- Email: [email protected]
Effect of life in a constant light environment on the course of hypertension in Dahl rats
Physiology& Behavior,Vol. 53, pp. 1219-1222, 1993
0031-9384/93 $6.00 + .00 1993 Pergamon Press Ltd.
Printed in the USA.
BRIEF COMMUNICATION
Effect of Life in a Constant Light Environment on the Course of Hypertension in Dahl Rats BENJAMIN
H. N A T E L S O N , l R I C H A R D J. S E R V A T I U S , W A L T E R A N D J O H N E. O T T E N W E L L E R
N. T A P P , J E N N I F E R
L. G R O S S
Neurobehavioral Unit (127A), VA Medical Center, East Orange, N J 07018 and Department o f Neurosciences, N e w Jersey Medical School, Newark, N J 07103 R e c e i v e d 8 S e p t e m b e r 1992 NATELSON, B. H., R. J. SERVATIUS, W. N. TAPP, J. L. GROSS AND J. E. OTTENWELLER. Effect of life in a constant light enviromnent on the course of hypertension in Dahl rats. PHYSIOL BEHAV 53(6) 1219-1222, 1993.--An important goal for biobehavioral scientists is to evaluate treatments that might extend life in the presence and absence of disease. The prototypic example of such a treatment is food restriction. Importantly, we have shown that exposure to a life-long environment of constant light extends life in hamsters with severe, life-threatening heart disease. The purpose of this experiment was to determine whether constant light would also extend the life of rats with an inherited form of hypertension. Constant light neither delayed the progression of hypertension nor extended life in this model. These data suggest that constant light may have a more limited use as an experimental therapeutic modality to extend life as compared to food restriction. Hypertension
Stress
Longevity
Constant light
Spontaneous
T H E only treatment that is known to increase longevity across a wide variety of species, both in the presence and absence of disease, is food restriction (2). Because of the importance of developing other biobehavioral manipulations that would extend life, our finding that exposure to an environment of constant light extended life in hamsters with heart disease seemed particularly important (3,6-8). The purpose of this experiment was to determine whether the therapeutic effect of constant light could be extended to another animal model of disease--a rat with a genetic trait to develop hypertension of such a magnitude that lifespan is significantly shortened (5). One reason for choosing a rat with genetic hypertension was an earlier report which noted that allowing spontaneously hypertensive rats to live in constant dark slowed the progression of their hypertension (1). This finding resembled the therapeutic effect we had achieved with constant light and supported our hypothesis that such manipulations had their health-enhancing effects via alterations of the biological clock. METHOD Male R a p p - D a h l salt-sensitive rats (n = 52) were obtained from Harlan Sprague-Dawley (Indianapolis, IN). Rats were 4
Feeding
weeks old and weighed 100-175 g on arrival. They were individually housed in shoebox cages and maintained on a 12:12 h light:dark cycle with the onset of light at 0700 h. They had free access to tap water and Purina Rodent Laboratory Chow containing 0.28% Na + by dry weight. Two weeks after arrival, the rats were habituated to the blood pressure apparatus for 30-min periods for 7 days. In these sessions, rats were placed into clear, Plexiglas restraint tubes (3" diameter) and a photoelectrically sensitive sensor in an inflatable cuff (B60, IITC Life Science, Inc., Woodland Hills, CA) was placed on their tails. To assure vasodilation during blood pressure measurements, the temperature was maintained between 27 and 29°C in the room where blood pressures were taken. Blood pressures (BPs) were taken the week following habituation (i.e., the 4th week after arrival). To measure BP, rats were transferred to the BP room and placed in the apparatus with a cuffon their tail. After a 10-15-min acclimation period, multiple BPs were taken in each session to obtain reliable physiological records. When artifacts were not evident on the records, only three readings were taken, but when artifacts were seen, as many as seven readings were made. From the multiple records, outliers were discarded if systolic BP values deviated by more than 3 standard deviations from others obtained in the same session.
J Requestsforrepfintsshouldbeaddressed to Be~amin H. Natelson, Neurobehavioral Unit(127A), VAMC, 385 Tremont Avenue, East Orange, NJ 07018-1095.
1219
1220
NATH.S()N
t~ I ,~,l
moo + A ÷
E uJ er
I.I.I
nO. a
8 m rJ n
O)
150
100
1110
2OO
25O
ANIMAL AGE IN DAYS
FIG. 1. Systolic blood pressure (+SEM) in mmHg measured from ages 1 to 8 months in Rapp-Dahl rats. Rats housed in constant light (top line) had higher blood pressures than those in LD until 5 months of age. Differences: +p < 0.05.
