Caloric restriction lowers blood pressure in the spontaneously hypertensive rat

Metabolism Clinical atid Experimental VOL. XXVII,

PRELIMINARY

NO. 12

DECEMBER

1978

REPORT:

Caloric Restriction Lowers Blood Pressure in the Spontaneously Hypertensive Rat James

B. Young,

Deborah

Mullen,

In the spontaneously hypertensive rat (SHR), caloric restriction without sodium restriction is associated with reduced blood pressure. Four days of fasting lowered blood pressure 19% while 4 days of eating 50% of ad lib intake reduced blood pressure 10%.

and Lewis

Landsberg

Similar dietary changes had less effect on blood pressure in normotensive rats of the same strain (Wistar-Kyoto-WKY). These data are consistent with the hypothesis that caloric restriction lowers sympathetic activity.

T

HE SPONTANEOUSLY hypertensive rat (SHR), developed by Japanese investigators in the early 1960s is a widely employed animal model considered to resemble at least some forms of human essential hypertension. Although the exact pathophysiologic mechanisms leading to hypertension in the SHR are unknown, convincing evidence implicating heightened sympathoadrenal activity has been developed, particularly in the rapid blood pressure rise observed in SHR at 2-4 mo of age.le3 The role of the sympathoadrenal system in the maintenance of an elevated blood pressure in SHR in later life is less clear. In light of recent work from this laboratory indicating the importance of caloric intake in the regulation of sympathetic activity, 4,5the present study was designed to determine the influence of hypocaloric feeding upon blood pressure and pulse in SHR and control rats. The results show that caloric restriction produces a striking and highly significant reduction in blood pressure in the SHR. Fourteen SHR and 14 Wistar-Kyoto (WKY) rats (Charles River Breeding Laboratories, Wilmington, Mass.) were obtained at 7 wk of age and were fed a From the Thorndike Laboratory and the Department of Medicine, Harvard Medical School and Beth Israel Hospital, Boston, Mass. Receivedforpublication March 16, 1978. Supported in part by USPHS Grants AM-20378 and RR-76. Dr. Young is the recipient of USPHS Fellowship AM-05755. Address reprint requests to Dr. James B. Young, Department of Medicine, Beth Israel Hospital, 330 Brookline Avenue, Boston, Mass. 02215. 0 1978 by Grune & Stratton, Inc., 0026-0495/78/27/2-0001$01.00/0 Metabolism. Vol. 27, No. 12 (December), 1978

