Phenotypic differences in cardiovascular regulation in inbred rat models of aerobic capacity

LAUREN GERARD KOCH1, STEVEN L. BRITTON1, JOHN C. BARBATO1, DAVID W. RODENBAUGH2 and STEPHEN E. DICARLO2

1 Department of Physiology and Molecular Medicine, Medical College of Ohio, Toledo, Ohio 43614-5804
2 Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan 48201-1908


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Koch, Lauren Gerard, Steven L. Britton, John C. Barbato, David W. Rodenbaugh, and Stephen E. DiCarlo. Phenotypic differences in cardiovascular regulation in inbred rat models of aerobic capacity. Physiol. Genomics 63–69, 1999.—The Dark Aouti (DA) inbred strain of rats has superior aerobic treadmill running capacity compared with the Copenhagen (COP) strain of inbred rats. This difference in aerobic capacity provides a model to explore the genetic basis of variation in this trait. The present study evaluated intermediate phenotypic differences between 10 male COP inbred rats and 10 male DA inbred rats that might contribute to the difference in aerobic capacity between the strains. Five autonomically regulated cardiovascular variables were evaluated during rest or exercise by measuring the response to autonomic antagonists. The DA rat had enhanced autonomic function for the regulation of peripheral blood flow and cardiac output. Specifically, at rest the DA rats had significantly more sympathetic (123 ± 8 vs. 99 ± 7 beats/min) and parasympathetic (35 ± 5 vs. 12 ± 3 beats/min) tonus for heart rate control and more sympathetic support of blood pressure (70 ± 7 vs. 38 ± 6 mmHg) compared with the COP rats. During three graded levels of treadmill exercise the DA rats had higher blood pressures (16% on average) and higher heart rates (4% on average) relative to the COP rats. In addition, the DA rats had a 27% greater heart weight-to-body weight ratio compared with the COP strain of rats (3.63 ± 0.08 vs. 2.85 ± 0.07 g/kg). All five of these intermediate phenotypes could participate as variables causative of the difference in treadmill running capacity between the DA and COP strains of rats.

genetics; hemodynamics; autonomic function; endurance; exercise; oxygen consumption; performance; treadmill


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
ALTHOUGH EVIDENCE from twin and other heritability studies in humans (4, 15) suggests a substantial genetic component to aerobic exercise capacity, the genes determining the difference between low and high capacity remain largely undefined. A long-term goal of our group is to identify and understand the function of genes underlying inherited differences in aerobic exercise capacity.

Two different kinds of animal models can be of value in identification of the genetic origin of complex traits such as aerobic capacity (20). First, animal lines selectively bred for low and high capacity for a given trait are of value because genes determining the trait variance are concentrated at the extremes, which increases the power of genetic analysis. Indeed, we are currently in the long-term process of developing divergent lines of rats selectively bred for low and high capacity for aerobic endurance running on a treadmill (16). Second, already available inbred strains developed from nonselected stocks can be of direct value if strains that differ widely for the trait can be identified. We recently tested 11 different inbred strains of rats for aerobic treadmill running capacity and found a continuum in capacity (3); the Dark Agouti (DA) strain of rats displayed the highest whereas the Copenhagen (COP) strain of rats displayed the lowest capacity for endurance running.

Therefore, the present study was designed to evaluate intermediate phenotypic differences between COP inbred rats (low capacity) and DA inbred rats (high capacity) that might be causative of the difference in aerobic capacity between the strains. Autonomic regulation of cardiac output and peripheral blood flow is known to be of central importance in determining the magnitude of oxygen consumption in mammals during exercise (1, 19, 22, 23). Investigators examining genetic or species influences on endurance performance have primarily focused on cardiac regulation. However, autonomic regulation of peripheral blood flow also contributes to endurance performance. Therefore, we evaluated five autonomic variables that regulate cardiac output and peripheral blood flow during rest and exercise in the DA and COP strains of rats. Our data demonstrate significant differences in cardiovascular autonomic regulation that might explain at least part of the difference in aerobic capacity between these two strains of rats.


    METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Animals
Ten male rats of the DA and COP strains were purchased from the colonies of Harlan Sprague-Dawley (Indianapolis, IN) at 9 wk of age. When not being studied, the rats were housed 1 per cage. The rats were provided food and water ad libitum and were placed on a 12:12-h light-dark cycle with the light cycle occurring during daytime. All procedures were carried out with approval by our Institutional Animal Care and Use Committees and were conducted in accordance with the "Guiding Principles in the Care and Use of Animals" as approved by the Council of the American Physiological Society.

Surgical Procedures
All instrumentation was performed using aseptic surgical procedures when the rats were 12 wk old (i.e., after testing for maximal treadmill running capacity; protocol 1). Anesthesia was produced with a mixture of ketamine (40 mg/kg), xylazine (8 mg/kg), and chlorpromazine (4 mg/kg), and supplemental doses were administered as needed. Rats were instrumented with a polytetrafluoroethylene catheter inserted into the descending aorta via the left common carotid artery for measurements of arterial blood pressure and heart rate. The arterial catheter was also used for the infusion of cardiac autonomic antagonists. The arterial catheter was flushed daily, filled with heparin (1,000 U/ml), and plugged with a stainless steel obturator. Rats were monitored for signs of infection and changes in body weight during recovery from the surgery. During this time, the rats were familiarized with the experimental procedures. At the time of the experimental protocols all rats were in apparently good health and gaining weight.

Experimental Measurements
Arterial pressure and heart rate were measured by connecting the arterial catheter to an Ohmeda DT-XX pressure transducer coupled to a data acquisition system and laboratory computer (MacLab/8S analog-to-digital converter, Analog Digital Instruments, and a Power Macintosh 9600/300 computer) for subsequent analysis.

Experimental Protocols
Protocol 1: Test of maximal aerobic running capacity.
The protocol for maximal running capacity required 2 wk and was started when the rats were 10 wk old. Each rat was introduced to treadmill (Model Exer-2, Columbus Instruments, Columbus, OH) running for gradually increasing durations each day. The goal of the first week was to expose each rat to enough treadmill education so that they could run for 5 min at a speed of 10 m/min on a 15° slope. This amount of exposure to treadmill running is below that required to produce a measurable adaptational change in aerobic capacity (2, 11).

The first 2 days of introduction to treadmill running consisted of simply placing the rat on the belt that was moving at a velocity of 10 m/min (15° slope) and picking the rat up and moving it forward if it started to slide off the back of the belt; that is, the rats were not allowed to slide onto the 15 x 15 cm electric shock grid located at the back of the treadmill. During introduction days 3–5, failure to run caused the rats to slide off of the moving belt and onto the shock grid, which delivered 1.2 mA of current at 3 Hz. The rats were left on the grid for ~1.5 s and then moved forward onto the moving belt. This process was repeated until the rats learned to run in order to avoid the mild shock.

During the second week, each rat was evaluated for maximal endurance running capacity on five consecutive days. Each daily endurance trial was performed at a constant slope of 15° with the starting velocity at 10 m/min; running performance was evaluated at about the same time each day (between 10 A.M. and noon). Treadmill velocity was increased by 1 m/min every 2 min, and each rat was run until exhaustion. Exhaustion was operationally defined as the third time the rat was willing to slide onto the shock grid and sustain 2 s of shock rather than run. At the moment of exhaustion, the current to the grid was stopped and the rat was removed from the treadmill.

For each of the five running trials, three parameters were used to estimate aerobic capacity: the duration of the run (min), the total distance run (m), and the vertical work (kg · m) performed. The distance run was calculated from the duration of the run. The vertical work performed was derived because it incorporates the body weight of the animal into the estimate of performance. Vertical work was calculated as the product of the body weight (kg) and vertical distance (m) the rat reached at the completion of the run, which was performed at a slope of 15° [vertical distance = (distance run)(sin 15°)]. For each rat, the single best daily performance of the five trials was considered the trial most closely associated with the genetic component of aerobic capacity.

Protocol 2: Determination of resting autonomic variables.
Resting values for heart rate and arterial pressure were determined for each experimental trial and averaged to obtain one resting value for each animal. These resting values were then averaged within groups to determine arterial pressure and heart rate for the DA and COP strains.