The measures for a session were averaged a n d used for subseq u e n t analyses. Rats were stratified on their systolic BPs a n d then r a n d o m l y assigned in pairs to either constant light (LL) (n = 25) or a 12: 12 h light:dark cycle (LD) (n = 26) group. Initial body weights
1.0
0.8
........... m ]
were equivalent between rats in L L ( m e a n = 295.5 g) and LD ( m e a n = 287.8 g). Blood pressures were measured at m o n t h l y intervals. After 7 monthly BP measurements, animal death made further analysis of the m e a n systolic pressures statistically problematic because
!_, i.
=) it. O )-
m O ¢t-
0.e ¸
0.4 -
.J < z O z 02' O o
~ "
"1
!1 k.. . . . . I
0.0'
DEATH AGE (DAYS)
FIG. 2. Survival curves of Rapp--Dahl rats in constant light (LL; solid lines) and in LD 12:12 (LD: dashed line). No significant difference was found for rats living in the two lighting conditions.
CONSTANT LIGHT AND RAT HYPERTENSION
1221
÷ 4-
_O
300-
ANIMAL AGE IN DAYS
FIG. 3. Body weights (g _+ SEM) in Rapp-Dahl rats measured from ages 1 to 8 months. Weights were the same in the two lightingconditions for the first 5 months of their lives. Then, despite food intake being the same between the two groups, rats reared in constant light weighed significantly more than those in LD. Differences: +p < 0.05.
data censure was related to the treatment under study. Thus, only the first seven BP measures are reported. Body weights were also measured throughout the lifespans of the rats when BP measurements were taken. Finally, food intake was measured daily. Within 24 h after death, rats were necropsied, and heart, kidney, testes, adrenal, and lung weights were taken. In addition, pleural and peritoneal fluids were collected and weighed. RESULTS
Systolic BP The systolic BPs were analyzed with a 2 × 7 (light regimen × age) mixed analysis of variance (ANOVA). The main effects of light regimen, F(I, 40) = 9.64, and age, F(6, 235) = 86.35 (both p < 0.001), were significant. These were qualified by the significant light regimen × age interaction, F(6, 235) = 2.95, p < 0.01 (see Fig. 1). At the start of the experiment, when rats were 2 months old, systolic BPs for rats in the two light regimens were equivalent (LL mean = 163.8 mmHg, LD mean = 166.7 mmHg). Dunnett's tests indicated that the mean systolic BP of the LL rats was higher than that in the LD rats when rats were 94 days old (tD = 1.81), and when rats were 130 days old (tD = 1.97) (both p < 0.05). Systolic BP then leveled offand was equivalent for the two groups when rats were 158, 193, and 225 days old. Then, on the final BP measurement, when rats were 248 days old, BPs for the LL group were again higher than those for the LD group (tD = 2.43, p < 0.01). Because of the possibility that deaths in any one group from hypertension might bias the analysis of BPs in surviving rats, we did another analysis based on paired data. To do this, we took the BPs of rat pairs (formed when rats were stratified for initial BP) in which both lived through the first 6 measurement days (n = 10 pairs).
The 2 x 6 (light regimen X age) mixed ANOVA yielded significant main effects of light regimen, F(1, 18) = 7.09, and age, F(5, 90) = 49.22 (both p < 0.01 ). Consistent with the analysis of the full data set, LL rats of a pair exhibited higher mean systolic BPs when they were 3, 4, and 8 months old (tDs = 1.77, 2.48, and 1.67, respectively, all p < 0.05).
Longevity Kaplan-Meier estimates of the conditional probability of survival indicated that there were no differences in longevity between the two groups (X2 = 0.2, p = 0.63) (see Fig. 2). The median death ages for LL and LD rats were 259 and 254 days, respectively.
