Cardiovascular Research

Cardiovascular Research 1997 35(1):132-137; doi:10.1016/S0008-6363(97)00079-5
© 1997 by European Society of Cardiology

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Copyright © 1997, European Society of Cardiology

Spontaneous running increases aortic compliance in Wistar-Kyoto rats

Bronwyn A Kingwell^*, Pamela J Arnold, Garry L Jennings and Anthony M Dart

Alfred and Baker Medical Unit, Baker Medical Research Institute, Commercial Road, Prahran 3181, Australia

^* Corresponding author. Tel.: +61 3) 9276 2071; fax: +61 (3) 9276 3488/2495.

Received 3 October 1996; accepted 20 February 1997

	Abstract

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion References

 
Objective: Previous studies in humans have found, using non-invasive methodology, that arterial compliance is elevated with exercise training. Forced exercise in animals has corroborated these findings, but the association of this type of exercise with psychological stressors limits its relevance to humans. We have investigated the effects of spontaneous running exercise from 4–20 weeks of age on aortic and mesenteric compliance and vascular reactivity in Wistar-Kyoto (WKY) rats. Methods: Animals were killed using CO₂ asphyxia and the aorta, mesentery and heart rapidly removed. The heart was dissected and weighed. The aorta was separated into 3 4-mm rings which were mounted on wires in organ baths for determination of compliance and vascular reactivity to noradrenaline, acetylcholine and sodium nitroprusside. The slope of diameter–pressure relationship derived using Laplace's equation was used as an index of compliance. Results: During the final 2 weeks of training WKY rats ran an average of 7.9±1.0 km/24 h. Body weight was not affected by training. Training significantly increased the weight of the atria, left and right ventricles as well as total heart weight and left ventricular/body weight ratio. Aortic compliance was increased from 12.3±0.4 to 14.2±0.5 µm/mmHg (P<0.05) after training. There was no effect of training on aortic reactivity to noradrenaline, acetylcholine or sodium nitroprusside. Conclusion: Exercise training increased intrinsic aortic compliance in WKY rats which provides evidence for a structural basis for the elevated compliance reported previously with 4 weeks of aerobic exercise in man.

KEYWORDS Compliance; Exercise; Vascular reactivity; Noradrenaline; Acetylcholine; Nitrates; Rat, arteries

	1 Introduction

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion References

 
The proximal aorta plays an important role in buffering pulsatile cardiac ejection and providing a continuous delivery of blood to the periphery. Aortic stiffening which occurs with ageing and the development of cardiovascular disease impairs this buffering capacity with a resultant increase in cardiac afterload and impairment of coronary perfusion [1, 2]. While the difficulties surrounding measurement of arterial compliance in humans have prohibited studies directly relating arterial compliance to outcomes such as death and myocardial infarction, indirect indices of compliance such as pulse pressure do show a positive relationship to outcome [3, 4]. Such studies highlight the importance of proximal aortic compliance as a therapeutic target.

Exercise training represents one possible modulator of proximal aortic properties. We and others have shown that athletes have greater arterial compliance compared with matched sedentary controls [5–7]. Furthermore, we have shown that 4 weeks of moderate intensity exercise performed for 30 min, 3 times per week, also increases arterial compliance in previously sedentary individuals [8]. While part of this change may have resulted from the passive effects of blood pressure reduction on compliance, compliance normalised to a standard blood pressure was also higher after training, suggesting a change in intrinsic arterial elastic properties. This change may relate to modification of elastin, collagen or smooth muscle or to altered loading conditions of these fibres through changes in vascular tone. Direct determination of the effects of exercise on intrinsic arterial compliance is however impossible in the intact human.

The primary aim of this study was to determine whether exercise training could alter the intrinsic compliance of the aorta. To this end, we studied the effects of 16 weeks of spontaneous running on ex vivo aortic compliance in Wistar-Kyoto (WKY) rats. A secondary aim was to determine whether exercise-induced changes in vascular reactivity might represent a potential mechanism which could contribute to changes in compliance in the intact animal through altered vascular tone. To fulfil this aim, we studied aortic reactivity to noradrenaline and used acetylcholine and sodium nitroprusside to determine endothelium-dependent and -independent responses to nitric oxide, respectively. We chose the spontaneous running model since it has previously been associated with blood pressure reduction [9]and may equate more closely to human exercise practices compared with forced running which induces stress responses and often blood pressure elevation [10, 11].

