44
Hypertriglyceridemia in Dahl Rats: Effect of Sodium Intake and Gender G. M. Reaven, J. Twersky, Helen Ho and Helen Chang Department of Medicine, Stanford University School of Medicine and Geriatric Research, Education and Clinical Center, VA Medical Center, Palo Alto, California, U. S. A.
after removal of all food. Awake systolic blood pressure was measured at the same time in quietly restrained rats as described previously O'Donnell, Kasiske and Keane (1989) have recently {Hwang et al. 1987). In one series of experiments all measurements were made before and at weekly intervals for two weeks after increasshown that plasma triglyceride (TG) concentration is higher in Dahl ing the dietary content of the chow from 0.6 to 8 % NaCl. Results are salt-sensitive (S) than in Dahl salt-resistant (R) rats prior to salt feedexpressed as mean + SEM, and statistical comparisons made by oneing, and the difference between the two groups increased in response way analysis of variance (ANOVA) using a SAS program in a VAX 724 to a 4% NaCl diet. Hypertriglyceridemia has also been described in untreated patients with hypertension (Shieh, Shen, Fuh, Chen and Re- computer. aven 1987), as well as in rats with either spontaneous (Reaven and Chang, in press) or fructose-induced {Hwang, Ho, Hoffman and ReResults aven 1987) hypertension. The relationship between human and rodent hypertension is obscure, but the apparent ubiquitousness of the assoBody weight, blood pressure, and plasma TG conciation between hypertension and hypertriglyceridemia seems to centration in male Dahl S, Dahl R and S-D rats fed conventional rat make the phenomenon worthy of further study. chow are shown in Table 1. Although the weights of the three groups were essentially identical, plasma TG concentration was lowest in S-D rats, highest in Dahl S rats, and intermediate in Dahl R rats. All three Methods groups were significantly different from each other (P < 0.05—0.001, one-way ANOVA). In addition, blood pressure was higher in Dahl S Dahl salt-sensitive (S) and resistant (R) Brookhavenrats(P < 0.01)thanintheothertwogroups. derived rats were obtained from Harlan Sprague Dawley, Inc., Indianapolis, IN, as were control Sprague-Dawley rats. They were fed ad lib with conventional rat chow (Ralston Purina Co.), containing 0.6% Table 1 also lists the weight, blood pressure and plasma TG concentration, before and one and two weeks after the iniNaCl ad lib, which, in some experiments, was replaced with the same basic diet containing 8 % NaCl. Water was given ad lib, and rats were tiation of a 8 % NaCl diet in male Dahl S and Dahl R rats. These data demonstrate the divergent effect of a high salt diet on blood pressure of maintained on a 12 h light (0600-1800), dark (1800-0600) cycle. Plasma triglyceride concentration was measured {Wahlefeld 1974) on Dahl S and Dahl R rats, but plasma TG concentration did not change in either group in response to manipulation of dietary salt. Weight gain blood drawn from the tail vein of unanesthetized rats at 1400 h, 6 h
Table 1 Body weight, blood pressure and triglyceride concentration in male and female Sprague-Dawley (S-D) and Dahl salt-sensitive (S) and resistant (R) rats (mean ±SEM). Blood Pressure (mmHg) Basal
Weight (g) Group
Gender
S-D (n = 10) Dahl S (n = 10) Dahl R (n = 10)
Male Male Male
Group
Gender
Dahl S (n = 7) Dahl R (n = 7)
Male Male
Group
Gender
Basal
S-D ( = 10) S-D (n = 10) Dahl S (n = 10) DahlS (n10)
Female Male Female Male
235 + 2 253 + 2 239 + 2 226 ± 6
Basal
116 + 4 138 ± 6 123 ± 7
283 + 4 284 ± 7 276 + 8 Basal 260+15 261 ±11
Weight (g) 1 Wk* 311 + 11 299 + 4
2Wk* 333 + 12 319+ 14
Weight (g)
(mg/dl)
113± 13 205+11 155 ± 9
Blood Pressure (mmHg) Basal 1 Wk 2 Wk 147 ± 4 133 + 5
Triglyceride Basal
170±2 137 + 3
181 ± 6 141+4
Blood Pressure (mmHg) Basal 127 + 3 121+3 139 + 4 145 ± 2
Triglyceride (mg/dl) Basal 1 Wk 2 Wk 201 + 11 165 + 9
215±14 169±17
199 + 8 153+11
Triglyceride (mg/dl) Basal 106 + 5 12318 111 + 10 196 + 16
*1 and 2 weeks after initiation of a diet containing 8% NaCl.
Horm.metab.Res.23(1991)44-45 © Georg Thieme Verlag Stuttgart • New York
Received: 28 Sept. 1990
Accepted: 120ct. 1990
Downloaded by: Universite Laval. Copyrighted material.
