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Am J Physiol Heart Circ Physiol 294: H2069-H2077, 2008. First published February 29, 2008; doi:10.1152/ajpheart.01163.2007
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Integrative control of coronary resistance vessel tone by endothelin and angiotensin II is altered in swine with a recent myocardial infarction

Vincent J. de Beer,1 Oana Sorop,1 Daniël A. Pijnappels,1 Dick H. Dekkers,2 Frans Boomsma,3 Jos M. J. Lamers,2 Dirk J. Duncker,1 and Daphne Merkus1

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

Submitted 8 October 2007 ; accepted in final form 26 February 2008


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Several studies have indicated an interaction between the renin-angiotensin (ANG II) system and endothelin (ET) in the regulation of vascular tone. Previously, we have shown that both ET and ANG II exert a vasoconstrictor influence on the coronary resistance vessels of awake normal swine. Here, we investigated whether the interaction between ANG II and ET exists in the control of coronary resistance vessel tone at rest and during exercise using single and combined blockade of angiotensin type 1 (AT1) and ETA/ETB receptors. Since both circulating ANG II and ET levels are increased after myocardial infarction (MI), we investigated if the interaction between these systems is altered after MI. In awake healthy swine, coronary vasodilation in response to ETA/ETB receptor blockade in the presence of AT1 blockade was similar to vasodilation produced by ETA/ETB blockade under control conditions. In awake swine with a 2- to 3-wk-old MI, coronary vasodilator responses to individual AT1 and ETA/ETB receptor blockade were virtually abolished, despite similar coronary arteriolar AT1 and ETA receptor expression compared with normal swine. Unexpectedly, in the presence of AT1 blockade (which had no effect on circulating ET levels), ETA/ETB receptor blockade elicited a coronary vasodilator response. These findings suggest that in normal healthy swine the two vasoconstrictor systems contribute to coronary resistance vessel control in a linear additive manner, i.e., with negligible cross-talk. In contrast, in the remodeled myocardium, cross-talk between ANG II and ET emerges, resulting in nonlinear redundant control of coronary resistance vessel tone.

coronary blood flow; exercise; left ventricular remodeling; neurohormones; receptor

CORONARY VASOMOTOR TONE is tightly regulated by a myriad of vasodilator and vasoconstrictor influences to closely match coronary blood flow (CBF) to myocardial oxygen demand and maintain a consistently high level of myocardial oxygen extraction over a wide range of physical activities (14, 16, 29–31, 33). We have previously shown that swine lack significant {alpha}-adrenergic control of coronary resistance vessel tone (17), whereas endothelin (ET) and angiotensin II (ANG II) do exert coronary vasoconstrictor influences in this species (34, 35). Interestingly, while endogenous ANG II exerts a tonic vasoconstrictor influence in the coronary microcirculation, i.e., its influence is similar at rest and during exercise (34), the ET-mediated coronary vasoconstriction that is present under resting conditions wanes with increasing exercise intensity, thereby facilitating exercise-induced coronary resistance vessel dilation (35). These observations support the concept that metabolic vasodilation may not only be mediated by the increased production of vasodilators but also by the blunting of vasoconstrictor influences (30, 32, 49).

It has been proposed that ANG II produces vasoconstriction, at least in part, via stimulation of the ET system. Thus, several investigations have shown increases in preproendothelin and/or big ET (42, 48) after an ANG II infusion (20, 23). However, this is not a ubiquitous finding as inhibition of endogenous ANG II unmasked a vasodilator effect of subsequent ET receptor blockade in the systemic circulation of rats (41), suggesting that the vasoconstrictor influence of ET was increased following angiotensin type 1 (AT1) receptor blockade. Furthermore, the different coronary vasodilator responses to AT1 versus ETA/ETB receptor blockade in exercising swine suggest that both vasoconstrictor influences act independently (i.e., additive) rather than in concert. The interaction between endogenous ANG II and ET in the control of coronary resistance vessel tone has not been investigated to date. Consequently, the first aim of the present study was to investigate the integrative control of coronary resistance vessel tone by ANG II and ET in swine at rest and during exercise. Specifically, we tested the hypothesis that both vasoconstrictors contribute to coronary resistance vessel control in a linear additive, rather than nonlinear redundant (16, 50), fashion.