	2 Methods

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion References

 
2.1 Study design
Experiments were approved by the Baker Medical Research Institute Ethics Committee and conformed with the Guide for the Care and Use of Laboratory Animals (US National Institutes of Health). Twenty 4-week-old WKY rats were housed singly in cages (475x318x165 mm) under temperature conditions ranging from 18–20°C and humidity ranging from 45–70% on a 12 h dark/light cycle. Food and water were available ad libitum. Each cage was fitted with a modified high top containing a running wheel (diameter = 225 mm and width = 80 mm). Litter mates were randomised to either be housed in cages with the wheel locked (10 sedentary) or in cages where the wheel was unlocked (10 trained). The distance run by rats was monitored daily using a bicycle odometer (Cateye Mity2 Cyclocomputer Model CC-MT200) and weight was monitored weekly. This regimen has been previously shown to slow the development of hypertension in the spontaneously hypertensive rat [9].

At 20 weeks of age one sedentary and one trained litter mate were sacrificed using CO₂ asphyxia and studied on each experimental day. Activity wheels were locked at 5.00 pm on the evening prior to experimentation to exclude the effects of acute exercise. The aorta and mesentery were rapidly removed and placed in ice-cold Krebs' solution (composition in mmol/l: NaCl 119, KCl 4.7, MgSO₄·7H₂0 1.17, NaHCO₃ 25, KH₂PO₄ 1.18, CaCl₂ 2.5 and glucose 11) and gassed with carbogen (5% CO₂; 95% O₂). The heart was also excised and dissected free of all fat and connective tissue. The atria, right ventricular free wall, left ventricular free wall and septum were carefully separated and weighed.

Three 4-mm segments of aorta from each rat were mounted on 500 µm wires in 5 ml organ baths gassed with carbogen. The lower hook was connected to a micrometer while the upper hook was attached to a force transducer (FTO3 force transducer, Grass Scientific Instruments, Mitutoyo, Japan). The force development was amplified and then digitised using a MacLab data acquisition system (MacLab 8E, Apple Computer Inc, Cupertina, CA) connected to an Apple Macintosh SE. All vessels equilibrated for 30 min at 37°C under zero tension. The most proximal aortic segment was used for estimation of aortic compliance while the 2 more distal segments were used in the reactivity studies as described in Section 2.3.

2.2 Estimation of compliance
An exponential fit has been used previously to relate tension and diameter to provide an index of vessel stiffness in isolated resistance vessels [12]. While the tension–diameter relationship approximated an exponential function, the model T = To·e^(β·D) (where T represents tension, β the stiffness factor and D vessel diameter) failed to adequately fit aortic data, particularly in the lower diameter range. Transformation of the data to a diameter–pressure relationship as previously described by Koutsis et al. [13]was therefore performed. This relationship was fitted adequately by a linear equation, the slope of which relates directly to compliance (Fig. 1). A comparison of the root mean square values expressed as a percentage for the exponential fit (11.1±8.2) versus the linear fit (2.3±1.7; P<0.0001) validated the choice of the linear model. Our data indicated that compliance measured ex vivo in WKY rats does not vary significantly over the physiological pressure range [13].

View larger version (30K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Upper panel shows the diameter–pressure relationship for the aorta of sedentary (open circles) and trained (solid circles) Wistar-Kyoto litter mates in a single experiment (left) and mean data calculated from linear regression (right). Lower panel shows the aortic compliance calculated from the slope of the diameter–pressure relationship (left) and the mean diameter at 100 mmHg for sedentary (open bars) and trained (solid bars) rats (right). Error bars are standard error of the mean and * signifies significant differences for the comparisons indicated (P<0.05).

