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Cardiovascular Research 1998 37(1):108-114; doi:10.1016/S0008-6363(97)00208-3
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Copyright © 1998, European Society of Cardiology

Low-dose aspirin improves in vivo hemodynamics in conscious, chronically infarcted rats

Regien G Schoemaker*, Pramod R Saxena and Ed A.J Kalkman

Department of Pharmacology, Faculty of Medicine and Health Sciences, Erasmus University, P.O. Box 1738, NL-3000 DR Rotterdam, The Netherlands

* Corresponding author. Tel. +31 10 4087530/47; Fax +31 10 4366839.

Received 23 April 1997; accepted 5 August 1997


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Objective: The equivalent of the clinically used low(=antiplatelet)-dose aspirin, inhibited collagen deposition in the non-infarcted myocardium in rats with myocardial infarction. In the present study, the in vivo hemodynamic consequences of this daily low-dose aspirin were investigated in conscious, chronically instrumented, infarcted rats. Methods: Rats, treated with 25 mg/kg aspirin daily from 2 days before to 3 weeks after coronary artery ligation, were chronically instrumented with an electromagnetic flow-probe and arterial and venous catheters, to record cardiac output, and arterial and venous blood pressure, respectively, in the conscious freely moving animal. In parallel, isolated hearts were studied with regard to left ventricular stiffness (pressure/volume relationships), maximal cardiac perfusion (adenosine), and in vitro heart rate and β-adrenergic responsiveness. Plasma catecholamine levels were measured. Results: Aspirin normalized the increased heart rate after infarction, at a preserved cardiac output. This was accompanied by a (non-significant) increase in stroke volume, at unchanged cardiac loading conditions. The lower heart rate after aspirin was due to reduced intrinsic heart rate rather than to lower sympathetic activation of the heart, since similar effects were observed in isolated perfused hearts, while circulating levels of catecholamines and β-adrenergic responsiveness were not influenced. The improved stroke volume was not explained by reduced left ventricular stiffness or increased maximal perfusion after aspirin. Conclusion: In addition to the antithrombotic action, effects of low-dose aspirin on cardiac remodeling could be associated with favorable hemodynamic effects, as reflected by a lower heart rate for the same cardiac output. Although the underlying mechanisms are still unknown, it suggests a clinically relevant beneficial effect which deserves further investigation.

KEYWORDS Aspirin; Hemodynamics; Remodeling; Rat; Heart rate


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
Aspirin (acetylsalicylic acid, ASA) administered at low-dose reduces platelet production of pro-aggregatory and vasoconstrictor thromboxane in favor of anti-aggregatory and vasodilator prostaglandins [1, 2]. Low-dose ASA has become standard therapy in primary and secondary prophylaxis of myocardial infarction (MI). Its favorable effect on prognosis [3]is mainly attributed to its anti-thrombotic action [4].

In a well-established rat model for the functional and structural consequences of MI, we recently reported effects of ASA on cardiac remodeling, at doses equivalent to the clinically used low dose. Low-dose ASA affected collagen deposition in the non-infarcted part of the myocardium, while leaving collagen deposition in the infarct relatively unaltered [5]. Hypertrophy of the spared myocardium was not affected.

The aim of the present study was to investigate the functional consequences of the above treatment; daily low-dose ASA during the first 3 weeks after MI. Firstly, mechanical consequences of the inhibited interstitial and perivascular collagen deposition by ASA [5]on left ventricular and vascular compliance were evaluated in the isolated perfused heart, by means of left ventricular pressure volume relations [6]and coronary flow during maximal vasodilation [7], respectively.

Left ventricular function in vitro was not improved by ASA treatment [5]. However, since absence of improvement of in vitro left ventricular function [5, 8]does not necessarily imply absence of changes in in vivo cardiac function [9, 10], the effects of ASA were studied in conscious unrestrained rats, chronically instrumented for hemodynamic measurements [10–12]. Because of the interesting observation of a reduced heart rate in these experiments, two additional experiments were performed to examine whether this observation could be attributed to a lower sympathetic drive or to reduced intrinsic heart rate.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
2.1 Animals
Male Wistar rats (Harlan, Zeist, The Netherlands) weighing 270–320 g at the time of operation were used; they were housed in groups of 2 or 3, on a 12:12-h light/dark cycle, with standard rat chow and water available ad libitum. Animals used in the hemodynamic studies were housed separately after implantation of measuring equipment. Saline or 25 mg/kg aspirin (lysine-acetylsalicylic acid, Aspégic, Lorex, Maarssen, The Netherlands) dissolved in saline was administered as daily i.p. injections of 1 ml/kg starting 2 days before surgery, and was continued until the end of the protocol 21 days after surgery [5]. At all stages, the experiments conform with the Guide for Care and Use of Laboratory Animals.

