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Am J Physiol Heart Circ Physiol 291: H2082-H2089, 2006. First published June 23, 2006; doi:10.1152/ajpheart.00861.2005
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Coronary vasoconstrictor influence of angiotensin II is reduced in remodeled myocardium after myocardial infarction

Daphne Merkus,1 David B. Haitsma,1 Oana Sorop,1 Frans Boomsma,2 Vincent J. de Beer,1 Jos M. J. Lamers,3 Pieter D. Verdouw,1 and Dirk J. Duncker1

1Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter; 2Department of Internal Medicine; and 3Department of Biochemistry, Cardiovascular Research School COEUR, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands

Submitted 12 August 2005 ; accepted in final form 6 June 2006


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
The renin-angiotensin system plays an important role in cardiovascular homeostasis by contributing to the regulation of blood volume, blood pressure, and vascular tone. Because AT1 receptors have been described in the coronary microcirculation, we investigated whether ANG II contributes to the regulation of coronary vascular tone and whether its contribution is altered during exercise. Since the renin-angiotensin system is activated after myocardial infarction, resulting in an increase in circulating ANG II, we also investigated whether the contribution of ANG II to the regulation of vasomotor tone is altered after infarction. Twenty-six chronically instrumented swine were studied at rest and while running on a treadmill at 1–4 km/h. In 13 swine, myocardial infarction was induced by ligation of the left circumflex coronary artery. Blockade of AT1 receptors (irbesartan, 1 mg/kg iv) had no effect on myocardial O2 consumption but resulted in an increase in coronary venous O2 tension and saturation both at rest and during exercise, reflecting coronary vasodilation. Despite increased plasma levels of ANG II after infarction and maintained coronary arteriolar AT1 receptor levels, the vasodilation evoked by irbesartan was significantly reduced both at rest and during exercise. In conclusion, despite elevated plasma levels, the vasoconstrictor influence of ANG II on the coronary circulation in vivo is reduced after myocardial infarction. This reduction in ANG II-induced coronary vasoconstriction may serve to maintain perfusion of the remodeled myocardium.

renin-angiotensin system; coronary circulation; remodeling; heart failure; autonomic nervous system

THE RENIN-ANGIOTENSIN SYSTEM plays an important role in cardiovascular homeostasis by contributing to the regulation of blood volume, blood pressure, and vascular tone. ANG II exerts its effects on vascular tone through binding to the AT1 receptor, resulting in vasoconstriction, as well as to the AT2 receptor, evoking vasodilation (5). Both receptor subtypes have been identified in the coronary microcirculation (1, 39), suggesting that endogenous ANG II may contribute to the regulation of coronary vascular tone and to the regulation of myocardial perfusion. Studies regarding the role of endogenous ANG II have shown ambiguous results; AT1 receptor blockade had either no effect at rest (25, 27, 29, 30, 40) and during exercise (3, 40) or induced coronary vasodilation at rest (26, 31, 33) and during exercise (30, 32). The majority of these studies did not correlate changes in blood flow or vascular tone to possible changes in myocardial metabolic demand produced by AT1 receptor blockade, which makes interpretation of these studies difficult. The first aim of the present study was, therefore, to investigate how AT1 receptor blockade affects coronary vascular tone in relation to the myocardial O2 balance in exercising swine.

Under pathological circumstances, i.e., after myocardial infarction (MI), the renin-angiotensin system is activated, resulting in increased plasma levels of ANG II, particularly during exercise (10, 12). Moreover, there is evidence that AT1 receptor density in the viable region of the myocardium is increased early after MI (19, 37), suggesting that its vasoconstrictor influence on the coronary vasculature could be increased, which may limit myocardial perfusion, thereby exacerbating left ventricular (LV) dysfunction. Consequently, the second aim of the study was to investigate whether the influence of endogenous ANG II on the coronary vasculature is altered after MI.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Studies were performed in accordance with the American Physiological Society's "Guiding Principles in the Care and Use of Animals" and with approval of the Animal Care Committee of Erasmus Medical Center. A total of 40 crossbred Landrace x Yorkshire swine of either sex (2 to 3 mo old; 22 ± 1 kg at the time of surgery) were entered into the study.