Left ventricular (LV) dysfunction leads to neurohumoral activation, causing an increase in circulating levels of both ET and ANG II, particularly during exercise (21, 34, 36). Moreover, LV dysfunction results in an increased heart rate and LV diastolic pressure, which will lead to enhanced (extravascular) compression of the coronary vasculature. The increased extravascular compression combined with neurohumoral activation can impede myocardial perfusion. Indeed, the O2 balance in the remodeled myocardium is perturbed after myocardial infarction (MI), particularly during exercise (15). Unexpectedly, however, coronary vasodilation in response to blockade of either ETA/ETB or AT1 receptors was blunted in swine with MI compared with normal swine, suggesting that the vasoconstrictor influences of ET and ANG II were reduced (34, 36). Interestingly, in dogs with pacing-induced heart failure, the coronary vasodilator response to combined blockade of AT1 and ETA/ETB receptors was greater than the sum of the vasodilator responses to individual AT1 and ETA/ETB receptor blockade (9). These observations suggest that the interplay between ET and ANG II may be altered in the coronary circulation in the presence of LV dysfunction. Consequently, the second aim of the present study was to study the integrative control of coronary resistance vessel tone by ET and ANG II in remodeled myocardium of swine with a recent MI. Specifically, we tested the hypothesis that the blunted vasodilator responses to either AT1 or ET receptor blockade are the result of redundant, compensatory vasoconstrictor influences.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Animals. Studies were performed in accordance with the American Physiological Society's "Guiding Principles in the Care and Use of Laboratory Animals" and with approval of the Animal Care Committee of Erasmus Medical Center. A total of 46 crossbred Yorkshire x Landrace swine of either sex (2–3 mo old, 22 ± 1 kg at the time of surgery) were entered into the study.

Surgical procedures. Thirty-four swine were sedated (20 mg/kg im ketamine + 1 mg/kg im midazolam), anesthetized (15 mg/kg iv thiopental sodium), intubated, and ventilated with a mixture of O2 and N2O (1:2) to which 0.2–1.0% (vol/vol) isoflurane was added (18, 36). Anesthesia was maintained with midazolam (2 mg/kg + 1 mg·kg–1·h–1 iv) and fentanyl (10 µg·kg–1·h–1, iv). Swine were instrumented under sterile conditions as previously described (18, 36). Briefly, a thoracotomy was performed in the fourth intercostal space. Subsequently, 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 (ABL 505, Radiometer), and O2 saturation and hemoglobin concentration (OSM3, Radiometer). A high-fidelity Konigsberg pressure transducer was inserted into the LV via the apex for the measurement of the LV pressure and maximum rate of rise in LV pressure (LV dP/dtmax). Fluid-filled catheters were implanted in the LV, left atrium (LA), and pulmonary artery. Furthermore, a small angiocatheter was inserted into the anterior interventricular vein for coronary venous blood sampling (17). Finally, a Transonic flow probe was placed around the proximal left anterior descending coronary artery (LAD) (36). In all animals, the proximal part of the left coronary circumflex artery (LCx) was exposed, but only in the 15 swine that were designated to the MI group was the LCx permanently occluded with a silk suture (21). Two MI swine died during surgery due to recurrent fibrillation. Electrical wires and catheters were tunnelled subcutaneously to the back. The chest was closed, and the animals were allowed to recover.

Animals received analgesia (0.3 mg im buprenorphine) for 2 days and antibiotic prophylaxis (25 mg/kg iv amoxicillin and 5 mg/kg iv gentamycin) for 5 days. Two MI swine died overnight following surgery.