Two trials were required to determine cardiac sympathetic and parasympathetic tonus. On day 1, the rats were placed unrestrained in a large Plexiglas box (30.5 cm x 30.5 cm x 30.5 cm). The rats were allowed to adapt to the laboratory environment for 1 h so that baseline hemodynamic variables could be obtained. After the adaptation period, the heart rates, arterial pressures, and mean arterial pressure responses to cardiac autonomic sympathetic and parasympathetic blockade (ß1-adrenergic and muscarinic cholinergic receptor blockade) were determined. Drug doses for the sympathetic and parasympathetic antagonists were calculated relative to the animal's body weight on each experimental day. Cardiac muscarinic-cholinergic receptor blockade was achieved by infusion of the nonspecific muscarinic-cholinergic receptor antagonist methylatropine (3 mg/kg) through the carotid arterial catheter. The heart rate response to methylatropine reached its peak in 10–15 min; therefore, heart rate measurements were always taken 15 min after administration of methylatropine. Cardiac ß1-adrenergic receptor blockade was achieved by infusion of the specific ß1-adrenergic receptor antagonist metoprolol (10 mg/kg) into the carotid arterial catheter. Metoprolol was infused 15 min after methylatropine, and again the heart rate response was measured 15 min later. At this time, complete ganglionic blockade was produced by infusing hexamethonium (20 mg/kg) and methylatropine (0.05 mg/kg) to estimate the sympathetic support of blood pressure. The entire resting data collection took ~2 h. At the end of the experiment, the rats were returned to their housing facilities. On an alternate day (>48 h), trial 2 was conducted. Rats were treated identically as described in trial 1 except that the order of blockade was reversed.

Intrinsic heart rate (HRI) was taken as the heart rate after complete cardiac autonomic blockade (muscarinic cholinergic + ß1-adrenergic receptor blockade).

Sympathetic tonus and parasympathetic tonus were estimated from the following calculations


where HRM is heart rate after muscarinic-cholinergic blockade and HRß1 is heart rate after ß1-adrenergic receptor blockade. Finally, sympathetic support of blood pressure was calculated as the maximum reduction in arterial pressure after ganglionic blockade (hexamethonium).

Protocol 3: Determination of heart rate and blood pressure during exercise.
On the day of the experiment, the rats were placed on the treadmill. Arterial pressure and heart rate were monitored for 60 min to estimate the initial values. After all variables obtained steady state, control values were recorded over a 15-s interval immediately before the onset of exercise. Subsequently, the rats ran on the treadmill at 6 m/min, 10° grade, while the data were recorded continuously throughout the exercise. After hemodynamic variables reached steady state (~3 min), the speed of the treadmill was increased to 12 m/min. After hemodynamic variables reached steady state at this higher workload (~3 min), the speed of the treadmill was increased to 18 m/min. Exercise responses were obtained during the last 15 s of each stage.

Protocol 4: Determination of heart weight-to-body weight ratio.
After completion of the studies, the hearts of the rats were excised, and the cardiac chambers were opened, rinsed clean of all clots, and weighed. Heart weight-to-body weight ratio was calculated and compared between groups.

Drugs
Methylatropine and metoprolol were purchased from Sigma Chemical. Ketamine hydrochloride was purchased from Aldrich Chemical. Chlorpromazine hydrochloride was purchased from Rugby Laboratories. Xylazine was purchased from Mobay. Hexamethonium chloride was purchased from ICN Pharmaceuticals.

Data Analysis
All data are expressed as means ± SE. Separate nonpaired t-tests were used to compare the following: run duration, distance run, and vertical work performed (Fig. 1); resting arterial pressure and heart rate (Fig. 2); sympathetic tonus, parasympathetic tonus, and intrinsic heart rate (Fig. 3); sympathetic support of blood pressure (Fig. 4); and heart weight-to-body weight ratio between DA and COP rats (Fig. 5). Two separate two-way ANOVAs with repeated measures were used to compare arterial pressure and heart rate during the graded exercise test between DA and COP rats (Fig. 6).



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Fig. 1. Three estimates of aerobic capacity. Means ± SE for time run (A), distance run (B), and work performed (C) for DA and COP rats. DA rats ran longer (42%) and farther (68%) and performed more work (65%). * P < 0.05.