Food Intake and Body Weight To rule out the possibility that differences in food intake and/or body weight might contribute to any effect on longevity, we monitored food intake and body weight. The two treatment groups exhibited different patterns of feeding. Whereas the pattern of feeding of the LD rats remained relatively constant over days, the food intake of LL rats waxed and waned with rats undereating for half the week and then overeating for the rest of the week. However, total food consumption of the two groups over the 1-week period was equivalent. Of all the measurements taken, food intake between the two groups diverged significantly across one 2-week period only. When this occurred, we yoked the LL groups' feeding to the LD group. Subsequently, total consumption of the two groups reconverged. Analysis of body weights revealed a significant main effect of age, F(6, 240) = 1223.39, and a light regimen X age interaction, F(6, 240) = 2.21 (both p <0.05) (see Fig. 3). Body weights increased at the same rate for LL and LD rats for the first 5 months of the experiment. However, LL rats exhibited higher
1222
NAIllSON
body weights at 193, 225, and 248 days of age (tDs = 3.32, 4.06, and 6.66, respectively, all p < 0.01). Obviously, metabolic dill ferences across the lighting conditions would have to exist to explain these results.
Necrop,U, After adjustment for body weight, only adrenal weight showed statistically significant differences between groups. The adrenals of LL rats were heavier than those of LD rats, t(48) = 2.18, p < 0.05. DISCUSSION In contrast to food restriction, which seems to extend life in a variety of animals and in the face of many different diseases (2), the life-extending effects of living in constant light appear more limited. Although that treatment was effective in delaying the progression of heart failure and extending the life of cardiomyopathic (CM) hamsters, it neither slowed the progression of hypertension in Rapp-Dahl rats with inherited hypertension nor did it extend their lives. In fact, our data suggest that life in constant light exacerbated the hypertensive process at least until rats were 5 months old. Prior efforts to determine the effects of atypical illumination schedules reported equivocal results in healthy rats. In evaluating those studies, we reasoned that diverse disease processes were probably the cause of death in aging populations of rats. If atypical illumination schedules extended life from one disease process and shortened it from another disease process, the net result
I I
\!
would be no effect. Because of that line of thinking, we turned our attention to the CM hamster, whose life is significantly shortened by the lethal process of congestixe hcart faiturc (4). Those experiments were a success: ('M hamsters li~ing in constant light showed a delay in the rate of development of signs of heart thilure, sustained more severe indices of failure, and lived longer than those on standard I D regimens i{~). Obviously, an important next step would be to see if constanl Light was protective in other animal models of disease. We chose to study a rat that developed hypertension on a genetic basis tbr several reasons. First, by mechanisms different from those in the CM hamster, the hypertensive animal also frequently develops congestive heart failure, a, nd second, a biobehavioral manipulation--allowing rats to live in constant dark--delayed the development of hypertension in spontaneously hypertensive rats ( 1). The lack of protection of constant light in the Rapp-Dahl spontaneously hypertensive rat suggests a limited generalizability of using constant light to extend life. However, a difficulty in interpretation lies with the nature of the hypertensive process. Although heart failure is a c o m m o n accompaniment of malignant hypertension, other life-threatening processes also occur, such as intracerebral hemorrhage and renal failure. Perhaps constant light delayed the process of heart failure but exacerbated one of the other pathophysiological concomitants of malignant hypertension. Further experiments will be needed to evaluate this possibility. A(KNOWLkDGEMENI This work was supported by VA medical research funds.
REFERENCES 1. Lais, L. T.; Bhatnagar, R. A.; Brody, M. J. Inhibition by dark adaptation of the progress of hypertension in the spontaneously hypertensive rat (SHR). Circ. Res. 34-35(Suppl. I):155-160; 1974. 2. Masoro, E. J.; Shimokawa, I.; Yu, B. P. Retardation of the aging processes in rats by food restriction. Ann. NY Acad. Sci. 621:337352: 1991. 3. Natelson, B. H.; Tapp, W. N.: Drastal, S.; Gross, J.; Ottenwetler, J. E. Constant light extends life in hamsters with heart disease. Proc. Soc. Exp. Biol. Med. 202:69-74; 1993. 4. Ottenweller, J. E.; Tapp, W. N.; Chen, T. S.; Natelson, B. H. Cardiovascular aging in Syrian hamsters: Similarities between normal aging and disease. Exp. Aging Res. 13:73-84: 1987.
5. Rapp, J. P. Dahl salt-susceptible and salt-resistant rats: A review. Hypertension 4:753-763; 1982. 6. Tapp, W. N.; Natelson, B. H. Life extension in heart disease: An animal model. Lancet i:238-240; 1986. 7. Tapp, W. N.; Natelson, B. H.; Khazam, C.: Ottenweller, J. E. Gonadal function during prolongation of life produced by constant light in hamsters with heart failure. Physiol. Behav. 40:243-246: 1987. 8. Tapp, W. N.: Ottenweller, J. E.: Natelson, B. H. Effect ofdift~rent Nght-dark schedules on survival from heart failure. Life Sci. 46:17391746: 1990.