2.2 Myocardial infarction
Rats were subjected to either coronary artery ligation or sham operation, using a modification [10]of the method of Fishbein et al. [13]. Briefly, animals were anesthetized with pentobarbital (60 mg/kg i.p.) and the trachea was intubated (PE-240). The skin overlying the fourth intercostal space was cut, and underlying muscles were separated and kept aside. The thorax was opened after positive pressure respiration was started and the heart was carefully pushed to the left by applying pressure to the right side of the thorax. A silk (6-0) suture was looped under the left descending coronary artery near the origin of the pulmonary artery. When the heart was returned to its normal position, the suture was closed. In sham animals the suture was not closed. The ribs were pulled together with 3-0 silk, the muscles were returned to their normal position and the skin was closed. The anatomy of the coronary vasculature in the rat is such that accidental occlusion of only a side branch leads to a small infarction (<20%), and therefore exclusion from further analysis. Proper occlusion of the coronary artery resulted in a extensive transmural infarction comprising a major part of the left ventricular free wall, with small variations in size [5]. Mortality was ±30% and occurred mainly within the first 24 h. Since our previous study on ASA treatment, in part specifically designed to determine effects on infarct size, showed no effect of this treatment, in the present study infarct sizes were only measured in one set of experiments.

2.3 In vivo hemodynamics
Two weeks after coronary artery ligation rats were re-anesthetized with pentobarbital (60 mg/kg, i.p.), and an electromagnetic flow probe (Skalar, Delft, The Netherlands) was placed on the ascending aorta according to previously described techniques [10, 14]. Briefly, after intubation and starting positive pressure respiration, the thorax was opened at the third right intercostal space, and the ascending aorta was dissected from surrounding tissue. A 2.6-mm diameter probe was placed around the aorta 1–2 mm above the outlet of the heart. The cable was fixed to the ribs, the thorax was closed in layers, and the connector was exteriorized in the neck, where it was sutured to the skin.

Five days later, rats were re-anesthetized and implanted with a catheter (PE-10 heat-sealed to PE-50) in the abdominal aorta through the femoral artery to measure arterial blood pressure (MAP). Furthermore, through the femoral veins, a catheter (PE-10 heat-sealed to PE-50) was implanted into the abdominal vena cava for infusion and a Silastic (602-175, Dow Corning, Midland, MI, USA) catheter was placed in the thoracic vena cava for measurement of central venous pressure (CVP). All catheters were exteriorized in the neck, filled with heparinized saline, and closed with metal plugs. Animals were allowed to recover another 2 days before measurements started.

On the experimental day, rats were connected to the measuring equipment. Signals were fed into a 68B09-based microprocessor and compatible microcomputer, sampling at 500 Hz. Mean values were obtained for arterial (MAP) and central venous pressure (CVP). Cardiac output (CO), heart rate (HR), duration of the ejection phase as a measure of systolic time (ET), and stroke volume (SV) were obtained from the aortic flow signal. Total peripheral resistance was calculated as (MAP–CVP)/CO. Heart period (HP) and diastolic time were calculated as 60 000/HR and HP minus ET, respectively. All derivations (except the latter two) were made on-line and stored on disk for later analysis.

After 45–60 min stabilization time, baseline values were obtained for 10 min. Then a rapid infusion of 12 ml (37°C) Ringer's solution (composition in mM: NaCl 154, KCl 2.7, CaCl2 1.8 and NaHCO3 1.2) was infused in 1 min through the abdominal vena cava catheter. This procedure [10–12]and a very similar method in anaesthetized rats [9, 15]has been shown to increase CO to a plateau level, which can be used as an indicator for maximal cardiac function, and is referred to as COmax.