Surgical Procedures

Swine were sedated (ketamine, 20 mg/kg im), anesthetized (thiopental sodium, 10–15 mg/kg iv), intubated, and ventilated with a mixture of O2 and N2O (1:2) to which 0.2–1.0% (vol/vol) isoflurane was added (9, 22). Anesthesia was maintained with midazolam (2 mg/kg + 1 mg·kg–1·h–1 iv) and fentanyl (10 µg·kg–1·h–1 iv). Under sterile conditions, 32 swine were instrumented as previously described (9, 22). Briefly, a polyvinylchloride catheter was inserted into the aortic arch for the measurement of mean aortic pressure and blood sampling for the determination of PO2, PCO2, pH (ABL5, Radiometer), O2 saturation, and hemoglobin concentration (OSM2, Radiometer). A high-fidelity Konigsberg pressure transducer was inserted into the LV via the apex for measurement of LV pressure and maximum rate of rise in LV pressure (LV dP/dtmax). Fluid-filled catheters were also implanted in the left atrium for pressure measurements and in the pulmonary artery for infusion of drugs. A small angiocatheter was inserted into the anterior interventricular vein for coronary venous blood sampling (9). A Transonic flow probe (22) was placed around the proximal left anterior descending coronary artery. In all animals the proximal part of the left coronary circumflex artery (LCx) was exposed, but only in the 19 swine designated to the MI group was the LCx permanently occluded with a silk suture (12, 36, 37). Three MI swine died during surgery due to recurrent fibrillation. Electrical wires and catheters were tunneled subcutaneously to the back, the chest was closed, and animals were allowed to recover. Animals received analgesia (0.3 mg buprenorphine im, for 2 days) and antibiotic prophylaxis (25 mg/kg amoxicillin and 5 mg/kg gentamicin iv, for 5 days). Three MI swine died overnight during the first week after surgery.

Experimental Protocols

Exercise studies. Studies were performed 2 to 3 wk after surgery. After hemodynamic measurements (lying and standing), blood samples (lying), and rectal temperature (standing) had been obtained, swine were subjected to a four-stage exercise protocol on a motor-driven treadmill (1–4 km/h). Hemodynamic variables were continuously recorded and blood samples collected during the last 60 s of each 3-min exercise stage, at a time when hemodynamics had reached a steady state.

After 90 min of rest, the AT1 receptor antagonist irbesartan (a gift from Bristol-Myers Squibb; 1 mg/kg in 40 ml saline, pH 8) was infused intravenously over a 10-min period, followed by 5 min of stabilization, before the second exercise trial in 13 normal (5 male and 8 female) and 13 MI (8 male and 5 female) swine. Irbesartan is a highly selective AT1 receptor blocker with an IC50 of ~1 nM for the AT1 receptor and an IC50 of 10 µM for the AT2 receptor (2). Because there were no significant differences in the results from male and female swine, data from both sexes were pooled.

We have previously shown excellent reproducibility of the hemodynamic responses to consecutive bouts of exercise in both normal (9) and MI swine (13).

Western blot analysis of AT1 receptor protein. A separate group of swine (n = 8) was used for isolation of coronary arterioles and determination of AT1 receptor density. Initial surgery was performed as described in Surgical Procedures, but no catheters were implanted. The LCx coronary artery was dissected free in all eight swine and ligated to induce MI in four swine. Swine were euthanized 3 wk after induction of MI or sham operation.