 
The vessels were assumed to be cylinders, the length of which did not vary with changes in radius. Since the vessels were found to be flat between the wires, the internal circumference (L) and hence diameter of each vessel segment were calculated using the equation below where d is the diameter of the mounting wires and s is the separation of the wires from each other's inner surface [14]:

(1)

The circumferential wall force per unit length is the passive wall tension and was calculated from Eq. (2) which took into account the fact that the forces produced by a ring are equal to twice the force which would have been produced by an equivalent aortic strip, where F is the force exerted by the vessel on the tension transducer and g is the vessel length:

(2)

Effective transmural pressure p was calculated from Laplace's equation where L is the internal circumference corresponding to the wall tension:

(3)

Since previous studies have shown a difference between the first and subsequent diameter–tension curves (which are superimposable), an initial ‘pre-stretch’ curve was performed [14]. Each vessel was pre-stretched using 20 mmHg pressure increments until a transmural pressure of 250 mmHg was achieved. The micrometer was then advanced until the 2 mounting wires barely touched. A passive length–tension curve was derived by advancing the micrometer in approximately 20 mmHg steps at 2 min intervals [12, 14].

2.3 Aortic reactivity
All vessels were ‘pre-stretched’ and a passive diameter–tension curve was performed as described above. Dose–response curves to noradrenaline were performed in the 2 more distal aortic segments and subsequently one segment was used to construct a dose–response curve to acetylcholine and the other to sodium nitroprusside. The noradrenaline dose–response curves did not vary between segments and the results are therefore only reported for the middle of the 3 aortic segments dissected. Reactivity to acetylcholine and sodium nitroprusside was assessed after pre-constriction of the vessel with 3x10^–8 M noradrenaline and expressed as a percentage of this response. Dose–response curves were performed at a diameter equivalent to a transmural pressure of 90% of the relaxed (unstimulated) diameter at 100 mmHg. This diameter has been shown previously in mesenteric resistance arteries to give maximum vasoconstrictor-induced tension [15]and ensures that vessels of different internal diameters were stretched to a similar point on their length–tension curves.

2.4 Drugs
Norepinephrine bitartrate salt (Sigma, USA), acetylcholine chloride (Sigma, USA), and sodium nitroferricyanide (Sigma, USA) were all dissolved in Krebs' solution.

2.5 Statistics
All data are expressed as mean±s.e.m. Comparisons between sedentary and trained WKY rats were made using unpaired t-tests. The level of significance employed was P<0.05.

	3 Results

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion References

 
WKY rats ran an average of 7.9±1.0 km/24 h during the last week of training. Body weight was not affected by training (sedentary 372±6 g; trained 366±9 g). Training increased the weight of the atria, left and right ventricles as well as total heart weight and left ventricular/body weight ratio (Fig. 2).

View larger version (24K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 The mean weight of the atria, ventricular septum, left ventricle (LV), right ventricle (RV), total heart and left ventricular/body weight ratio are shown for sedentary (open bars) and trained (solid bars) Wistar-Kyoto (WKY) rats. Error bars are standard error of the mean and * signifies significant differences for the comparisons indicated (P<0.05).

 
Ex vivo aortic compliance did not vary with calculated pressure. Training increased aortic compliance from 12.3±0.4 to 14.2±0.5 µm/mmHg (P<0.05; Fig. 1). Consistent with this finding aortic diameter (at 100 mmHg) was greater in trained compared with sedentary WKY.

We found no effect of training on aortic reactivity to noradrenaline, acetylcholine or sodium nitroprusside (Fig. 3).

View larger version (16K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 3 Aortic reactivity to noradrenaline (NA, upper panel), acetylcholine (ACh, centre panel) and sodium nitroprusside (SNP, lower panel) for sedentary (open circles) and trained (solid circles) rats. Error bars are standard error of the mean.

 

	4 Discussion

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion References

 
Spontaneous running produced a significant training response in WKY rats as assessed by changes in cardiac mass. Proximal aortic compliance was also elevated by 16 weeks of spontaneous running. This result shows that the elevation in arterial compliance observed with exercise training in human studies may have a structural basis and not simply result from the passive effects of reduced blood pressure or vasodilatation which may alter loading of collagen or elastin [1]. Chronic reduction in blood pressure may however be one factor contributing to the structural modifications. The elevation observed in arterial compliance was not associated with a change in reactivity to noradrenaline, acetylcholine or sodium nitroprusside.