2.4 Maximal coronary flow in vitro
At 3 weeks after MI, under pentobarbital anesthesia, hearts were rapidly excised and mounted for perfusion with an oxygenated modified Krebs–Henseleit buffer (composition in mM: NaCl 125, KCl 4.7, CaCl2 1.35, NaHCO3 20, NaH2PO4 0.4, MgCl2 1.0, D-glucose 10; pH 7.4, 37°C), at constant perfusion pressure of 85 mmHg. A water-filled latex balloon was placed in the left ventricle via the left atrium, kept in place by a suture round the left atrial auricle. Left ventricular end-diastolic pressure was set to 5 mmHg by adjusting the balloon volume. Although we realize that 5 mmHg may not correspond with the actual in vivo left ventricular end-diastolic pressure in infarcted hearts, pilot studies did not show different results on coronary flows at 5 and 25 mmHg left ventricular end-diastolic pressure in infarcted hearts. Hearts were paced at 350 beats/min. Coronary flow was continuously registered through an in-line flow probe (Transonic Systems, Ithaca, NY, USA) placed in the tubing just before the aorta.

After a stabilization period of 15–30 min, baseline values were obtained and maximal coronary flow during vasodilation was determined. For that, adenosine (0.1 ml of a 10–2 M solution, Janssen Chimica, Geel, Belgium) was injected into the perfusion buffer (as a fixed dose since baseline coronary flows were comparable for all groups) just before it entered the coronary arteries, and maximal coronary flow was measured. The used dose of adenosine was found to induce maximal effect in complete dose–response curves obtained in pilot studies.

2.5 Left ventricular pressure volume relationship
Hearts were dissected and perfused as described above. After stabilization (±30 min), hearts were arrested in diastole with a 0.5-ml injection of a 1 M potassium chloride solution into the perfusing buffer, just before it entered the coronary arteries. At 10 to 20 different left ventricular balloon volumes, diastolic pressures in the range of 0–40 mmHg were measured. For each heart, values were fitted into the equation: Pressure=c·e(k·volume)+a (r>0.99).

2.6 Catecholamines
In a separate group of rats, under pentobarbital anesthesia (60 mg/kg, i.p.) the left common carotid artery was cannulated. The catheter was passed to the neck subcutaneously, where it was fixated and exteriorized. Rats were allowed to recover for at least one day. Then, blood samples were taken in the last hour of the light period of the rats' light/dark cycle. For that, the carotid catheter was extended with saline-filled tubing to obtain blood samples without disturbing the rat. After at least 30 min habituation, 2-ml blood samples were obtained, and processed according to Boomsma et al. [16]. Briefly, blood was collected in syringes prepared with 20 µl EDTA (0.1 M), and put on ice. After centrifuging plasma was collected in prechilled tubes filled with 1.2 mg glutathione and stored at –70°C. Plasma concentration of noradrenaline, adrenaline and dopamine were determined by HPLC and electrochemical detection, as described in detail by Boomsma et al. [16].

2.7 In vitro heart rate
Hearts were dissected and perfused as described for measurement of maximal coronary flow, but without pacing the hearts. When hearts had stabilized (±30 min), baseline values for heart rate were obtained. Then heart rate was maximally stimulated with isoproterenol (L-isoproterenol hydrochloride, Sigma Chemicals, St. Louis, USA) by injecting 0.1 ml of 10–5 M in the buffer just before it entered the coronary arteries. The dose of isoproterenol was validated to induce maximal effect in complete dose–response curves obtained in pilot experiments. Hearts from this experiment were used for measurement of infarct size.

2.8 Infarct size
After termination of the in vitro experiments hearts were arrested in diastole by injecting KCl (1 M) into the perfusion buffer. After removal from the perfusion apparatus, hearts were placed in ice-chilled buffer and cut into four transversal slices from apex to base. Tissue was processed as described before [7]. Slices were kept in 3.6% phosphate-buffered formaldehyde for at least 24 h. After fixation the slices were dehydrated and paraffin-embedded. Deparaffinized 5-µm thick sections were incubated for 5 min with 0.2% (w/v) aqueous phosphomolybdic acid, and subsequently incubated for 45 min with 0.1% Sirius Red F3BA (C.I. 35780, Polysciences, Northampton, UK) in saturated aqueous picric acid, washed for 2 min with 0.01 M HCl, dehydrated, and mounted with Entellan (Merck, Darmstadt, Germany). The infarcted area was demarcated by intense red staining of the collagen fibers in the scar tissue. Infarct size was measured by planimetry (Jandell, Germany), as the lengths of infarcted area and spared muscle for both the endocardial and epicardial surfaces of the sections [10, 11]. Infarct size is expressed as the percentage of left ventricular (left ventricular free wall and interventricular septum) circumference.