The apex of the LV was placed in ice-cold MOPS buffer (23), and coronary arterioles were then isolated (internal diameter, ~150 µm), rinsed in MOPS buffer, placed in liquid N2, and stored at –80°C. Arterioles together with 10 mM Tris·HCl were homogenized with a microdismembrator unit (B. Braun Biotech International) at 1,700 rpm for 4 min in a Teflon vial with a Teflon sphere and diluted (1:1) in ice-cold 2x-concentrated Laemmli loading buffer, followed by 5 cycles of sonification (on ice-water amplitude 10 µm, 5 x 10 s with 30 s pauses in between). The homogenate was centrifuged at 9,700 g for 10 min at 4°C, and the supernatant was used for the analysis. Protein concentrations were determined by RcDc protein assay kit (Bio-Rad).

Equivalent amounts of protein (20 µg) were separated on a 12% 1D-SDS polyacrylamide gel. Proteins were then transferred onto nitrocellulose membrane (Hybond-P Amersham PVDF, 0.45 µm) overnight at 40 V. Blots were preincubated in Tris-buffered saline with Tween (TTBS) buffer (10 mmol/l Tris·HCl, pH 7.6; 150 mmol/l NaCl; and 0.1% Tween), supplemented with 5% nonfat milk powder for 1 h at room temperature, and incubated with primary rabbit antibody against AT1 receptors (Santa Cruz Biotechnology, dilution 1:400 in TTBS with 5% nonfat milk powder) for 1 h at room temperature and then overnight at 4°C. After being washed with TTBS, blots were probed and incubated with peroxidase-conjugated goat anti-rabbit secondary antibody (1:2,000 dilution; Pierce). Immunoreactivity was visualized with an ECL Western blotting detection kit (Pierce). Quantitative assessment of band densities was performed by calibrated scanning densitometry (GS800, Bio-Rad).

Data Analysis

Digital recording and off-line analysis of hemodynamic data and computation of myocardial O2 consumption (MVO2) and myocardial O2 extraction (MEO2) have been described in detail elsewhere (9, 22). Plasma levels of renin, ANG II, and catecholamines were determined as previously described (18, 37).

Statistical analysis of hemodynamic data and plasma levels of ANG II and catecholamines was performed using three-way (MI, drug treatment, and exercise) or two-way (MI and exercise) ANOVA for repeated measures, as appropriate. When significant effects were detected, post hoc testing for the effects of exercise, drug treatment, and MI was performed using Scheffé's test. To test for the effects of MI and drug treatment on the relation between MVO2 and coronary venous O2 tension (PcvFormula), saturation (ScvFormula), or MEO2, regression analysis was performed with animal as a dummy variable and with MI, drug treatment, and MEO2 as independent variables. Band densities of the Western blots were compared by using an unpaired t-test. Statistical significance was accepted at P ≤ 0.05 (two-tailed). Data are presented as means ± SE.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Systemic Hemodynamics and LV Function

The infarcted area approximates 20% of the LV (12, 28). Despite the loss of viable myocardial tissue, the LV weight-to-body weight ratio in MI swine (3.7 ± 0.2 g/kg) tended to be slightly higher than in normal swine (3.2 ± 0.4 g/kg), reflecting hypertrophy of surviving myocardium. In agreement with previous observations in our laboratory (12, 23, 36), MI swine were characterized by a lower LV dP/dtmax (10%) and a two-fold higher mean left atrial pressure, whereas heart rate was slightly elevated (10%) under resting conditions (Fig. 1). Exercise resulted in blunted increments of LV dP/dtmax in MI compared with normal swine, while the increase in heart rate was maintained (Fig. 1).


Figure 1
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  		Fig. 1. Top: relationship between heart rate [in beats/min (bpm)] and maximum rate of rise of left ventricular (LV) pressure (LV dP/dtmax, left), left atrial pressure (middle), and LV systolic pressure (right). Data points at rest (lying and standing) and during exercise (1–4 km/h) of normal (N) swine and swine with myocardial infarction (MI) are shown. Bottom: relationship between heart rate and arterial plasma levels of norepinephrine (left), renin (middle), and angiotensin II (right). Data points at rest (lying) and at 2 and 4 km/h are shown. Data are means ± SE; *P < 0.05 MI vs. N swine.