Exercise protocols. Experiments were performed ~2 wk after surgery on different days and in random order. With swine (17 normal and 9 MI animals) lying quietly on the treadmill, resting hemodynamic measurements were obtained and blood samples were collected. Hemodynamic measurements were repeated, and rectal temperature was measured with animals standing on the treadmill. Subsequently, a five-stage exercise protocol (1–5 km/h) was started for normal swine; alternatively, a four-stage (1–4 km/h) treadmill exercise protocol was started for MI swine. Each exercise stage lasted 2–3 min. Hemodynamic variables were continuously recorded, and blood samples were collected during the last 45 s of each stage. After completing the control exercise protocol, animals were allowed to rest on the treadmill for 90 min. Subsequently, the mixed ETA/ETB receptor antagonist tezosentan (3 mg/kg iv + 6 mg·kg–1·h–1 iv; a gift from Dr. Clozel, Actelion Pharmaceuticals, Allschwil, Switzerland) was infused, and the exercise protocol was repeated (35, 36). Tezosentan has a pA2 of 9.5 for ETA receptors and a pA2 of 7.7 for ETB receptors, indicating only a 63-fold selectivity for ETA compared with ETB receptors (13, 47). We have previously shown excellent reproducibility of the hemodynamic response in two consecutive bouts of exercise in both normal and MI swine (17, 18).

Ninety minutes after six normal and five MI swine had undergone a control exercise trial (as described above), the AT1 receptor antagonist irbesartan (1 mg/kg iv; a gift from Bristol- Myers Squibb) was infused over a 10-min period and completed 5 min prior to the second exercise trial (34). 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 (10). Ninety minutes later, animals received irbesartan (0.5 mg/kg iv, infused over a 5-min period) and tezosentan (3 mg/kg iv + 6 mg·kg–1·h–1 iv), and the exercise protocol was repeated.

Digital recording and off-line analysis of hemodynamic data and computation of myocardial O2 consumption (MVO2) and myocardial O2 extraction (MO2ex) have been described in detail elsewhere (17, 18, 35). The diastolic pressure time index (DPTI ) was calculated as the product of the diastolic time fraction (37) and the difference between mean arterial pressure and LA pressure (LAP). DPTI represents the coronary perfusion pressure corrected for backpressure and for perfusion time. DPTI can therefore be used as a net coronary perfusion pressure index that corrects for extravascular, mechanical influences on myocardial perfusion. Plasma levels of ET-1 were determined as previously described (36).

Western blot analysis of receptor proteins. A separate group of swine (n = 12) was used for the isolation of coronary arterioles and the subsequent determination of ETA and AT1 receptor expressions. Surgery was performed without catheter implantation (34, 52). The LCx was dissected free in all 12 swine but ligated in 6 swine to produce MI. Swine were killed 3 wk after the induction of MI or sham operation.

The apex was placed in ice-cold MOPS buffer (36), and coronary arterioles were then isolated (internal diameter ~150 µm), placed in liquid N2, and stored at –80°C. Arterioles were homogenized with a microdismembrator unit (B. Braun Biotech) at 1,700 rpm for 4 min followed by five cycles of sonification with a sonicator (MSE Soniprep 150, on ice water, amplitude 10 µm, 5 x 10 s with 30-s pauses). Protein concentrations were determined using a RcDc protein assay kit (Bio-Rad). Equivalent amounts of protein were separated on a 12% one-dimensional SDS polyacrylamide gel. Proteins were then transferred overnight onto a nitrocellulose membrane (Protran BA nitrocellulose membranes, Whatman). Membranes were incubated (1 h at room temperature and then overnight at 4°C) with a primary antibody (Santa Cruz Biotechnology) against either the ETA receptor [ETAR (N-15), goat polyclonal affinity purified antibody, dilution 1:2,000 in Tween-Tris-buffered saline (TTBS) with 0.5% nonfat milk powder] or the AT1 receptor [AT1 (N-10), rabbit polyclonal affinity purified antibody, dilution 1:1,000 in TTBS with 0.5% nonfat milk powder]. After being washed with TTBS, membranes were incubated with a secondary peroxidase-conjugated antibody [ETA: rabbit anti-goat secondary antibody (dilution 1:200,000, Pierce) and AT1: goat anti-rabbit secondary antibody (dilution 1:2,000, Pierce)]. Immunoreactivity was visualized with an ECL Western blotting detection kit (West Femto, Pierce) on film (CL-X Posure Film; Pierce). Receptor expressions were determined by the quantitative assessment of band densities using calibrated scanning densitometry (GS800, Bio-Rad). This assessment resulted in an optical density per area (OD·mm2) that was displayed in arbitrary units (au).