 


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Fig. 2. Means ± SE for arterial pressure (A) and heart rate (B) at rest for DA and COP rats. DA rats had a significantly higher arterial pressure (8%; * P = 0.0008) but not heart rate (P = 0.415). bpm, Beats/min.

 


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Fig. 3. Means ± SE for sympathetic tonus (A), parasympathetic tonus (B), and intrinsic heart rate (C) at rest for DA and COP rats. DA rats had a higher resting sympathetic tonus (24%), resting parasympathetic tonus (192%), and intrinsic heart rate (18%). * P < 0.05.

 


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Fig. 4. Means ± SE for sympathetic support of arterial pressure at rest for DA and COP rats. Resting sympathetic support of arterial pressure was 84% higher in DA rats. * P < 0.05.

 


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Fig. 5. Means ± SE for heart weight-to-body weight ratio for DA and COP rats. DA rats had a 27% greater heart weight-to-body weight ratio. * P < 0.05.

 


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Fig. 6. Means ± SE for arterial pressure (A) and heart rate (B) at rest and during graded exercise for ~3 min at 6, 12, and 18 m/min. DA rats had higher arterial pressure and heart rate during exercise. * P < 0.05.

 

    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
As predicted from previous work (3), the DA rats scored better than the COP rats on all three indexes of aerobic running to the operationally defined point of exhaustion (Fig. 1). The DA rats ran on average for 47 ± 1 min and the COP rats ran for 33 ± 1 min, which represents a 42% difference. In terms of distance, the DA rats ran on average for 982 ± 34 m whereas the COP rats ran for 586 ± 26 m (68% difference). The average body weight of the DA rats (216 ± 5 g) was not significantly different (P = 0.265) from that of the COP rats (209 ± 5 g). The DA rats performed 56 ± 2 kg · m of vertical work, whereas the COP performed 34 ± 2 kg · m (65% difference).

Figure 2 shows the blood pressures and heart rates obtained during resting conditions before experimental maneuvers as averaged from all experiments. Blood pressure for the DA rats averaged 131 ± 2 mmHg, and the heart rate averaged 423 ± 9 beats/min. Blood pressure for the COP rats averaged 121 ± 3 mmHg, and the heart rate averaged 410 ± 12 beats/min. DA rats had significantly higher blood pressures (8%; P = 0.0008) but not heart rates (P = 0.415) compared with the COP.

In general, the pharmacological tests of autonomic function support the contention that the DA rats have a wider range of autonomic control for both heart rate and blood pressure. Figure 3 shows the parasympathetic tonus (independent influence of the parasympathetic nervous system on heart rate) and sympathetic tonus (independent influence of the sympathetic nervous system on heart rate) (5). Sympathetic tonus of the DA rats was greater than sympathetic tonus of the COP rats (123 ± 8 vs. 99 ± 7 beats/min; 24% difference in sympathetic tonus). Parasympathetic tonus was 35 ± 5 beats/min for DA but only 12 ± 3 beats/min for COP (192% difference in parasympathetic tonus). Thus the estimated total range of autonomic control of heart rate (sympathetic + parasympathetic tonus) was 158 beats/min for the DA rats and 111 beats/min for the COP rats (42% difference). Figure 3C displays the heart rate obtained after combined sympathetic and parasympathetic blockade and was defined as the intrinsic heart rate. Intrinsic heart rate averaged 376 ± 3 beats/min in the DA rats and 318 ± 7 beats/min in the COP rats (18% difference).

Sympathetic support of arterial blood pressure was estimated from the decline in blood pressure subsequent to autonomic ganglionic blockade (hexamethonium). Hexamethonium was administered superimposed on the above-described combined parasympathetic and sympathetic blockade. As shown in Fig. 4, the DA rats had a significantly greater sympathetic support of blood pressure. Complete sympathetic blockade decreased blood pressure of the DA rats 70 ± 7 mmHg and decreased blood pressure of the COP rats 38 ± 6 mmHg (84% difference in sympathetic support of blood pressure).