 
AT1 receptor blockade with irbesartan resulted in similar decreases in mean aortic pressure at rest and during exercise in normal (Table 1) and MI (Table 2) swine, which were accompanied by small, probably baroreflex-mediated, increases in heart rate, particularly at lower levels of physical activity.


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  		Table 1. Effect of the AT1 receptor blocker irbesartan in thirteen normal swine

 

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  		Table 2. Effect of the AT1 receptor blocker irbesartan in thirteen swine with myocardial infarction

 
Neurohormones

In normal swine, circulating renin and circulating ANG II levels were minimally affected by exercise (Fig. 1). In contrast, exercise resulted in an increase in circulating norepinephrine concentrations (up to 3-fold at 4 km/h, P < 0.05; Fig. 1), whereas the difference between coronary venous and arterial norepinephrine concentrations tended to increase (Fig. 2). Plasma levels of renin, ANG II, and norepinephrine were significantly elevated in MI swine, particularly during exercise (Fig. 1), whereas MI had no significant effect on the coronary arteriovenous difference in norepinephrine levels (Fig. 2).


Figure 2
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  		Fig. 2. Effect of AT1 receptor blockade with irbesartan on arterial plasma levels of renin (first), angiotensin II (second), norepinephrine (third), and difference between arterial and coronary venous levels of norepinephrine (fourth) in N (n = 5) and MI (n = 7) swine at rest and during exercise at 2 and 4 km/h. Data are means ± SE; *P < 0.05 vs. corresponding control relation; {dagger}P < 0.05 vs. N swine.

 
In both normal and MI swine, AT1 receptor blockade with irbesartan resulted in robust increases in circulating renin and ANG II. In contrast, norepinephrine levels increased only slightly in normal swine after administration of irbesartan and remained unaltered in MI animals. Furthermore, the arteriocoronary venous norepinephrine concentration difference was not affected by AT1 receptor blockade in either normal or MI swine (Fig. 2).

AT1 Receptor Density

AT1 receptor density, as determined by Western blot analysis (Fig. 3), tended to be higher in MI swine [7.7 ± 1.2 arbitrary units (au)] compared with that in normal swine (6.0 ± 0.4 au), although this trend failed to reach levels of statistical significance (P = 0.20).


Figure 3
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  		Fig. 3. AT1 receptor density [in arbitrary units (au)] tends to be slightly higher on coronary arterioles from MI (n = 4) compared with N (n = 4) swine. Inset: representative example from Western blot analysis of 1 N and 1 MI swine. Data are means ± SE.

 
Coronary Vasomotor Tone and Myocardial O2 Balance

In accordance with previous studies from our laboratory, coronary blood flow increased commensurate with the exercise-induced increased metabolic demand of the myocardium, so that MEO2 and hence ScvFormula and PcvFormula remained constant (Fig. 4, top). AT1 receptor blockade with irbesartan resulted in coronary vasodilation in normal swine, thereby increasing myocardial O2 delivery at each level of myocardial O2 demand. This small increase in O2 delivery allowed the myocardium to extract less oxygen to fulfill its metabolic demands, leading to an increase in ScvFormula and PcvFormula(Fig. 4, top). The effect of irbesartan on coronary resistance vessel tone was independent of the exercise level.


Figure 4
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  		Fig. 4. Effect of AT1 receptor blockade with irbesartan (1 mg/kg iv) on relationship between myocardial O2 consumption (MVO2) and myocardial O2 extraction (MEFormula), coronary venous O2 saturation (ScvFormula) and coronary venous O2 tension (PcvFormula) in 9 N swine (top) and 10 MI swine (bottom). For the sake of legibility, standard errors in MVO2 have been omitted. These can be found in Table 1 and 2. Data are means ± SE; *P < 0.05 vs. corresponding control relation; {dagger}P < 0.05, effect of irbesartan different in MI vs. N animals.