Statistical analysis. Statistical analysis of hemodynamic data was performed using three-way (MI, drug treatment, and exercise) or two-way (MI and exercise or drug treatment 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 PO2 (PCVFormula), saturation (SCVFormula), or MO2ex, regression analysis was performed with each animal as a dummy variable and with MI, drug treatment, and MVO2 as independent variables. Statistical analysis of the Western blots was performed using an unpaired t-test to compare data from normal and MI swine. Statistical significance was accepted at P ≤ 0.05 (two-tailed). Data are presented as means ± SE.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
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Effects of MI on exercise responses. Exercise produced graded increments in heart rate, LV systolic pressure, and LV dP/dtmax with minimal effects on mean aortic blood pressure (Fig. 1 and Table 1). The consequent increases in MVO2 were met by commensurate increases in CBF (Table 2), so that MO2ex and hence PCVFormula and SCVFormula remained relatively constant in normal healthy swine (Fig. 1).


Figure 1
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  		Fig. 1. Effect of myocardial infarction (MI) on hemodynamic and myocardial O2 consumption (MVO2) responses to treadmill exercise. Top: relations between heart rate [in beats/min (bpm)] and mean arterial pressure (MAP), left ventricular (LV) systolic pressure (LVSP), maximum rate of rise of LV pressure (LV dP/dtmax), and left atrial pressure (LAP). Data points at rest (lying) and during exercise are shown for all 19 normal swine (0–5 km/h) and all 12 MI swine (0–4 km/h). Bottom: myocardial O2 balance, i.e., relation between MVO2 and myocardial O2 extraction (MO2ex), coronary venous PO2 (PCVFormula), coronary venous O2 saturation (SCVFormula), and diastolic pressure time index (DPTI). Values are means ± SE. *P ≤ 0.05 vs. normal swine.

 

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  		Table 1. Hemodynamic effects of tezosentan and irbesartan in swine

 

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  		Table 2. Effect of tezosentan and irbesartan on myocardial O2 balance in swine

 
MI resulted in significant LV dysfunction, as evidenced by a marked increase in LAP and lower levels of LV dP/dtmax, LV systolic pressure, and mean aortic pressures, whereas heart rate slightly increased (Fig. 1 and Table 1). The increases in heart rate and LAP in conjunction with the slight decrease in mean aortic pressure resulted in a decrease in DPTI (Fig. 1). MVO2 was slightly higher in swine with MI at rest and at each corresponding level of exercise (Fig. 1 and Table 2), most likely as a result of the elevated heart rate, in conjunction with increases in wall stress as a result of LV dilation (52). The increase in MVO2 was met by an increase in CBF under resting conditions, so that MO2ex and coronary venous O2 content were maintained. However, during exercise, MO2ex increased, whereas PCVFormula and SCVFormula decreased, indicating that in swine with MI, O2 delivery did not increase adequately to compensate for the exercise-induced increase in MVO2 (all P ≤ 0.05; Fig. 1). These findings indicate that the O2 balance in the remodeled myocardium after MI is slightly perturbed during exercise.

Effects of ETA/ETB and AT1 receptor blockade on systemic hemodynamics. The mixed ETA/ETB receptor antagonist tezosentan decreased aortic blood pressure to a similar extent in normal and MI swine. This decrease in aortic pressure was accompanied by small, probably baroreceptor reflex-mediated, increases in heart rate and LV dP/dtmax, particularly in normal swine (Table 1). Consequently, tezosentan resulted in a small decrease in DPTI (Fig. 2). Tezosentan had no significant effect on other hemodynamic variables in either normal or MI swine.


Figure 2
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  		Fig. 2. Effects of endothelin (ET) and ANG II on the myocardial O2 balance of normal swine. Shown are the relations between MVO2 and MO2ex, PCVFormula, SCVFormula, and DPTI. Top: effects of mixed ETA/ETB receptor blockade with tezosental (Tezo; 3 mg/kg followed by 6 mg·kg–1·h–1). Bottom: effects of angiotensin type 1 (AT1) receptor blockade with irbesartan (Irb; 1 mg/kg iv) and effects of combined AT1 and ETA/ETB receptor blockade. Values are means ± SE. *P ≤ 0.05, drug effect vs. corresponding control; {dagger}P ≤ 0.05, Irb + Tezo vs. Irb alone. {ddagger}P ≤ 0.05, Irb + Tezo vs. Tezo alone.