2.9 Data analysis
All data are presented as mean±s.e.m. Data of infarcted rats were only included if the infarction comprised the major part of the left ventricular free wall, since small infarctions are found to be hemodynamically fully compensated [10, 15]. Differences between groups were analyzed using one-way analysis of variance and Bonferroni's t-tests for multiple group comparisons [17]. Differences were regarded statistically significant if P<0.05.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
All experimental groups together are characterized in Table 1. Heart weight was not significantly different after MI. However, because MI rats gained less weight, they appeared significantly lighter 3 weeks after MI, resulting in a significantly increased heart weight to body weight ratio. ASA-treated rats were comparable to non-treated rats in this regard. The lack of effect on heart weight in infarcted rats, despite replacement of the infarcted part of the left ventricle (on average ±40% of left ventricular circumference) by lighter scar tissue implies hypertrophy of the spared myocardium.


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  		Table 1 Characterization of experimental groups

 
3.1 In vivo hemodynamics
Hemodynamics were measured in vivo in conscious, unrestrained rats. Left ventricular dysfunction in these rats was substantiated by decreased CO and SV at rest (Fig. 1), and after maximal stimulation during volume loading (COmax 120±4 and 98±3 ml/min; SVmax 303±15 and 231±9 µl in sham and infarcted rats, respectively). HR was significantly increased after infarction (cf. Fig. 1). ASA treatment did not affect CO at rest or after volume loading (COmax: 92±4 ml/min). However, although CO at rest was not increased, it was composed of a significantly lower HR and a (non-significantly) higher SV (Fig. 1).


Figure 1
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  		Fig. 1 Heart rate and stroke volume measured in vivo in conscious sham, non-treated, and apirin-treated infarcted rats (n = 7), as well as the resulting cardiac output (inlay). *Significant effect of myocardial infarction; #significant effect of treatment.

 
To study the HR changes in more detail, HP was calculated and ET was subtracted to obtain diastolic time. Data are presented in Fig. 2. Comparable to total HP, diastolic time was significantly decreased after infarction and restored by ASA treatment. In the different experimental groups, time balance between systolic and diastolic time was not significantly different (percentage diastolic time of total heart period: 62.6±0.6%, 58.8±2.0% and 62.9±0.7% in sham, non-treated infarcted and ASA-treated infarcted rats), though the tendency to a relatively lower diastolic period (as percentage of the heart period) in infarcted rats was restored by ASA.


Figure 2
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  		Fig. 2 Heart period and its constituencies, systolic and diastolic time, measured in vivo in conscious sham, non-treated, and apirin-treated infarcted rats (n = 7). *Significant effect of myocardial infarction; #significant effect of treatment, for total heart period and diastolic time.

 
ASA-induced changes in SV in the present study could not be attributed to altered loading conditions of the heart, since CVP, as a measure for preload, and MAP and TPR as measures for afterload were not changed by ASA treatment (Table 2).


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  		Table 2 In vivo loading conditions on the heart

 
3.2 Maximal coronary flow
In vitro left ventricular dysfunction after MI was evident from a reduced left ventricular developed pressure (51±4 in non-treated and 49±4 in ASA-treated infarcted hearts, compared to 75±5 mmHg in sham hearts), at similar coronary flow. Maximal coronary flow was similar in all three groups, as was flow corrected for heart weight, cardiac perfusion (maximal perfusion with adenosine 22.6±1.2, 22.4±2.3 and 23.5±1.7 ml/min/g in sham, MI and MI+ASA, respectively).

3.3 Left ventricular stiffness
Left ventricular stiffness was determined from the pressure/volume relationships in diastolically arrested hearts, which are presented in Fig. 3. The curve representing the pressure/volume relationship in infarcted heart had shifted to the right, and is less steep (k-values: 71±6(10–4) and 115±7(10–4), in infarcted and sham hearts, respectively). Three weeks of ASA treatment did not change that (k-value: 62±8(10–4)).