Introduction
Hypertriglyceridemia in Dahl Rats
Table 1 also shows that plasma TG concentrations were essentially identical in female and male S-D rats and in female Dahl S rats, whereas plasma TG concentration was approximately twice as high in male Dahl S rats. This difference was highly statistically significant when compared to the other three groups (P < 0.001; one-way ANOVA). However, there were no differences between the plasma TG concentrations of male or female S-D and female Dahl S rats. It can also be seen that the increase in plasma TG concentration in male Dahl S rats was not related to obesity. Discussion The results confirm the earlier finding that plasma TG concentration is increased in Dahl S rats when they are eating conventional rat chow. However, this change in lipid metabolism of Dahl S rats appears to be gender-dependent, and is not seen in female Dahl S rats. Although previous studies in human beings (Wood, Stern, Silvers, Reaven and von der Groeben 1972) and rats (Reaven 1978) have revealed a tendency for plasma TG concentration to be higher in males than in females, these differences were markedly less than the case in Dahl S rats. By matching weights of male and female rats, differences in degree of obesity cannot account for the gender differences noted.
Since blood pressure increases within one week of placing Dahl S rats on a high salt diet, it is difficult to put into perspective an increase in plasma TG concentration reported to occur in Dahl S rats after 18 weeks of significant hypertension. In summary, both Dahl R and Dahl S rats are hypertriglyceridemic in comparison to weight-matched S-D rats. This difference exists before Dahl rats are placed on a high-salt diet, and is of greater magnitude in Dahl S rats. However, hypertriglyceridemia is only seen in male Dahl S rats. Plasma TG concentration in female Dahl S rats is comparable to values in S-D rats of either sex, and only one-half of the concentration of male Dahl S rats. Finally, the elevated plasma TG concentrations in Dahl S or Dahl R rats remain constant for a two-week period when dietary salt intake is raised, while blood pressure only increases in Dahl S rats. These results serve as another example of the association between high blood pressure and hypertriglyceridemia, as well as providing a new model in which to define the significance of this relationship.
Acknowledgements This work was supported by research grants from the Research Service of the Veterans Administration and the Sandoz Research Institute. References
The data presented have also shown that plasma TG Hwang, I.S., H. Ho, B. B. Hoffman, G. M. Reaven: Hypertension 10: concentration is increased above control in male Dahl R rats consum512-516(1987) ing conventional rat chow. Although at odds with the results of O'Don- O'Donnell, M. P., B. L. Kasiske, W. F. Keane: Am. J. Hypertens. 2: 9 nell, Kasiske and Keane (1989), the differences may be more apparent 13(1989) than real. Table 1 shows that plasma TG concentrations of male Dahl Reaven, G. M.: J. Gerontology 33:368-371 (1978) R rats are higher than in male S-D rats, but lower than values for male Reaven, G. M., H. Chang: Am. J. Hypertens. (in press) Dahl S rats. Since O'Donnell, Kasiske and Keane (1989) did not Shieh, S.-M., M. Shen, M. M.-T. Fuh, Y.-D. I. Chen, G. M. Reaven: directly compare S-D to Dahl R rats, they may have been unable to disAtherosclerosis 67:49-55 (1987) cern the fact that Dahl R rats were also relatively hypertriglyceridemic, Wahlefeld, A. W.: In: Methods of Enzymatic Analysis. H. V. Bergbut to a lesser degree than were Dahl S rats. meyer (ed.). New York, Academic Press (1984), pp. 1831 -1835 Wood, P.-D. S., M. P. Stern, A. Silvers, G. M. Reaven, J. von der GroeOur inability to detect differences in the impact of a ben:Circ.45:114-126(1972) high salt diet on plasma TG concentration in Dahl S and Dahl R rats may also be due to study design. We assessed dietary effect over a twoweek period, whereas O'Donnell, Kasiske and Keane (1989) carried Requests for reprints should be addressed to: out their studies for 18 weeks after initiation of the high salt diet. Plasma TG concentration was stable in Dahl R rats for the entire 18 Gerald M. Reaven, M. D. weeks. Plasma TG concentration in Dahl S rats also did not change GRECC(182-B) during the first 6 weeks of the 8% NaCl diet, but was higher after 18 weeks of the high-salt diet (O'Donnell, Kasiske mdKeane 1989). Thus, VA Medical Center 3801 Miranda Avenue the effect of a high salt diet on plasma TG concentration was limited to Palo Alto, CA 94304 (U. S. A.) Dahl S rats, and could only be seen after 18 weeks of a high salt diet.
Downloaded by: Universite Laval. Copyrighted material.
was also similar in the two groups. It should be noted that plasma TG concentration was higher in both Dahl S and Dahl R rats than in the control S-D rats seen in Table 1.