0031-9384/93 $6.00 + .00 1993 Pergamon Press Ltd.
Printed in the USA.
BRIEF COMMUNICATION
Effect of Life in a Constant Light Environment on the Course of Hypertension in Dahl Rats BENJAMIN
H. N A T E L S O N , l R I C H A R D J. S E R V A T I U S , W A L T E R A N D J O H N E. O T T E N W E L L E R
N. T A P P , J E N N I F E R
L. G R O S S
Neurobehavioral Unit (127A), VA Medical Center, East Orange, N J 07018 and Department o f Neurosciences, N e w Jersey Medical School, Newark, N J 07103 R e c e i v e d 8 S e p t e m b e r 1992 NATELSON, B. H., R. J. SERVATIUS, W. N. TAPP, J. L. GROSS AND J. E. OTTENWELLER. Effect of life in a constant light enviromnent on the course of hypertension in Dahl rats. PHYSIOL BEHAV 53(6) 1219-1222, 1993.--An important goal for biobehavioral scientists is to evaluate treatments that might extend life in the presence and absence of disease. The prototypic example of such a treatment is food restriction. Importantly, we have shown that exposure to a life-long environment of constant light extends life in hamsters with severe, life-threatening heart disease. The purpose of this experiment was to determine whether constant light would also extend the life of rats with an inherited form of hypertension. Constant light neither delayed the progression of hypertension nor extended life in this model. These data suggest that constant light may have a more limited use as an experimental therapeutic modality to extend life as compared to food restriction. Hypertension
Stress
Longevity
Constant light
Spontaneous
T H E only treatment that is known to increase longevity across a wide variety of species, both in the presence and absence of disease, is food restriction (2). Because of the importance of developing other biobehavioral manipulations that would extend life, our finding that exposure to an environment of constant light extended life in hamsters with heart disease seemed particularly important (3,6-8). The purpose of this experiment was to determine whether the therapeutic effect of constant light could be extended to another animal model of disease--a rat with a genetic trait to develop hypertension of such a magnitude that lifespan is significantly shortened (5). One reason for choosing a rat with genetic hypertension was an earlier report which noted that allowing spontaneously hypertensive rats to live in constant dark slowed the progression of their hypertension (1). This finding resembled the therapeutic effect we had achieved with constant light and supported our hypothesis that such manipulations had their health-enhancing effects via alterations of the biological clock. METHOD Male R a p p - D a h l salt-sensitive rats (n = 52) were obtained from Harlan Sprague-Dawley (Indianapolis, IN). Rats were 4
Feeding
weeks old and weighed 100-175 g on arrival. They were individually housed in shoebox cages and maintained on a 12:12 h light:dark cycle with the onset of light at 0700 h. They had free access to tap water and Purina Rodent Laboratory Chow containing 0.28% Na + by dry weight. Two weeks after arrival, the rats were habituated to the blood pressure apparatus for 30-min periods for 7 days. In these sessions, rats were placed into clear, Plexiglas restraint tubes (3" diameter) and a photoelectrically sensitive sensor in an inflatable cuff (B60, IITC Life Science, Inc., Woodland Hills, CA) was placed on their tails. To assure vasodilation during blood pressure measurements, the temperature was maintained between 27 and 29°C in the room where blood pressures were taken. Blood pressures (BPs) were taken the week following habituation (i.e., the 4th week after arrival). To measure BP, rats were transferred to the BP room and placed in the apparatus with a cuffon their tail. After a 10-15-min acclimation period, multiple BPs were taken in each session to obtain reliable physiological records. When artifacts were not evident on the records, only three readings were taken, but when artifacts were seen, as many as seven readings were made. From the multiple records, outliers were discarded if systolic BP values deviated by more than 3 standard deviations from others obtained in the same session.
J Requestsforrepfintsshouldbeaddressed to Be~amin H. Natelson, Neurobehavioral Unit(127A), VAMC, 385 Tremont Avenue, East Orange, NJ 07018-1095.
1219
1220
NATH.S()N
t~ I ,~,l
moo + A ÷
E uJ er
I.I.I
nO. a
8 m rJ n
O)
150
100
1110
2OO
25O
ANIMAL AGE IN DAYS
FIG. 1. Systolic blood pressure (+SEM) in mmHg measured from ages 1 to 8 months in Rapp-Dahl rats. Rats housed in constant light (top line) had higher blood pressures than those in LD until 5 months of age. Differences: +p < 0.05.