 
Because arterial norepinephrine levels increased slightly after AT1 receptor blockade in normal swine, it is possible that the vasodilator effect of AT1 receptor blockade was, in part, mediated through increased beta-adrenergic vasodilation. Therefore, we performed additional experiments in six normal swine, in which the effects of AT1 receptor blockade were assessed in the presence of beta-blockade with propranolol [0.5 mg/kg iv, before the first exercise trial, and 0.25 mg/kg iv, before the second exercise trial (6, 8, 9)]. In the presence of propranolol, irbesartan resulted in an increase in PcvFormula that was similar to the response from the absence of propranolol (Table 3), indicating that the vasodilator effect of AT1 receptor blockade was principally the result of a direct effect on the coronary resistance vessels.


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  		Table 3. Effect of the AT1 receptor blocker irbesartan in six normal swine on myocardial O2 balance in the absence and presence of beta-blockade with propranolol

 
In MI swine, resting coronary blood flow and MVO2 tended to be slightly larger than in normal swine (Table 1 and 2), probably due to the slightly higher heart rate and the moderate LV hypertrophy in MI swine. In MI swine, the coronary vasodilation induced by irbesartan was markedly reduced, i.e., PcvFormula and ScvFormula were only slightly increased (Fig. 4, bottom). Thus, despite the increase in ANG II levels and the tendency toward increased AT1 receptor density in MI swine, endogenous ANG II-induced vasoconstriction in the coronary circulation was reduced compared with that in normal swine.


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The main findings of the present study are that 1) ANG II exerts a direct tonic vasoconstrictor influence on the coronary circulation of normal swine; and 2) the vasoconstrictor influence of ANG II on the coronary vasculature is reduced after myocardial infarction, despite increased arterial ANG II plasma levels and a tendency toward increased coronary AT1 receptor expression, suggesting that desensitization of the AT1 receptors contributed to the blunted ANG II vasoconstrictor influence.

Effect of Endogenous Angiotensin II on Coronary Vasomotor Tone in Normal Swine

Several studies have investigated the role of ANG II in the regulation of coronary vasomotor tone. There is ample evidence that intravenous as well as intracoronary administration of ANG II produces coronary vasoconstriction in a variety of species, including the rat (20, 29), dog (24, 40), and pig (18, 39), indicating that the AT1 receptor is present in the coronary vasculature and is capable of influencing coronary vasomotor tone. However, a role for endogenous ANG II in the regulation of coronary vasomotor tone is less clear, because several studies have reported either a coronary vasodilator response (26, 30–33) or no effect (3, 25, 27, 29, 40) after administration of an AT1 receptor blocker. Several reasons could be forwarded to explain these divergent results, including the parameter employed to assess vasomotor tone, the use of systemic versus intracoronary administration of the AT1 receptor blocker, the presence or absence of anesthesia, and interspecies variation.

The myocardial O2 balance provides the most sensitive way to assess changes in coronary vasomotor tone in response to AT1 receptor blockade. Thus the relationship between coronary venous O2 levels and MVO2 reflects changes in resistance vessel tone corrected for changes in myocardial metabolism, thereby providing a way to assess changes in coronary vasomotor tone independently of the changes in myocardial O2 demand (7, 9, 11, 35). This appears to be particularly important when AT1 receptor blockers are administered systemically, because AT1 receptor blockade results in alterations in systemic hemodynamics. However, even when AT1 antagonists are administered directly into the coronary artery to avoid systemic hemodynamic effects (25, 27), myocardial O2 demand can be altered as a result of a decreased contractility both directly, through blockade of AT1 receptors located on the cardiomyocytes (5), and indirectly, through blockade of AT1 receptors on the sympathetic nerve endings, blunting of norepinephrine release and reduced beta-adrenergic stimulation of the cardiomyocytes (17, 34). Hence, the lack of an increase in coronary blood flow produced by an intracoronary infusion of losartan in humans with endothelial dysfunction (25) may have been, in part, due to the a decrease in myocardial O2 demand produced by presynaptic and cardiomyocyte AT1 blockade. These observations illustrate that for a careful assessment of the role of AT1 receptors in the regulation of coronary blood flow, coronary vasomotor tone should be studied in relation to myocardial O2 demand (7, 35).