Horm. metab. Res. 23 (1991)
Hypertriglyceridemia in Dahl Rats: Effect of Sodium Intake and Gender G. M. Reaven, J. Twersky, Helen Ho and Helen Chang Department of Medicine, Stanford University School of Medicine and Geriatric Research, Education and Clinical Center, VA Medical Center, Palo Alto, California, U. S. A.
after removal of all food. Awake systolic blood pressure was measured at the same time in quietly restrained rats as described previously O'Donnell, Kasiske and Keane (1989) have recently {Hwang et al. 1987). In one series of experiments all measurements were made before and at weekly intervals for two weeks after increasshown that plasma triglyceride (TG) concentration is higher in Dahl ing the dietary content of the chow from 0.6 to 8 % NaCl. Results are salt-sensitive (S) than in Dahl salt-resistant (R) rats prior to salt feedexpressed as mean + SEM, and statistical comparisons made by oneing, and the difference between the two groups increased in response way analysis of variance (ANOVA) using a SAS program in a VAX 724 to a 4% NaCl diet. Hypertriglyceridemia has also been described in untreated patients with hypertension (Shieh, Shen, Fuh, Chen and Re- computer. aven 1987), as well as in rats with either spontaneous (Reaven and Chang, in press) or fructose-induced {Hwang, Ho, Hoffman and ReResults aven 1987) hypertension. The relationship between human and rodent hypertension is obscure, but the apparent ubiquitousness of the assoBody weight, blood pressure, and plasma TG conciation between hypertension and hypertriglyceridemia seems to centration in male Dahl S, Dahl R and S-D rats fed conventional rat make the phenomenon worthy of further study. chow are shown in Table 1. Although the weights of the three groups were essentially identical, plasma TG concentration was lowest in S-D rats, highest in Dahl S rats, and intermediate in Dahl R rats. All three Methods groups were significantly different from each other (P < 0.05—0.001, one-way ANOVA). In addition, blood pressure was higher in Dahl S Dahl salt-sensitive (S) and resistant (R) Brookhavenrats(P < 0.01)thanintheothertwogroups. derived rats were obtained from Harlan Sprague Dawley, Inc., Indianapolis, IN, as were control Sprague-Dawley rats. They were fed ad lib with conventional rat chow (Ralston Purina Co.), containing 0.6% Table 1 also lists the weight, blood pressure and plasma TG concentration, before and one and two weeks after the iniNaCl ad lib, which, in some experiments, was replaced with the same basic diet containing 8 % NaCl. Water was given ad lib, and rats were tiation of a 8 % NaCl diet in male Dahl S and Dahl R rats. These data demonstrate the divergent effect of a high salt diet on blood pressure of maintained on a 12 h light (0600-1800), dark (1800-0600) cycle. Plasma triglyceride concentration was measured {Wahlefeld 1974) on Dahl S and Dahl R rats, but plasma TG concentration did not change in either group in response to manipulation of dietary salt. Weight gain blood drawn from the tail vein of unanesthetized rats at 1400 h, 6 h
Table 1 Body weight, blood pressure and triglyceride concentration in male and female Sprague-Dawley (S-D) and Dahl salt-sensitive (S) and resistant (R) rats (mean ±SEM). Blood Pressure (mmHg) Basal
Weight (g) Group
Gender
S-D (n = 10) Dahl S (n = 10) Dahl R (n = 10)
Male Male Male
Group
Gender
Dahl S (n = 7) Dahl R (n = 7)
Male Male
Group
Gender
Basal
S-D ( = 10) S-D (n = 10) Dahl S (n = 10) DahlS (n10)
Female Male Female Male
235 + 2 253 + 2 239 + 2 226 ± 6
Basal
116 + 4 138 ± 6 123 ± 7
283 + 4 284 ± 7 276 + 8 Basal 260+15 261 ±11
Weight (g) 1 Wk* 311 + 11 299 + 4
2Wk* 333 + 12 319+ 14
Weight (g)
(mg/dl)
113± 13 205+11 155 ± 9
Blood Pressure (mmHg) Basal 1 Wk 2 Wk 147 ± 4 133 + 5
Triglyceride Basal
170±2 137 + 3
181 ± 6 141+4
Blood Pressure (mmHg) Basal 127 + 3 121+3 139 + 4 145 ± 2
Triglyceride (mg/dl) Basal 1 Wk 2 Wk 201 + 11 165 + 9
215±14 169±17
199 + 8 153+11
Triglyceride (mg/dl) Basal 106 + 5 12318 111 + 10 196 + 16
*1 and 2 weeks after initiation of a diet containing 8% NaCl.
Horm.metab.Res.23(1991)44-45 © Georg Thieme Verlag Stuttgart • New York
Received: 28 Sept. 1990
Accepted: 120ct. 1990
Downloaded by: Universite Laval. Copyrighted material.