Figure 3
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  		Fig. 3 Left ventricular (LV) pressure volume relationships in diastolic arrested hearts from sham (n = 33), non-treated (n = 20), and apirin-treated (n = 13) infarcted rats.

 
3.4 In vitro heart rate
Left ventricular function and coronary flow in spontaneously beating hearts were comparable to the values obtained in paced hearts. Heart rate measured in isolated perfused hearts showed similar results as the in vivo measurements, though even more pronounced; significantly increased HR in infarcted compared to sham hearts, and significant reduction of HR after ASA treatment, back to sham values (Fig. 4). After maximal stimulation with isoproterenol, a similar pattern could be observed, although the significant difference between sham and infarcted hearts had disappeared (Fig. 4). Infarct size was not different for non-treated (42±4%) and ASA-treated hearts (45±2%).


Figure 4
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  		Fig. 4 Baseline and maximal (after isoproterenol) heart rate measured in vitro in sham, non-treated, and apirin-treated infarcted rats (n = 6–9). *Significant effect of myocardial infarction; #significant effect of treatment.

 
3.5 Plasma catecholamines
Measurements of plasma levels of catecholamines revealed a 43% increase in plasma noradrenaline in infarcted rats, which was not affected by ASA treatment (Fig. 5). Plasma adrenaline and dopamine levels were not different between the experimental groups.


Figure 5
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  		Fig. 5 Plasma catecholamine levels of conscious sham, non-treated, and apirin-treated infarcted rats (n = 6–9).

 

   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
Chronic treatment of MI rats with low-dose ASA affects collagen deposition in non-infarcted myocardium as part of the remodeling process. The present study was carried out to investigate whether this effect could be associated with improved hemodynamics after infarction. The major findings were: (1) ASA treatment of MI rats did not increase pump capacity of the heart in vivo, but CO was achieved by a significantly lower heart rate compared to non-treated MI rats. (2) As indicated by similar observations on HR in isolated perfused hearts, and unaltered catecholamine levels and β-adrenergic responsiveness, the in vivo reduced HR could be attributed to changes in intrinsic HR rather than to impaired sympathetic activity. (3) ASA-induced stroke volume changes could not be attributed to changes in passive stiffness of the left ventricle (associated with the previously reported effects on collagen deposition in the non-infarcted myocardium [5]), nor by different in vivo loading conditions of the heart.

Low-dose ASA treatment has become an established strategy in the prevention of thrombotic complications of coronary disease and myocardial infarction, although a recent publication indicates that also an antiinflammatory action of ASA is beneficial in prevention of myocardial infarction [18]. An equivalent treatment in rats, based on the clinical rationale for the low-dose; that is inactivation of thromboxane production in favor of prostaglandin production, has been evaluated in our previous study on ASA [5]. Daily intraperitoneal injections of 25 mg/kg inhibited platelet thromboxane production, while leaving vascular prostaglandin production intact. When started 2 days before infarction, it did not affect infarct size and had no significant effect on infarct collagen content, indicating no major anti-inflammatory effects. However, low-dose ASA affected collagen deposition in the non-infarcted myocardium [5]. Morphometrically assessed interstitial and perivascular collagen content was reduced, and inspection of the sections with polarizing microscopy suggested a greater amount of thin fibers with ASA treatment. The study indicates that low-dose ASA may interfere with post-MI remodeling, which can have consequences for post-MI hemodynamics.

Since interstitial collagen is associated with left ventricular stiffness [6, 19], an improved diastolic compliance could be anticipated after ASA treatment. On the other hand, interference which reduced the collagen network is associated with deleterious aggravation of left ventricular dilatation [20, 21]. However, pressure volume curves of MI rats treated with ASA were identical to those obtained in non-treated infarcted rats, indicating similar diastolic compliance and no enhanced left ventricular dilatation. However, absence of effects of ASA on passive characteristics of the left ventricle does not exclude effects on properties of the actively pumping heart.

