BASIC SCIENCES: Original Investigations
Hypertension is a significant health concern in Western society because it has increased 30% over the last decade and afflicts nearly 65 million Americans (5). Chronic hypertension is a precursor for congestive heart failure by inducing pathological, concentric hypertrophy associated with the recapitulation of a fetal cardiac phenotype (3). Functionally, increased left ventricular (LV) diastolic stiffness and a reduced β-adrenergic responsiveness are hallmarks of pathological, concentric hypertrophy and are thought to be precursors for the development of heart failure (3,6,7,10). Clearly, life expectancy decreases once overt heart failure is diagnosed (1,14).
We have recently shown that exercise training in the spontaneously hypertensive rat model (SHR) during the early compensation phase of left ventricular hypertrophy benefits the heart (10). In the present study, we examined whether chronic training could prolong survival in a salt-sensitive hypertension model. In this regard, our hypothesis was that training would increase survival in Dahl salt-sensitive rats. The Dahl salt-sensitive rat model was chosen for this study because of its well-characterized progression from normotension to hypertension to left ventricular hypertrophy and heart failure following 3-4 months of consuming a high-salt diet (9,13).
Male inbred Dahl salt-sensitive rats (N = 17) were obtained from Harlan Sprague Dawley (Indianapolis, IN). All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH Publication No. 85-23, revised 1985).
Rats were fed ad libitum, with some modification, according to the protocol described by Inoko et al. (9). The rats arrived at 8 wk of age and were fed a low-salt diet (0.12% NaCl) during a 1-wk acclimatization period. At the end of this period, all rats were then fed a high-salt diet (7.8% NaCl, Harlan Teklad; Madison, WI). Following the 1-wk acclimatization period on low salt, arterial systolic blood pressure (SBP) was measured via the tail-cuff method (Kent Instruments, Torrington, CT). SBP was again measured at 2 wk and 2 months on the high-salt diet. A minimum of three measurements of SBP was determined in each animal during each session; each measurement was conducted in a quiet, warm (28°C) room.
Rats were randomly divided into a sedentary control group (N = 8) or an exercise training group (N = 9). Exercise training was performed on a calibrated, custom-made motor-driven treadmill. Exercise training was initiated the second day after the animals arrived at the laboratory, concurrent with the consumption of the low-salt diet. Exercise training consisted of running 20 m·min−1, 0% incline, 60 min·d−1, 5 d·wk−1. Following prolonged treatment with the high-salt diet, exercise intolerance was observed in the exercise group, and thus the training program was reduced in both intensity and duration on an individual basis. Control animals were handled daily. Animal cages were checked two times daily, 7 d·wk−1 for surviving animals. Survival was measured as the number of days survived from the time of arrival to the laboratory.
Data are presented as mean ± SEM. Overall survival was assessed by Kaplan-Meier analysis. Mean survival and blood pressure were analyzed with unpaired two-tailed Student's t-tests. A value of P < 0.05 was considered significant.
Echocardiography was attempted at the onset of salt feeding to characterize cardiac size and function. Three rats in the control group died as the result of a light ketamine or xylazine cocktail (35 and 5 mg·kg−1, respectively) used for the procedure, and thus echocardiography was discontinued. Moreover, one rat in the exercise training group was involved in a fatal treadmill accident, necessitating that only 13 rats be included in the final data analysis, control (N = 5) and exercise trained (N = 8).
Tail-cuff determined SBP with the low-salt diet (Fig. 1) was almost identical different between groups. After 2 wk of consuming a high-salt diet, SBP was similarly elevated in both control and exercise groups relative to their respective low-salt values. Moreover, body weight was similar between the control and exercise groups (control: 379 ± 13 g vs exercise: 367 ± 19 g, P = NS) after 2 wk of consuming a high-salt diet. After 2 months of consuming the high-salt diet and after five control rats had already died, blood pressure and body weight were once again measured. At 2 months, SBP (control: 217 ± 5 mm Hg vs exercise: 222 ± 4 mm Hg, P = NS) and body weight SBP (control: 415 ± 9 mm Hg vs exercise: 379 ± 17 mm Hg, P = NS) were similar between surviving animals.