The hearts of the DA rats weighed 0.782 ± 0.010 g and were significantly (P = 0.0001) heavier than the hearts of the COP rats, which averaged 0.593 ± 0.015 g. The body weight of the COP rats (209 ± 5 g) was not significantly different from the body weight of the DA rats (216 ± 5 g). Figure 5 shows that the heart weight-to-body weight ratio averaged 3.63 ± 0.08 g/kg for the DA rats and 2.85 ± 0.07 g/kg for the COP rats (27% difference).

Figure 6 displays the blood pressure and heart rate responses to a three-step graded exercise protocol. Arterial blood pressure during the preexercise rest period averaged 124 ± 3.5 mmHg in the DA rats and 108 ± 2.7 mmHg in the COP rats (14% difference, P < 0.05). Pressure for both strains increased ~20 mmHg at the first step increase of running to 6 m/min. Pressures of both strains remained elevated ~20 mmHg above the preexercise levels during the increases in speed to 12 and 18 m/min. Heart rates during the preexercise rest period were essentially identical for both strains and averaged 353 ± 10 beats/min in the DA rats and 352 ± 6 beats/min in the COP rats. At each level of the three levels of exercise the DA rats had small, but significantly greater, heart rates compared with the COP rats (48, 18, and 14 beats/min, respectively).


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The goal of this study was to find intermediate phenotypic differences between COP inbred rats and DA inbred rats that might be contributing to the difference in aerobic capacity between these strains (12, 17). We tested for possible differences in autonomic nervous system function because autonomic regulation of cardiac output and peripheral blood flow is central to the ability of mammals to consume oxygen (21). Ashkar and Hamilton (1) demonstrated the overall importance of the autonomic nervous system during exercise in conscious dogs. After complete surgical sympathectomy that included adrenal denervation and bilateral vagotomy, exercise caused the oxygen consumption to increase only twofold compared with the normal increase of three- to sevenfold. In addition, cardiac output increased only 13–14% of normal, and arterial pressure decreased 20%.

Results from this study demonstrate that autonomic regulation of cardiac function is greater in the high-performing DA rats compared with the low-performing COP rats. Importantly, autonomic control of peripheral vascular function was also greater in the DA rats. Because endurance capacity is dependent on the exquisite matching of cardiac output and peripheral vascular tone, these phenotypic differences between DA and COP rats might be causative of the differences in aerobic capacity between the strains.

Joyner (14) presented a model of endurance running performance that is the product of three physiological factors: 1) the maximal rate at which oxygen and nutrient substrates can be utilized (O2 max) to produce energy in the form of ATP, 2) the percentage of O2 max at the threshold for lactate release, and 3) the efficiency of running. We have used this model as a guide to decompose the complexity of running aerobic capacity into functionally relevant components. We hypothesize that cumulative allelic differences that underlie each of these three intermediate phenotypes will largely account for the variance in aerobic capacity. Obviously, each of these intermediates is polygenic in origin and highly complex in physiological expression as exemplified by the apparently large influence of autonomic function as a singularity.

Essentially all of the observations of the present study are consistent with the hypothesis that differences in autonomic function are causative of the variation in capacity between the DA and COP rats. Our current view is that autonomic differences operate by influencing the maximal rate at which oxygen and nutrient substrates can be utilized (O2 max) to produce energy (factor 1 of the Joyner model). That is, all of the differences between the DA and COP rats are directionally correct to increase the maximal rate at which oxygen and nutrients can be utilized via adjustments in cardiac output and peripheral blood flow regulation.

Differences in autonomic function between the DA and COP rats have a direct effect on peripheral blood flow regulation. The higher resting blood pressure of the DA rats (8%) that was maintained during exercise (Fig. 6) created a larger arterial-venous pressure gradient for the perfusion of active tissue. Hobbs and McCloskey (13) examined the direct effect of perfusion pressure on force production in skeletal muscle in anesthetized cats and conscious humans. These investigators found that reducing perfusion pressure from 125 to 75 mmHg in cats decreased blood flow 53% and force production 57% in the soleus and medial gastrocnemius muscles (slowly fatiguing fibers); similar reductions in arterial pressure did not affect force production in muscle composed mainly of fast-fatiguing fibers. In experiments on humans, the same investigators found that during rhythmic, constant-force contractions, the electromyogram of the ankle extensor muscle increased as the contracting muscles were raised above the heart by a legs-up tilt (13). These results demonstrate the importance of the magnitude of arterial pressure on the performance of skeletal muscle during aerobic exercise.