 
The AT1 receptor antagonist irbesartan decreased aortic pressure in both normal and MI swine (Table 1) (which was not accompanied by significant changes in heart rate or LV dP/dtmax in either normal or MI swine), which resulted in a small decrease in DPTI (Fig. 3). In the presence of AT1 receptor blockade, tezosentan produced a similar decrease in aortic pressure as under control conditions in both normal and MI swine, with minimal effects on heart rate and LV dP/dtmax (Table 1).


Figure 3
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  		Fig. 3. Effects of ET and ANG II on the myocardial O2 balance of swine with MI. Shown are the relations between MVO2 and MO2ex, PCVFormula, SCVFormula, and DPTI. Top: effects of mixed ETA/ETB receptor blockade with Tezo (3 mg/kg followed by 6 mg·kg–1·h–1). Bottom: effects of AT1 receptor blockade with Irb (1 mg/kg iv) and effects of combined AT1 and ETA/ETB receptor blockade. Values are means ± SE. *P ≤ 0.05 and **P ≤ 0.1, drug effect vs. corresponding control; {dagger}P ≤ 0.05, Irb + Tezo vs. Irb alone; {ddagger}P ≤ 0.05, Irb + Tezo vs. Tezo alone; ¶P ≤ 0.05, effect of Tezo different in the presence and absence of Irb; §P ≤ 0.05, drug effect different in MI vs. normal swine.

 
Effects of ETA/ETB and AT1 receptor blockade on myocardial O2 balance. In normal swine, the infusion of tezosentan produced coronary vasodilation under resting conditions that resulted in an increase in myocardial O2 delivery that was slightly larger than the increase in MVO2, leading to increases in PCVFormula and SCVFormula(Fig. 2); these vasodilator effects waned with incremental exercise intensity. Irbesartan resulted in coronary vasodilation at rest that persisted during exercise (Fig. 2) (34). In the presence of irbesartan, the tezosentan-induced increases in PCVFormula and SCVFormula were similar to the tezosentan-induced increases under control conditions (Fig. 2), indicating that tezosentan and irbesartan produced additive coronary vasodilation in normal swine. These findings were corroborated by the lack of effect of irbesartan on plasma ET levels (Table 3).


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  		Table 3. Effects of irbesartan on plasma endothelin levels during exercise

 
In MI swine, tezosentan had no effect on coronary vasomotor tone at rest or during exercise as evidenced by the unaltered levels of MO2ex, PCVFormula, and SCVFormula(Fig. 3). Similarly, irbesartan had no significant effect on MO2ex, PCVFormula, and SCVFormula in MI swine. Unexpectedly, however, tezosentan administration following AT1 receptor blockade produced significant coronary vasodilation at rest, which waned with increasing exercise intensity. This increase in ET vasoconstrictor influence was not associated with an increase in circulating ET levels, as plasma ET levels were also unaffected by irbesartan in MI swine (Table 3).

Coronary arteriolar ETA and AT1 receptor expression. ETA receptor expression in coronary arterioles (~150 µm), as determined by Western blot analysis, was not different between normal (1.34 ± 0.67 au, n = 6) and MI swine (1.21 ± 0.68 au, n = 6). Similarly, AT1 receptor expression was not significantly different between normal (1.67 ± 0.56 au, n = 6) and MI swine (1.05 ± 0.47 au, n = 6).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The main findings of the present study were that 1) in normal swine, ETA/ETB and AT1 receptor blockade produced coronary vasodilation in an additive manner; 2) in swine with a recent MI, the vasodilator response to either ETA/ETB receptor blockade or AT1 receptor blockade was lost, despite maintained ETA and AT1 receptor expressions; and 3) in contrast, coronary vasodilation emerged when ETA/ETB receptors were blocked in the presence of prior AT1 receptor blockade, which cannot be explained by increased circulating levels of ET following AT1 receptor blockade. The implications of these findings are discussed in detail below.

Methodological considerations. A sensitive way to study the regulation of coronary resistance vessel tone in vivo involves the assessment of the relation between coronary venous O2 levels and MVO2 (17, 25, 35, 50, 51). A decrease in resistance vessel tone increases the myocardial O2 supply at a given level of MVO2, resulting in a decrease in MO2ex and thus an increased coronary venous O2 content and an upward shift of the relation between MVO2 and coronary venous O2 levels. The coronary venous O2 content therefore represents an index of myocardial tissue oxygenation (i.e., the balance between O2 delivery and O2 consumption) that is determined by coronary resistance vessel tone.