Corresponding to the effects of ASA treatment on interstitial collagen accumulation, inhibition of perivascular collagen [5]could improve coronary vascular compliance, improving cardiac perfusion. However, ASA treatment did not affect absolute maximal coronary flow nor flow per heart weight, indicating no direct effect of ASA treatment on cardiac perfusion. An indirect effect on coronary flow due to the lower HR [22]cannot be excluded.

In the present study, in vivo cardiac pump capacity was not increased by ASA, but CO was achieved at a lower heart rate. Similar baseline cardiac output at a significantly lower heart rate indicates a energetically favorable hemodynamic state [22, 23], which may be associated with the effect on collagen accumulation in the spared myocardium without interference with compensatory hypertrophy [5]. Captopril treatment during the same period prevented both collagen accumulation as well as reactive hypertrophy of non-infarcted myocardium [24], and resulted in the unfavorable hemodynamic effect of a reduced SV at increased HR for the same CO [10]. Prevention of both hypertrophy and interstitial collagen accumulation by At1 blockade, however, was not associated with these unfavorable hemodynamic consequences [25]. At2 blockade during the healing phase revealed the same adverse higher HR and lower SV as captopril, and inhibited the hypertrophic response rather than the collagen accumulation (Smits, unpublished data). Overall, selective inhibition of collagen accumulation in spared myocardium with intact cardiomyocyte hypertrophic response may provide an optimum in pharmacological modulation of the early post-MI remodeling phase.

HR in vivo is strongly determined by both sympathetic (and parasympathetic) nerve activity as well as circulating catecholamines. Measurements in isolated, buffer perfused hearts, circumvent these influences. The effect of ASA treatment on HR appeared even stronger in vitro than in vivo, while HR responses to β-stimulation were preserved. Furthermore, circulating catecholamines during ASA treatment were not found altered in the present study, practically ruling this out as an explanation for the observed effects on HR. Finally, although heart rate may be influenced by infarct size, the heart rate effect of ASA treatment could not be attributed to differences in infarct size between the groups. These data indicate that the lower HR could be attributed to intrinsic changes in the heart, rather than to a changes in sympathetic outflow to the heart. Corresponding findings were reported after physical training [26]. In vivo bradycardia could be (further) unmasked by autonomic blockade, indicating even a counter-regulating effect of the autonomic nervous system. The authors suggest a direct effect on the sinus node. The sinus node consists of a major part of collagen [27], which could have been affected by ASA treatment as well. The same authors suggest a strong interrelation between interstitial collagen and sinus node activity, modulated by stretch. This may provide an attractive mechanistic explanation for both the interstitial fibrosis and tachycardia in non-treated infarcted rats and the prevention of it by ASA treatment. However, further experiments are needed to understand the role of ASA in coronary artery disease and to elucidate its mechanism of action on remodeling and HR.

From an energetic point of view, a lower heart rate would be beneficial. Hearts with myocardial infarction display lower mechanical efficiency already at rest, which is amplified when HR is increased [23]. The lower HR after ASA treatment in the present study was reflected in equally prolonged diastolic and systolic phases. A longer diastolic phase implies a prolonged phase of cardiac perfusion and hence oxygen supply, and in addition a prolonged cardiac filling phase, which could result in an increased SV. Although the origin of the reduced HR after ASA treatment in the present study is not clear, independent of its origin heart rate reduction is associated with capillary growth [28], which would provide high clinical benefit. Increased capillarization of non-infarcted myocardium would enhance oxygenation, even without changes in coronary flow [28].

In conclusion, in rats with myocardial infarction, the equivalent of the clinically used antiplatelet-dose of ASA for patients with myocardial infarction, is observed to interfere with cardiac remodeling and hemodynamics. The reduced collagen accumulation in spared myocardium, as well as the lower intrinsic heart rate, can be regarded as beneficial, since they did not coincide with aggravation of left ventricular dilatation, or decreased resting cardiac output and maximal pump function, respectively. Although underlying mechanisms have to be elucidated, if these effects of ASA would also occur in man, they could have contributed to the success of low-dose ASA treatment in patients.

Time for primary review 22 days.


   Acknowledgements
 
Frans Boomsma is gratefully acknowledged for his expert advice and help with the plasma catecholamine determinations, and Dineke de Mik (stress-free blood sampling) and Richard van Veghel (assistance with surgery) for their excellent technical support.


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 

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