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diet of standard rat chow (Purina) and water ad lib except as noted below. Animals were housed 2 per single cage or 5 per double cage for the duration of the experiment. After 3 wk of acclimatization of the animals to the laboratory and to the blood pressure recording apparatus, the study began. Daily food intake was monitored during the control period and averaged 8.3 g per 100 g body weight for WKY and 8.4 for SHR. During experimental period I (50% feeding) the control groups of WKY and SHR animals were given 8 g of rat chow per 100 g body weight per day and the diet groups of animals 4 g. In period II (fasting) the control groups were fed as in period I while the diet groups were fasted. Both experimental periods lasted 4 days with blood pressure and pulse measurements being made on the second and fourth days. A hypotonic electrolyte solution containing 78 mEq/l Na and 15 mEq/ 1 K replaced the drinking water for both control and diet animals during periods I and II. Blood pressure was measured indirectly by the rat tail cuff method through a Physiograph recorder (Narco Bio Systems) and pulse rate by direct counting of the pulse tracing. Statistical comparisons utilized paired and unpaired Student’s t tests. For the first 3 wk of the study, during which baseline observations were made, pulse and blood pressure measurements were identical in control and diet groups for both WKY and SHR (Fig. 1). While blood pressure in WKY changed little during this period, blood pressure in SHR rats rose 17% from 142 mm Hg to 166. With 50% feeding (period I), blood pressure was 10% lower in underfed SHR (diet group) compared to normally fed SHR (control group) (161 f 2.1 mm Hg (mean i SEM) versus 178 f 2.3 on the fourth day, p < 0.001). No consistent difference was observed in pulse rate in SHR or blood pressure in WKY in response to change in diet. During the 4 days of fasting (period II) (Fig. 1) blood pressure in fasted SHR was 14% below control on day 2 (150 i 2.0 mm Hg versus 174 * 2.6, p < 0.001) and 19% below control on day 4 (144 f 2.0 versus 178 f 1.7, p < 0.001). On the final day of fasting, pulse rate in SHR was also 18% lower than control (337 f 12 beats per min versus 410 f 10, p < 0.001). In WKY, blood pressure was lower in fasting animals, but to a lesser extent than in SHR, being 4% lower on day 2 (117 + 2.2 mm Hg versus 122 + 2.1, not significant) and 7% on day 4 (110 * 2.1 versus 118 * 2.1,~ < 0.025); pulse rate was unaffected by fasting in WKY. Na intake did not change with fasting in SHR (averaging 3.9 f 0.4 mEq/rat/day on ad lib intake and 4.0 L 0.6 during fasting) and increased slightly in WKY during the four-day fast, from 3.0 * 0.2 mEq/rat/day to 5.2 f 0.3. After 7 days of ad lib feeding following the fasting period, blood pressures in previously fasted WKY and SHR were the same as their respective controls. This study shows that reducing dietary intake by 50% for 4 days significantly reduced the blood pressure of the spontaneously hypertensive rat by 10%. Total fast (with electrolyte replacement) reduced blood pressure significantly by the second day (14%) and with an even greater fall by the fourth day (19%). The normotensive WKY control rats had a significant blood pressure reduction after 4 days of total fast (7%), indicating that caloric restriction has less of a hypotensive effect in the normotensive animals. Weight loss without salt restriction in obese hypertensive patients has recently been shown to reduce blood pressure significantly.6 It is not clear whether weight loss or caloric restriction is responsible for the hypotensive effect. In this study, al-

CALORIC

RESTRICTION

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Days Fig. 1. Effect of caloric restriction on blood pressure in Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Ten-week-old WKY and SHR rats were fed rat chow and water ad libitum except during periods I and II. In period I, diet animals 10) ware fed 4 g rat chow per 100 g body weight while controls (01 received 8 g per 100 g body weight. During period II, diet animals were fasted while controls were fed as in period I. Both diet and control groups drank a hypotonic electrolyte solution (78 mEq/l NA and 15 mEq/l K) instead of water during periods I and II. Blood pressures were measured after the second and fourth days of the experimental diets. With 50% feeding, WKY did not gain weight while SHR weights fell 8.4% below control. After fasting WKY weights fell 10.7% and SHR 22.2% below control. One week of ad lib feeding restored weights in WKY to 87.8% and in SHR to 84.5% of control while blood pressure returned to control levels. Each of the 4 groups contained 7 animals.‘

though the SHR lost significantly more weight than the WKY control rats on the hypocaloric diet and during the fast, the rapid reduction in blood pressure (within 2 days) and the fact that blood pressure was restored to hypertensive levels after 1 wk of refeeding at a time when the restricted SHR group was still 5% below the control SHR in body weight, suggest that caloric restriction and not loss of weight is responsible for the fall in blood pressure in this study. Although not addressing directly the mechanism(s) involved in the hypotensive effect of caloric restriction the findings reported here are consistent with suppression of sympathetic activity in the calorically deprived animals. Recent work in our laboratory suggests that fasting is associated with an active suppression, rather than a passive withdrawal, of central sympathetic outflow.’ Thus, the finding of a greater hypotensive effect in the hypertensive animals is not surprising since sympatholytic therapy of all types has a greater effect on blood pressure in hypertensive as compared with normotensive animals whatever the underlying cause of the hypertension. Finally, the changes in blood pressure demonstrated here emphasize the importance of controlling caloric intake in all blood pressure studies involving SHR.

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