The running activity and weight gain of WKY rats were similar to those reported previously by Shyu et al. [16]. The changes in cardiac mass occurring with training were characteristic of eccentric cardiac hypertrophy and included both left and right ventricular as well as atrial enlargement. The elevation in aortic compliance was consistent with previous work utilising forced running [13, 17]and forced swimming [18]. In accordance with the work of Koutsis and colleagues [13]we found that compliance measured ex vivo did not vary significantly over the physiological pressure range. In their study Koutsis [13]used a 12-week forced running regimen consisting of 1 h of running, 6 days per week at 32 m/min and a 6% grade and found a higher percentage of collagen in the tunica media of sedentary Wistar rats. However, the absolute amount of collagen in the aortic wall of sedentary and trained rats did not differ because the tunica media was 7.2% thicker in trained rats [13]. While the percentage of elastic tissue did not differ according to training status, there was a greater absolute amount of elastic tissue in the trained animals. Matsuda and colleagues [18]have also shown that swim training for 16 weeks modifies elastin in WKY rats via a reduction in calcium content and by lowering the proportion of polar amino acids which normally increase progressively with age [19]. Although there are clear differences between the training regimes used in these previous studies and the current study, it appears that spontaneous running induces directionally similar changes in aortic compliance compared to forced running and swimming which are associated with stress and the latter also with hypoxia [20]. The findings we have made with voluntary running in rats suggest that the increase in whole-body arterial compliance which we have documented in humans using non-invasive methodology with 4 weeks of moderate aerobic training is, in part, independent of the passive effects of blood pressure reduction and related to intrinsic changes in vessel properties [8].

The elevation in aortic compliance was independent of changes in reactivity to noradrenaline, acetylcholine and sodium nitroprusside. Forced training has been previously shown to alter reactivity to these substances in spontaneously hypertensive (SH) [21], Wistar [13]and Sprague-Dawley rats [22]. Previous findings with respect to noradrenaline have varied between studies possibly due to the different species and training regimens studied. In Wistar rats forced training increased the maximal aortic response to noradrenaline [13]. In SH [21]and Sprague-Dawley rats [22], however, the sensitivity of aortic vessels to noradrenaline was reduced with training. In these latter 2 studies, denudation of the preparation significantly attenuated this difference, suggesting changes in endothelium-dependent dilation with training. Consistent with this hypothesis, both studies also reported greater dilatory responses to acetylcholine in trained animals. In humans we have reported enhanced acetylcholine responsiveness in highly trained athletes compared with sedentary controls [23]; however, in a cross-over longitudinal study between 4 weeks of cycling and 4 weeks of normal sedentary activity, training failed to alter acetylcholine responsiveness although basal release of nitric oxide was elevated [24].

The absence of reactivity changes in our spontaneous running model may relate to the nature of spontaneous exercise. The average distance of 7.9 km per 24 h period ran by WKY rats was performed predominantly during the night over 10–12 h, which corresponds to an average running speed of 12 m/min. Running was however episodic and was typically performed in short high-intensity bursts separated by rest periods. In contrast, the enforced running of previous studies was performed at 15 m/min [21], 20 m/min [13]and 30 m/min up a 15° incline [22]. These intensities were performed continuously for 1 h per day. It is possible that such a continuous stimulus is necessary to evoke changes in vascular reactivity. In addition to these differences, enforced running is known to be associated with additional stress attributable to lack of control, known to evoke a pronounced adrenocortical response which increases the proportion of adrenaline in the adrenal glands whereas spontaneous running has no effect [10]. Such stress responses may alter circulating catecholamine levels and ultimately vascular reactivity.

4.1 Conclusion
Sixteen weeks of voluntary running increased aortic compliance in WKY rats. This type of exercise, in contrast to forced exercise regimens, is likely to more closely emulate the human exercise response and our finding thus supports our data in humans [8]which suggest changes to the intrinsic properties of the large arterial walls with moderate exercise training. These intrinsic changes associated with training may be amplified in vivo via the passive effects of lower blood pressure on arterial compliance [25, 26].

Time for primary review 20 days.

	Acknowledgements

 
Thanks to Dr Grant McPherson for my initiation into vascular pharmacology and to Ms Raewyn Laing and Ms Corina Backhouse for their care of all animals and management of the exercise distance recordings. Dr Kingwell is a National Heart Foundation of Australia Postdoctoral Research Fellow. This work was also supported by The Alfred Healthcare Group, Melbourne, Australia and by an Institute Grant to the Baker Medical Research Institute from the National Health and Medical Research Council of Australia.

	References

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion References

 

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