As Figure 2 illustrates, exercise training shifted the survival curve rightward (P = 0.018) and increased the mean number of days survived (P = 0.014) (Fig. 3) by approximately 30%, despite no observed attenuation of SBP with exercise training.
Although the present study is exclusively descriptive, the finding that exercise training increases survival in the Dahl salt-sensitive model of hypertension is an important and novel observation. Of interest, the enhanced survival observed with exercise training appears independent of training-induced SBP lowering effects, raising vast mechanistic possibilities for the observed effect. A recent report by Emter et al. (4) also showed that low-intensity treadmill running delayed the onset of overt heart failure and improved survival independent of hypertensive status in a model of spontaneously hypertensive heart failure (SHHF). Emter et al. (4) also showed that exercise training delayed the shift of alpha to beta myosin heavy chain but did not have an impact on sarco(endo)plasmic reticulum Ca2+ adenosine triphosphatase (ATPase), phospholamban, Na+, or Ca2+ exchanger protein expression. In the SHHF model, low-intensity training also offset the increases observed in proteinuria, plasma atrial natriuretic peptide, and leptin levels in sedentary SHHF (4).
Whereas chronic exercise is typically associated with lower blood pressure in hypertensive animals and humans (18), variable data have been reported with respect to exercise training studies in Dahl salt-sensitive rats. Some studies have shown that treadmill training attenuated blood pressure in Dahl rats (15,16), whereas others have not (12,19). Data in the present study are similar to data reported by Tipton et al.(19), who used the tail-cuff method to show that SBP was unaffected by training in unanesthetized, conscious Dahl salt-sensitive rats. The important point of the present study is that low-intensity exercise training prolonged survival in the Dahl salt-sensitive model of sustained hypertension.
In the present study, low-intensity exercise training was well tolerated throughout the initial weeks of the study protocol. After approximately 2 months of salt feeding, however, rats were unable to maintain the training paradigm such that the exercise intensity and duration required individual adjustment to tolerance. This observation is similar to a report from Guazzi et al. (8), who found that exercise capacity was well maintained during the first 8 wk of hypertension in salt-sensitive rats, but became compromised following 9 wk of hypertension. In their study, exercise intolerance following 9 wk of salt-induced hypertension coincided with significant left ventricular hypertrophy, normal left ventricular systolic function, and impaired resting left ventricular relaxation, suggesting that exercise intolerance stemmed from diastolic causes (8).
In patients with congestive heart failure (CHF), exercise training is clearly beneficial with respect to functional capacity, skeletal muscle physiology, vascular endothelial function, blood lipids, and psychological status or quality of life (14). However, whether the intervention of exercise can have a direct impact survival in patients with CHF remains unclear (2,14,17). Thus, the present study, albeit in a rodent model, provides some interesting, clinically relevant data. One limitation to our study is that, although the Dahl salt-sensitive rat is a well-characterized model of left ventricular hypertrophy and heart failure after consuming a high-salt diet for 3-4 months (9,13), in the present study we did not serially measure cardiac deterioration, thus making it difficult to conclude that all animals died as a result of overt heart failure. Rats did, however, exhibit symptoms of heart failure, including dyspnea at rest, low levels of basal activity, and enlarged abdomens several days before death (11). The relatively low sample size in the sedentary control group also deserves consideration as a study limitation. However, despite these limitations, the findings reported in the present study may provide a basis by which more mechanistic studies can be performed to examine how and whether exercise training has a beneficial impact on salt-sensitive hypertension and possibly heart failure can be performed.