Pigs have a negligible native collateral circulation, so that an acute occlusion of the LCX (without reperfusion) results in a large transmural MI. Even though 1 wk after LCx occlusion some "collateral" flow to the fibrotic infarct zone is present (<10% of flow to the normal myocardium), it is important to note that the anterior interventricular vein selectively drains the LAD perfusion territory (4), so that changes in O2 balance in the infarcted area will not be reflected in the PCVFormula in the anterior interventricular vein.

Using the myocardial O2 balance as an index of coronary vasomotor tone, we have previously shown that the loss of nitric oxide (NO) does not influence the contribution of endogenous adenosine (33). Moreover, the loss of NO and adenosine does not result in an altered contribution of ATP-sensitive K+ channels (33). Similarly, in the present study, the loss of ANG II does not alter the contribution of ET, as will be discussed in more detail below. Hence, vasomotor control in the coronary vasculature of healthy swine (in contrast to dogs) appears to follow a linear additive design, in which vasomoter control mechanisms act in parallel and apparently independent of each other (16).

Myocardial perfusion is not only determined by coronary resistance vessel tone but also by mechanical factors. Thus, the coronary vasculature, which is embedded in cardiac muscle, is compressed during each cardiac contraction, so that ~85% of CBF occurs during diastole. Consequently, coronary perfusion pressure during diastole and the duration of diastole are important determinants of the perfusion of the coronary microcirculation (3, 19). Coronary perfusion pressure equals coronary artery inflow pressure (approximately mean arterial pressure) minus coronary outflow pressure (i.e., coronary backpressure). In diastole, LV pressure is transmitted across the myocardium and compresses the coronary vasculature, thereby functioning as effective backpressure to myocardial perfusion (2, 56). Since LAP is a good approximation of diastolic LV pressure, we used LAP as coronary backpressure in the present study. To take into account the alterations in extravascular compressive forces during exercise in MI versus normal hearts and following drug administration, we computed DPTI as an estimate of the effective coronary perfusion pressure. An increase in heart rate and LAP, such as occurs during exercise, results in an increased extravascular compression and impedes the myocardial O2 supply while simultaneously increasing myocardial O2 demand. Because the heart already utilizes ~80% from O2 of the delivered blood under resting conditions, the ability of coronary resistance vessels to dilate (thereby decreasing coronary vascular resistance) in response to increments in myocardial O2 demand is extremely important to maintain an adequate O2 supply. Matching of O2 supply to O2 demand by alterations in resistance vessel tone is called metabolic regulation. In normal swine, an increase in myocardial O2 demand is met by an equivalent increase in myocardial O2 supply. Thus, MO2ex is maintained constant over a wide range of myocardial O2 demands, indicating that changes in extravascular compression are compensated by changes in coronary vasomotor tone. In contrast, in MI swine, MO2ex increased with incremental levels of exercise, suggesting that the increased extravascular compressive forces (higher heart rate and LAP) were not fully compensated by a decrease in coronary vasomotor tone (15).

Intravenous administration of blockers of vasoactive factors not only results in changes in coronary vascular resistance but also in changes in systemic vascular resistance. Thus, blockade of a vasoconstrictor pathway results in systemic vasodilation, causing a decrease in arterial pressure and an increase in heart rate. These alterations in systemic hemodynamics result in a decrease in DPTI, thereby potentially impeding myocardial perfusion and resulting in a decrease in coronary venous O2 content. However, the tezosentan- and irbesartan-induced decreases in DPTI were not different between normal and MI swine, indicating that they cannot explain the different responses in coronary venous O2 content to these drugs in normal and MI swine.

