertension, exacerbates a coronary {alpha}-constrictor tone during exercise, and increases coronary vascular adrenergic responsiveness.


*    Methods
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 *Methods
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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 {alpha}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 {alpha}1-adrenergic receptors. Adequate {alpha}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 {alpha}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 {alpha}-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.


*    Results
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
*Results
down arrowDiscussion
down arrowReferences
 
Series 1
This study was performed to test the hypothesis that an {alpha}-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 {alpha}1-adrenergic blockade with IC injection of 0.5 mg prazosin. A typical tracing from one dog is shown in Fig 1Down; data from all dogs are presented in Table 1Down. In the normotensive state, none of the measured variables were affected by IC administration of prazosin, indicating the absence of a coronary {alpha}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 {alpha}1-adrenergic coronary constriction in the resting dog.



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  		Figure 1. Representative tracings show the response to injection of prazosin (0.5 mg IC) in a resting dog before (normotensive) and 2 weeks after development of renovascular hypertension (hypertensive). Left ventricular systolic pressure and aortic pressures were higher after hypertension was induced by renal artery stenosis. Intracoronary injection of the {alpha}1-blocker had no effect on left circumflex blood flow velocity (CFV) in the normotensive state but caused a substantial increase in CFV in the hypertensive state.


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  		Table 1. Response to {alpha}1-Adrenergic Blockade Before and 2 Weeks After Renovascular Hypertension

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 2Down and Table 2Down. IC administration of these {alpha}-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 {alpha}-receptor sensitivity or density.



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  		Figure 2. Representative tracings showing the coronary flow response to intracoronary injection of norepinephrine (0.3 µg IC) in a resting dog before (normotensive) and 2 weeks after development of renovascular hypertension (hypertensive). Injection of norepinephrine is indicated by arrows. Both the vasodilatory and vasoconstrictor responses were greater in the hypertensive state.


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  		Table 2. Effects of Intracoronary Norepinephrine and Phenylephrine Before and 2 Weeks After Renovascular Hypertension

Series 2
The presence of a coronary {alpha}-constrictor tone during exercise was also examined in four of these dogs before and after development of hypertension. Data presented in Table 3Down demonstrate that while dogs were in a normotensive state, CFV increased 15±4% after IC administration of prazosin to remove an {alpha}-constrictor tone during exercise. In the hypertensive state, CFV increased 27±10%. These data suggest that a coronary {alpha}1-adrenergic constrictor tone was significantly greater during exercise after hypertension was induced.


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  		Table 3. Response to {alpha}-Blockade During Exercise

Series 3
To examine whether this {alpha}-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 {alpha}-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 4Down indicate that angiotensin II infusion resulted in a significant increase in LVSP, mean AoP, HR, and CFV. Intracoronary {alpha}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 {alpha}-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 {alpha}-constrictor tone in hypertensive dogs. This possibility requires further study.


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  		Table 4. {alpha}-Blockade During Angiotensin II Infusion


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
*Discussion
down arrowReferences
 
The most important finding of this study is that renovascular hypertension causes enhanced coronary vascular reactivity, a resting {alpha}1-adrenergic vasoconstrictor tone, and an enhanced {alpha}-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 {alpha}-agonists has been described.17 19 We observed that in contrast to normotensive dogs, there is a significant {alpha}1-constrictor tone in the resting conscious dog with renovascular hypertension. In addition, we observed an exacerbated coronary {alpha}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.


*    Acknowledgments
 
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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 up arrowAbstract
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 up arrowMethods
up arrowResults
up arrowDiscussion
*References
 

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