The measures for a session were averaged a n d used for subseq u e n t analyses. Rats were stratified on their systolic BPs a n d then r a n d o m l y assigned in pairs to either constant light (LL) (n = 25) or a 12: 12 h light:dark cycle (LD) (n = 26) group. Initial body weights
1.0
0.8
........... m ]
were equivalent between rats in L L ( m e a n = 295.5 g) and LD ( m e a n = 287.8 g). Blood pressures were measured at m o n t h l y intervals. After 7 monthly BP measurements, animal death made further analysis of the m e a n systolic pressures statistically problematic because
!_, i.
=) it. O )-
m O ¢t-
0.e ¸
0.4 -
.J < z O z 02' O o
~ "
"1
!1 k.. . . . . I
0.0'
DEATH AGE (DAYS)
FIG. 2. Survival curves of Rapp--Dahl rats in constant light (LL; solid lines) and in LD 12:12 (LD: dashed line). No significant difference was found for rats living in the two lighting conditions.
CONSTANT LIGHT AND RAT HYPERTENSION
1221
÷ 4-
_O
300-
ANIMAL AGE IN DAYS
FIG. 3. Body weights (g _+ SEM) in Rapp-Dahl rats measured from ages 1 to 8 months. Weights were the same in the two lightingconditions for the first 5 months of their lives. Then, despite food intake being the same between the two groups, rats reared in constant light weighed significantly more than those in LD. Differences: +p < 0.05.
data censure was related to the treatment under study. Thus, only the first seven BP measures are reported. Body weights were also measured throughout the lifespans of the rats when BP measurements were taken. Finally, food intake was measured daily. Within 24 h after death, rats were necropsied, and heart, kidney, testes, adrenal, and lung weights were taken. In addition, pleural and peritoneal fluids were collected and weighed. RESULTS
Systolic BP The systolic BPs were analyzed with a 2 × 7 (light regimen × age) mixed analysis of variance (ANOVA). The main effects of light regimen, F(I, 40) = 9.64, and age, F(6, 235) = 86.35 (both p < 0.001), were significant. These were qualified by the significant light regimen × age interaction, F(6, 235) = 2.95, p < 0.01 (see Fig. 1). At the start of the experiment, when rats were 2 months old, systolic BPs for rats in the two light regimens were equivalent (LL mean = 163.8 mmHg, LD mean = 166.7 mmHg). Dunnett's tests indicated that the mean systolic BP of the LL rats was higher than that in the LD rats when rats were 94 days old (tD = 1.81), and when rats were 130 days old (tD = 1.97) (both p < 0.05). Systolic BP then leveled offand was equivalent for the two groups when rats were 158, 193, and 225 days old. Then, on the final BP measurement, when rats were 248 days old, BPs for the LL group were again higher than those for the LD group (tD = 2.43, p < 0.01). Because of the possibility that deaths in any one group from hypertension might bias the analysis of BPs in surviving rats, we did another analysis based on paired data. To do this, we took the BPs of rat pairs (formed when rats were stratified for initial BP) in which both lived through the first 6 measurement days (n = 10 pairs).
The 2 x 6 (light regimen X age) mixed ANOVA yielded significant main effects of light regimen, F(1, 18) = 7.09, and age, F(5, 90) = 49.22 (both p < 0.01 ). Consistent with the analysis of the full data set, LL rats of a pair exhibited higher mean systolic BPs when they were 3, 4, and 8 months old (tDs = 1.77, 2.48, and 1.67, respectively, all p < 0.05).
Longevity Kaplan-Meier estimates of the conditional probability of survival indicated that there were no differences in longevity between the two groups (X2 = 0.2, p = 0.63) (see Fig. 2). The median death ages for LL and LD rats were 259 and 254 days, respectively.
Food Intake and Body Weight To rule out the possibility that differences in food intake and/or body weight might contribute to any effect on longevity, we monitored food intake and body weight. The two treatment groups exhibited different patterns of feeding. Whereas the pattern of feeding of the LD rats remained relatively constant over days, the food intake of LL rats waxed and waned with rats undereating for half the week and then overeating for the rest of the week. However, total food consumption of the two groups over the 1-week period was equivalent. Of all the measurements taken, food intake between the two groups diverged significantly across one 2-week period only. When this occurred, we yoked the LL groups' feeding to the LD group. Subsequently, total consumption of the two groups reconverged. Analysis of body weights revealed a significant main effect of age, F(6, 240) = 1223.39, and a light regimen X age interaction, F(6, 240) = 2.21 (both p <0.05) (see Fig. 3). Body weights increased at the same rate for LL and LD rats for the first 5 months of the experiment. However, LL rats exhibited higher
1222
NAIllSON
body weights at 193, 225, and 248 days of age (tDs = 3.32, 4.06, and 6.66, respectively, all p < 0.01). Obviously, metabolic dill ferences across the lighting conditions would have to exist to explain these results.