1. American Heart
Association. Heart Disease and Stroke Statistics-2005 update
, Dallas, TX: American Heart
2. Belardinelli, R., D. Georgiou, G. Cianci, and A. Purcaro. Randomized, controlled trial of long-term moderate exercise
training in chronic heart
failure: effects on functional capacity, quality of life, and clinical outcome. Circulation
3. Calderone, A., N. Takahashi, N. J. Izzo Jr, C. M. Thaik, and W. S. Colucci. Pressure- and volume-induced left ventricular hypertrophies are associated with distinct myocyte phenotypes and differential induction of peptide growth factor mRNAs. Circulation
4. Emter, C. A., S. A. McCune, G. C. Sparagna, M. J. Radin, and R. L. Moore. Low-intensity exercise
training delays the onset of decompensated heart
failure in the Spontaneously Hypertensive Heart
Failure (SHHF) rat. Am. J. Physiol. Heart Circ. Physiol.
5. Fields, L. E., V. L. Burt, J. A. Cutler, J. Hughes, E. J. Roccella, and P. Sorlie. The burden of adult hypertension
in the United States 1999 to 2000. A rising tide. Hypertension
6. Fouad, F. M., J. M. Slominski, and R. C. Tarazi. Left ventricular diastolic function in hypertension
: relation to left ventricular mass and systolic function. J. Am. Coll. Cardiol.
7. Frohlich, E. D., C. Apstein, A. V. Chobanian,et al. The heart
. N. Engl. J. Med.
8. Guazzi, M., D. A. Brenner, C. S. Apstein, and K. W. Saupe. Exercise
intolerance in rats
with hypertensive heart
disease is associated with impaired diastolic relaxation. Hypertension
9. Inoko, M., Y. Kihara, I. Morii, H. Fujiwara, and S. Sasayama. Transition from compensatory hypertrophy to dilated, failing left ventricles in Dahl salt-sensitive rats
. Am. J. Physiol.
10. MacDonnell, S. M., H. Kubo, D. L. Crabbe, et al. Improved myocardial beta adrenergic responsiveness and signaling with exercise
training in hypertension
11. McCune, S., S. Park, M. J. Radin, et al. SHHF/Mcc-facp rat model: effect of gender and genotype on age of expression of metabolic complications and congestive heart
failure and on response to drug therapy. In: Lessons from Animal Diabetes
, E. Shafrir (Ed.). London: Smith-Gorden, 1995, pp. 255-273.
12. Overton, J. M., J. M. VanNess, and H. J. Takata. Effects of chronic exercise
on blood pressure in Dahl salt-sensitive rats
. Am. J. Hypertens.
11(1 Pt 1):73-80, 1998.
13. Pfeffer, M. A., J. M. Pfeffer, I. Mirsky, and J. Iwai. Cardiac hypertrophy and performance of Dahl hypertensive rats
on graded salt diets. Hypertension
14. Pina, I. L., C. S. Apstein, G. J. Balady, et al. Exercise
failure: a statement from the American Heart
Association Committee on Exercise
, Rehabilitation, and Prevention. Circulation
15. Savage, M. V., C. P. Mackie, and G. F. Bolter. Effect of exercise
on the development of salt-induced hypertension
in Dahl-S rats
. J. Hypertens.
16. Shepherd, R. E., M. L. Kuehne, K. A. Kenno, J. L. Dursstine, T. W. Balon, and J. P. Rapp. Attenuation of blood pressure increases in Dahl salt-sensitive rats
. J. Appl. Physiol.
17. Smar, N., and T. H. Marwick. Exercise
training for patients with heart
failure: a systematic review of factors that improve mortality and morbidity. Am. J. Med.
18. Tipton, C. M. Exercise
, training and hypertension
: an update. Exerc. Sport Sci. Rev.
19. Tipton, C. M., J. M. Overton, E. B. Pepin, J. G. Edwards, J. Wegner, and E. M. Youmans. Influence of exercise
training on the resting blood pressures of Dahl rats
. J. Appl. Physiol.
Keywords:©2006The American College of Sports Medicine
EXERCISE; HYPERTENSION; EXPERIMENTAL HYPERTROPHY; HEART; RATS