DA rats have ~84% more sympathetic drive controlling blood pressure relative to the COP rats (Fig. 4). Sympathetic activity is important in the regulation of peripheral oxygen extraction during aerobic exercise. In general, it is hypothesized that sympathetic regulation can influence oxygen extraction by two related pathways: 1) precapillary arteriolar constriction in the vasculatures of the more vegetative organs and inactive skeletal muscle, and 2) redistribution of blood flow within active skeletal muscle. Decreases in blood flow to inactive skeletal muscle during exercise have been a relatively consistent observation from numerous laboratories in a wide variety of species (8, 22, 24). Furthermore, studies by Nellis et al. (19) support the contention that a sympathetically mediated redistribution of flow can increase the efficiency of oxygen extraction within exercising muscle. During contraction of dog gracilis muscle, the investigators produced decreases in blood flow either by infusing norepinephrine or by mechanical occlusion. Declines in blood flow produced mechanically were accompanied by significantly larger decrements in oxygen extraction relative to similar decreases in flow produced by norepinephrine. These results suggest that norepinephrine increases the efficiency of oxygen extraction by distributing blood flow to more active muscle fiber regions. This speculation is consistent with the observation that the {alpha}-adrenergic receptor antagonist phenoxybenzamine caused a decline in oxygen consumption in skeletal muscle during repetitive isotonic, tetanic contractions (23).

In addition to increasing the extraction of oxygen, vasoconstriction in inactive skeletal muscle also contributes to the increase in arterial pressure that accompanies both static and dynamic exercise. These studies emphasize the importance of the sympathetic nervous system for endurance performance. Furthermore, the results from this study identify a potential site for determining genetic difference in endurance capacity. That is, these data suggest that differences in peripheral receptor function, efferent sympathetic nerve activity, and possibly baroreceptor function may contribute to the differences in aerobic capacity between the strains (6, 9, 10).

The difference in autonomic function has a direct effect on cardiac output. The ~24% greater sympathetic tonus of the DA rats (Fig. 3) demonstrates the potential for more ß-adrenergic receptor-mediated control of both heart rate and cardiac contractility. In addition, the 27% greater heart weight-to-body weight ratio in DA vs. COP rats (Fig. 5) suggests that a major difference in stroke volume may exist between these strains. Although the resting heart rates were not different between the strains, the DA rats demonstrated small but consistently greater heart rates (48, 15, and 14 beats/min, respectively) at each of the three increasing levels of exercise (Fig. 6). These modest differences in heart rate, coupled with the hypothesized differences in stroke volume (based on the differences in heart weight), could account for a substantial difference in cardiac output between the strains.

Although it is well established that aerobic conditioning produces a decline in the resting heart rates of mammals (18), neither the exact physiological mechanism nor the genetic contribution of this response has been defined (7). Figures 2 and 6 show that both the DA and COP strains have resting heart rates that are similar even though the strains are quite different in aerobic capacity. These observations suggest that unconditioned aerobic capacity and resting heart rates are not genetically linked functions, at least in these strains.

In conclusion, the DA inbred strain of rat has superior aerobic running capacity compared with the COP strain of inbred rats. DA rats had enhanced autonomic function for the regulation of peripheral blood flow and cardiac output. These phenotypic differences in autonomic function may be causative of the variation in endurance performance between the strains. Furthermore, these results identify targets for genotypic exploration to understand the genomics of endurance performance in mammals (12, 17).


    ACKNOWLEDGMENTS
 
This work was supported by National Institutes of Health Grants GM-58071 (to S. L. Britton) and HL-58414 (to S. E. DiCarlo) and by a grant from the American Heart Association (to L. G. Koch).

Address for reprint requests and other correspondence: S. E. DiCarlo, Dept. of Physiology, Wayne State Univ. School of Medicine, Detroit, MI 48201-1908 (E-mail: sdicarlo{at}med.wayne.edu).


    FOOTNOTES
 
Article published online before print. See web site for date of publication (http://physiolgenomics.physiology.org).


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 DISCUSSION
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