Necrop,U, After adjustment for body weight, only adrenal weight showed statistically significant differences between groups. The adrenals of LL rats were heavier than those of LD rats, t(48) = 2.18, p < 0.05. DISCUSSION In contrast to food restriction, which seems to extend life in a variety of animals and in the face of many different diseases (2), the life-extending effects of living in constant light appear more limited. Although that treatment was effective in delaying the progression of heart failure and extending the life of cardiomyopathic (CM) hamsters, it neither slowed the progression of hypertension in Rapp-Dahl rats with inherited hypertension nor did it extend their lives. In fact, our data suggest that life in constant light exacerbated the hypertensive process at least until rats were 5 months old. Prior efforts to determine the effects of atypical illumination schedules reported equivocal results in healthy rats. In evaluating those studies, we reasoned that diverse disease processes were probably the cause of death in aging populations of rats. If atypical illumination schedules extended life from one disease process and shortened it from another disease process, the net result
I I
\!
would be no effect. Because of that line of thinking, we turned our attention to the CM hamster, whose life is significantly shortened by the lethal process of congestixe hcart faiturc (4). Those experiments were a success: ('M hamsters li~ing in constant light showed a delay in the rate of development of signs of heart thilure, sustained more severe indices of failure, and lived longer than those on standard I D regimens i{~). Obviously, an important next step would be to see if constanl Light was protective in other animal models of disease. We chose to study a rat that developed hypertension on a genetic basis tbr several reasons. First, by mechanisms different from those in the CM hamster, the hypertensive animal also frequently develops congestive heart failure, a, nd second, a biobehavioral manipulation--allowing rats to live in constant dark--delayed the development of hypertension in spontaneously hypertensive rats ( 1). The lack of protection of constant light in the Rapp-Dahl spontaneously hypertensive rat suggests a limited generalizability of using constant light to extend life. However, a difficulty in interpretation lies with the nature of the hypertensive process. Although heart failure is a c o m m o n accompaniment of malignant hypertension, other life-threatening processes also occur, such as intracerebral hemorrhage and renal failure. Perhaps constant light delayed the process of heart failure but exacerbated one of the other pathophysiological concomitants of malignant hypertension. Further experiments will be needed to evaluate this possibility. A(KNOWLkDGEMENI This work was supported by VA medical research funds.
REFERENCES 1. Lais, L. T.; Bhatnagar, R. A.; Brody, M. J. Inhibition by dark adaptation of the progress of hypertension in the spontaneously hypertensive rat (SHR). Circ. Res. 34-35(Suppl. I):155-160; 1974. 2. Masoro, E. J.; Shimokawa, I.; Yu, B. P. Retardation of the aging processes in rats by food restriction. Ann. NY Acad. Sci. 621:337352: 1991. 3. Natelson, B. H.; Tapp, W. N.: Drastal, S.; Gross, J.; Ottenwetler, J. E. Constant light extends life in hamsters with heart disease. Proc. Soc. Exp. Biol. Med. 202:69-74; 1993. 4. Ottenweller, J. E.; Tapp, W. N.; Chen, T. S.; Natelson, B. H. Cardiovascular aging in Syrian hamsters: Similarities between normal aging and disease. Exp. Aging Res. 13:73-84: 1987.
5. Rapp, J. P. Dahl salt-susceptible and salt-resistant rats: A review. Hypertension 4:753-763; 1982. 6. Tapp, W. N.; Natelson, B. H. Life extension in heart disease: An animal model. Lancet i:238-240; 1986. 7. Tapp, W. N.; Natelson, B. H.; Khazam, C.: Ottenweller, J. E. Gonadal function during prolongation of life produced by constant light in hamsters with heart failure. Physiol. Behav. 40:243-246: 1987. 8. Tapp, W. N.: Ottenweller, J. E.: Natelson, B. H. Effect ofdift~rent Nght-dark schedules on survival from heart failure. Life Sci. 46:17391746: 1990.