Introduction
Hypertriglyceridemia in Dahl Rats
Table 1 also shows that plasma TG concentrations were essentially identical in female and male S-D rats and in female Dahl S rats, whereas plasma TG concentration was approximately twice as high in male Dahl S rats. This difference was highly statistically significant when compared to the other three groups (P < 0.001; one-way ANOVA). However, there were no differences between the plasma TG concentrations of male or female S-D and female Dahl S rats. It can also be seen that the increase in plasma TG concentration in male Dahl S rats was not related to obesity. Discussion The results confirm the earlier finding that plasma TG concentration is increased in Dahl S rats when they are eating conventional rat chow. However, this change in lipid metabolism of Dahl S rats appears to be gender-dependent, and is not seen in female Dahl S rats. Although previous studies in human beings (Wood, Stern, Silvers, Reaven and von der Groeben 1972) and rats (Reaven 1978) have revealed a tendency for plasma TG concentration to be higher in males than in females, these differences were markedly less than the case in Dahl S rats. By matching weights of male and female rats, differences in degree of obesity cannot account for the gender differences noted.
Since blood pressure increases within one week of placing Dahl S rats on a high salt diet, it is difficult to put into perspective an increase in plasma TG concentration reported to occur in Dahl S rats after 18 weeks of significant hypertension. In summary, both Dahl R and Dahl S rats are hypertriglyceridemic in comparison to weight-matched S-D rats. This difference exists before Dahl rats are placed on a high-salt diet, and is of greater magnitude in Dahl S rats. However, hypertriglyceridemia is only seen in male Dahl S rats. Plasma TG concentration in female Dahl S rats is comparable to values in S-D rats of either sex, and only one-half of the concentration of male Dahl S rats. Finally, the elevated plasma TG concentrations in Dahl S or Dahl R rats remain constant for a two-week period when dietary salt intake is raised, while blood pressure only increases in Dahl S rats. These results serve as another example of the association between high blood pressure and hypertriglyceridemia, as well as providing a new model in which to define the significance of this relationship.
Acknowledgements This work was supported by research grants from the Research Service of the Veterans Administration and the Sandoz Research Institute. References
The data presented have also shown that plasma TG Hwang, I.S., H. Ho, B. B. Hoffman, G. M. Reaven: Hypertension 10: concentration is increased above control in male Dahl R rats consum512-516(1987) ing conventional rat chow. Although at odds with the results of O'Don- O'Donnell, M. P., B. L. Kasiske, W. F. Keane: Am. J. Hypertens. 2: 9 nell, Kasiske and Keane (1989), the differences may be more apparent 13(1989) than real. Table 1 shows that plasma TG concentrations of male Dahl Reaven, G. M.: J. Gerontology 33:368-371 (1978) R rats are higher than in male S-D rats, but lower than values for male Reaven, G. M., H. Chang: Am. J. Hypertens. (in press) Dahl S rats. Since O'Donnell, Kasiske and Keane (1989) did not Shieh, S.-M., M. Shen, M. M.-T. Fuh, Y.-D. I. Chen, G. M. Reaven: directly compare S-D to Dahl R rats, they may have been unable to disAtherosclerosis 67:49-55 (1987) cern the fact that Dahl R rats were also relatively hypertriglyceridemic, Wahlefeld, A. W.: In: Methods of Enzymatic Analysis. H. V. Bergbut to a lesser degree than were Dahl S rats. meyer (ed.). New York, Academic Press (1984), pp. 1831 -1835 Wood, P.-D. S., M. P. Stern, A. Silvers, G. M. Reaven, J. von der GroeOur inability to detect differences in the impact of a ben:Circ.45:114-126(1972) high salt diet on plasma TG concentration in Dahl S and Dahl R rats may also be due to study design. We assessed dietary effect over a twoweek period, whereas O'Donnell, Kasiske and Keane (1989) carried Requests for reprints should be addressed to: out their studies for 18 weeks after initiation of the high salt diet. Plasma TG concentration was stable in Dahl R rats for the entire 18 Gerald M. Reaven, M. D. weeks. Plasma TG concentration in Dahl S rats also did not change GRECC(182-B) during the first 6 weeks of the 8% NaCl diet, but was higher after 18 weeks of the high-salt diet (O'Donnell, Kasiske mdKeane 1989). Thus, VA Medical Center 3801 Miranda Avenue the effect of a high salt diet on plasma TG concentration was limited to Palo Alto, CA 94304 (U. S. A.) Dahl S rats, and could only be seen after 18 weeks of a high salt diet.
Downloaded by: Universite Laval. Copyrighted material.
was also similar in the two groups. It should be noted that plasma TG concentration was higher in both Dahl S and Dahl R rats than in the control S-D rats seen in Table 1.
Horm. metab. Res. 23 (1991)