Using this approach, we found that AT1 receptor blockade causes coronary vasodilation at rest and during exercise, indicating that endogenous ANG II exerts a tonic vasoconstrictor influence on the coronary microvasculature of awake swine. Our observations are in agreement with the AT1 blockade-induced increases in myocardial blood flow in swine during exercise reported by some (30, 32) but not all investigators (3). Importantly, the two studies (30, 32) that observed an increase in myocardial blood flow used a low dose of losartan that was devoid of systemic hemodynamic effects under resting conditions. In contrast, the study that failed to observe an increase in myocardial blood flow used two doses of valsartan that produced systemic vasodilation resulting in a decreased blood pressure (17 mmHg at rest and 22 mmHg during exercise) and reflex tachycardia at rest but not during exercise (3). These hemodynamic alterations likely resulted in decreased myocardial O2 demands, particularly during exercise. Consequently, the direct vasodilator effect of AT1 blockade may have been masked by an indirect vasoconstriction due to the decrease in metabolic demands.

Because presynaptic AT1 receptors on sympathetic nerve endings can facilitate norepinephrine release, AT1 receptor blockade may alter sympathetic outflow to the heart, i.e., decrease norepinephrine release (17, 34). Conversely, the decrease in blood pressure that often accompanies AT1 receptor blockade will activate the baroreceptor reflex, thereby increasing norepinephrine. In the present study, AT1 receptor blockade resulted in a slight increase in circulating norepinephrine levels, whereas the transmyocardial norepinephrine gradient remained unchanged, consistent with previous observations from our laboratory (18). These findings suggest that the baroreceptor-mediated increase in norepinephrine outweighed the decreased norepinephrine release through blockade of presynaptic AT1 receptors. In swine, norepinephrine exerts its effects on coronary vasomotor tone principally through activation of beta-adrenoceptors, thereby causing vasodilation, with negligible {alpha}-adrenoceptor influence (9). Hence, the small increases in norepinephrine in response to AT1 receptor blockade may have contributed to the AT1 blockade-induced coronary vasodilation. Importantly, however, the vasodilator effect of AT1 receptor blockade in the present study was essentially maintained after beta-receptor blockade with propranolol, indicating that the coronary vasodilation produced by systemic AT1 receptor blockade was not simply the result of increased coronary beta-adrenergic stimulation but rather a direct effect on the coronary resistance vessels.

In contrast to our observations in awake swine, Zhang et al. (40) found that AT1 receptor blockade with telmisartan had no effect on the relation between MVO2 and PcvFormula in awake normal dogs, suggesting that ANG II does not contribute to the regulation of vasomotor tone of coronary resistance vessels in the dog. In the latter study, systemic AT1 blockade was associated with an increase in heart rate suggestive of baroreflex-mediated activation of sympathetic activity. Because in the dog norepinephrine produces coronary vasoconstriction via {alpha}-adrenoceptors (4, 11), the direct coronary vasodilation produced by AT1 receptor blockade may have been masked by an increased {alpha}-adrenergic vasoconstrictor influence.