In the present study, we observed that, under resting conditions, PCVFormula was slightly elevated, whereas SCVFormula was slightly lower, in swine with MI compared with normal swine. These findings suggest a change in the O2 dissociation curve. The O2 dissociation curve can be influenced by pH, PCO2, and 2,3-diphosphoglycerate (2,3-DPG) (22). A decrease in pH and an increase in PCO2, as occur in exercising muscle, facilitate the dissociation of O2, thereby promoting the diffusion of O2 to the exercising tissue. As can be appreciated from the results shown in Table 2, neither pH nor PCO2 changed after MI, suggesting that alterations in 2,3-DPG may be responsible for this shift in the O2 dissociation curve. In accordance with this hypothesis, Kedziora et al. (26) showed that 2,3-DPG in erythrocytes is significantly increased 3 wk after MI. The increase in 2,3-DPG decreases the affinity of hemoglobin for O2 and could have resulted in an increase in PCVFormula while SCVFormula is decreased. Administration of either irbesartan or tezosentan resulted in similar changes in PCVFormula and SCVFormula, indicating that these substances had no influence on the O2 dissociation curve. This notion is supported by the observation that coronary venous pH and PCO2 remained essentially unchanged (Table 2).

ET and ANG II in the control of coronary vasomotor tone in normal swine. In accordance with previous observations from our laboratory (35, 36), endogenous ET contributed to basal resting tone in resistance vessels of the coronary circulation in normal swine. This vasoconstrictor influence of ET decreased gradually with increasing exercise intensity, thereby facilitating the exercise-induced coronary vasodilation. Conversely, AT1 receptor blockade elicited coronary vasodilation at rest that was maintained during exercise, indicating that endogenous ANG II exerts a tonic vasoconstrictor influence on the coronary microvasculature of normal swine. These observations are in agreement with previous observations by several (34, 43, 46), although not all (12), groups of investigators.

The interaction between the renin-angiotensin system (RAS) and ET system is complex in nature. Several studies have suggested that ANG II is capable of activating the ET system by increasing preproendothelin mRNA in endothelial cells (20, 24), vascular smooth muscle cells (20, 23), and cardiac myocytes (11) in vitro, resulting in an increase in ET release into the culture medium (20, 23, 40, 45). Moreover, intrapericardial ANG II infusion resulted in an increased myocardial big ET production in vivo (48). In contrast, ANG II infusion did not affect plasma ET concentrations in conscious dogs, although systemic and pulmonary vasoconstriction in response to high-dose but not low-dose ANG II infusion were blunted by ETA receptor blockade (5), suggesting that the involvement of the ET system in ANG II-induced vasoconstriction depends on the concentration of ANG II. In addition, Chen et al. (8) showed heterogeneity in the involvement of ET in vascular smooth muscle responsiveness to ANG II, as the vasoconstrictor response to ANG II was blunted by ETA receptor blockade in the rat tail artery and mesenteric artery, whereas the response was not affected by ETA receptor blockade in the rat aorta. These findings suggest that ANG II infusion stimulates the ET system in some but not all arterial vessels, which may depend on the location and/or size of the artery.

In contrast to the stimulation of the ET system by the infusion of exogenous ANG II reported in the aforementioned studies, Richard et al. (41) observed in rats that inhibition of endogenous ANG II unmasked a systemic vasodilator effect of subsequent ET receptor blockade, suggesting that the vasoconstrictor influence of ET was increased (rather than decreased) following AT1 receptor blockade. Similarly, Clair et al. (12) showed that high-dose AT1 blockade in conscious swine increased plasma ET levels, whereas low-dose AT1 blockade had no effect, suggesting that AT1 receptor stimulation by endogenous levels of ANG II inhibits rather than stimulates the ET system. In the present study, we observed that the vasodilator response to ETA/ETB blockade was similar in the presence and absence of AT1 blockade in normal swine. Thus, additive vasodilation occurs in response to simultaneous blockade of ETA/ETB and AT1 receptors. Moreover, AT1 blockade had no effect on plasma ET levels, suggesting that in normal swine the RAS and ET system contribute to the regulation of coronary vasomotor tone in a linear additive fashion. Taken together, these studies show that the interaction between ANG II and ET in the regulation of vasomotor tone may vary depending on local concentrations of these two vasoconstrictors, species, vessel size, and/or vascular bed.

Interaction between ET and ANG II in the control of coronary vasomotor tone in swine with MI. We have previously shown that LV dysfunction in swine with a recent MI is associated with neurohumoral activation, including increases in plasma ET and ANG II (21, 34, 36). Surprisingly, however, vasodilator responses to AT1 receptor blockade were markedly reduced (34) and vasodilator responses to both ETA and ETA/ETB blockade (36) were abolished after MI. This paradoxical finding might be explained by a decrease in AT1 and ETA receptor density in coronary arterioles. However, although one study (53) reported a decrease in AT1 receptor mRNA, other studies have reported an increase in ETA receptor mRNA (54) in coronary arteries after MI as well as increased AT1 (44) and ETA (27, 57) receptor expression in whole myocardial samples from failing hearts. Importantly, however, these studies were either performed in large coronary arteries or in myocardial tissue comprised of both microvessels and myocardium, making data interpretation difficult. For this purpose, we analyzed receptor expression in isolated coronary resistance vessels and observed no significant differences in either AT1 or ETA receptor expression between normal and MI swine. These findings demonstrate that the blunted vasoconstrictor influence of ANG II and ET on coronary resistance vessels after MI is unlikely to be due to changes in arteriolar receptor expression.

In contrast to the lack of effect of ETA/ETB receptor blockade under control conditions, an unexpected vasodilator response to ETA/ETB blockade emerged after prior blockade of the AT1 receptor. Similar to our findings in normal swine, this ET-mediated constriction was most marked under resting conditions and waned with increasing exercise intensity. In agreement with our findings, Cheng et al. (9) found in a canine model of pacing-induced severe congestive heart failure that combined blockade of ETA/ETB and AT1 receptors resulted in an increase in CBF at rest and during maximal treadmill exercise, whereas either ETA/ETB or AT1 receptor blockade alone had no effect. However, in the study of Cheng et al., the exercise-induced increase in heart rate was also greater after combined blockade of ETA/ETB and AT1 receptors. The increase in CBF in response to ETA/ETB and AT1 receptor blockade may therefore have been, at least in part, due to an increase in MVO2 rather than to a direct effect on coronary vasomotor tone.

The increase in endogenous ET-mediated vasoconstriction after AT1 receptor blockade in MI swine could be explained by an increase in ET production. However, we found no indication of such an increase in production, as plasma ET levels were unaltered by AT1 receptor blockade in MI swine either at rest or during exercise. Similarly, Clair et al. (12) found no change in plasma ET levels upon AT1 receptor blockade at rest or during exercise in pigs with pacing-induced severe congestive heart failure. Although plasma ET levels may not adequately reflect the myocardial interstitial concentration of ET, the lack of change in plasma ET levels upon AT1 receptor blockade could be interpreted to suggest an interaction between ET and ANG II at the postreceptor level. For instance, these vasoconstrictor systems have been shown to act, at least in part, via the same signaling pathways (6, 28). First, activation of the AT1 receptor as well as the ETA receptor results in the activation of PLC, which decreases the opening of Ca2+-sensitive K+ channels, thereby causing vascular smooth muscle cell depolarization and vasoconstriction (6, 38). Second, activation of PKC, through activation of NAD(P)H oxidase (28, 39), results in the generation of superoxide, thereby causing vasoconstriction (1, 7). In addition to the ANG II- and ET-mediated activation of NAD(P)H oxidase, this enzyme is activated in the presence of endothelial dysfunction (55), and its activity may therefore be increased following MI. Consequently, it could be speculated that increased NAD(P)H oxidase activity may have lead to an increased superoxide production that resulted in vasoconstriction to a level at which activation through one of these pathways would be sufficient to maintain vasoconstriction at rest. Hence, while blockade of one endogenous vasoconstrictor is sufficient to reduce its vasoconstriction in normal swine, it may not be sufficient to induce vasodilation in swine with MI.

In conclusion, in normal swine, ET and ANG II contribute to coronary resistance vessel tone in a linear additive manner, whereas within the remodeled myocardium, these vasoconstrictors contribute to coronary resistance vessel tone in a nonlinear redundant fashion.


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The support of The Netherlands Heart Foundation Grant 2000T042 is gratefully acknowledged.


   FOOTNOTES
 

Address for reprint requests and other correspondence: D. Merkus, Div. of Experimental Cardiology, Thoraxcenter, Erasmus Medical Center, Univ. Medical Center Rotterdam, PO Box 2040, Rotterdam 3000 CA, 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.


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