Effect of Angiotensin II on Coronary Vasomotor Tone After Myocardial Infarction

Myocardial dysfunction due to MI results in the loss of viable pump tissue and compensatory LV remodeling and neurohumoral activation. The remaining viable tissue hypertrophies and heart rate increases to compensate for the decreased stroke volume (12). These adaptations result in an increased MVO2 of the remote-noninfarcted myocardium and thus require additional coronary blood flow. Yet, coronary blood flow is impeded by insufficient growth of the coronary microvasculature in conjunction with an increase in extravascular compressive forces that is due to the increased heart rate and LV filling pressure (12, 23). The additional vasodilation that is required to meet the increased O2 demand of the remote myocardium and to overcome the augmented impediment of coronary blood flow results in a reduction in adenosine-recruitable flow reserve (15, 16, 41). Moreover, during exercise, when extravascular compressive forces increase further, the recruitment of vasodilator reserve in the remodeled heart is apparently not sufficient, thereby forcing the heart to increase its O2 extraction from the blood and resulting in decreased coronary venous O2 levels (12, 23).

In the present study, we observed a loss of ANG II-induced vasoconstrictor influence, despite increased plasma ANG II levels and a trend toward an increased coronary AT1 receptor expression in swine with MI. It is unlikely that decreased vasoconstrictor influence of endogenous ANG II is due to insufficient dosage of irbesartan in MI swine because the decrease in blood pressure was similar or slightly larger in MI compared with normal swine. It is also unlikely that a generalized loss of vasodilator capacity in the remote myocardium contributed to the blunted vasodilator response to irbesartan, because our laboratory (13) has previously shown that vasodilation produced by nitroprusside is unperturbed. Finally, although an increased AT2 receptor expression could have acted to limit ANG II-induced vasoconstriction (29), this is unlikely because AT2 mRNA was not altered in coronary arteries from patients with ischemic heart disease (38). Moreover, the dramatic increases in ANG II levels after irbesartan did not result in enhanced, but rather blunted, coronary vasodilation. Therefore, the observation of a reduced vasoconstrictor influence of endogenous ANG II is best explained by AT1 receptor desensitization. This concept is in accordance with studies in dogs with pacing-induced heart failure (24), in rats with pressure-overload LV hypertrophy (20), and in rats with LV remodeling after MI (29) that demonstrated blunted vasoconstrictor responses to exogenous ANG II.

Conclusions and Physiological Relevance

Under physiological circumstances, the heart matches its blood supply to the demand of the myocardium by altering the balance of vasodilator and vasoconstrictor influences, i.e., an increase in myocardial O2 demand results in an increased influence of vasodilators [opening of K+ATP channels, NO, adenosine (14), and beta-adrenergic vasodilation (9)] and a decreased influence of the potent vasoconstrictor endothelin-1 (21, 22). Our laboratory (23) has recently shown that after MI, the coronary vasoconstrictor influence of endogenous endothelin, similar to that of ANG II, is also reduced following MI. Taken together, these studies suggest that generalized loss of vasoconstrictor influences is one of the first adaptive mechanisms that occurs to recruit coronary flow reserve to adjust blood flow to the increased O2 demands of the myocardium. This adaptation is physiologically favorable because it is more energy efficient to blunt vasoconstrictor influences than to synthesize vasodilators.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
D. J. Duncker is the recipient of an Established Investigator stipend from the Netherlands Heart Foundation (2000T038) and of an Irbesartan Research Award from Bristol-Myers Squibb and Sanofi. D. Merkus is supported by a postdoctoral stipend from the Netherlands Heart Foundation (2000T042).


   ACKNOWLEDGMENTS
 
The authors gratefully acknowledge the technical assistance of Birgit Houweling, Hester van de Rieth, Daniel Pijnappels, Angelique van der Houwen, Leon van Dijk, and Dick Dekkers.


   FOOTNOTES
 

Address for reprint requests and other correspondence: D. Merkus, Experimental Cardiology, Thoraxcenter, Erasmus MC, Univ. Medical Center Rotterdam, Box 1738, 3000DR Rotterdam, The Netherlands (e-mail: d.merkus{at}erasmusmc.nl)

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.


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

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