The development of hypertension and hyperaldosteronism in a rodent model of life-long obesity

Abstract

Aldosterone has been linked to the deleterious cardiovascular effects of obesity in humans. The association of aldosterone with obesity in rodents is less well defined, particularly in models of diet-induced obesity. We hypothesized that adrenal aldosterone production and aldosterone synthase expression would be increased in rats with obesity-induced hypertension. Male Sprague Dawley rats were fed a high-fat (HF: 36% fat) or control diet from 3 wk of age, and mean arterial pressure (MAP) was measured by telemetry. MAP was increased after 4 wk of HF diet; this was 6 wk before changes in body weight. Mineralocorticoid receptor antagonism did not prevent the HF-induced increase in MAP. After 17 wk on the diets, HF rats had increased body and fat weights (abdominal and epididymal) and were insulin resistant (Homeostasis Model Assessment index: 3.53 ± 0.43 vs. 8.52 ± 1.77; control vs. HF, P < 0.05). Plasma aldosterone levels were increased in the HF rats (64.14 ± 14.96 vs. 206.25 ± 47.55 pg/ml; control vs. HF, P < 0.05). This occurred independently of plasma renin activity (4.8 ± 0.92 vs. 4.73 ± 0.66 ng/ml/h, control vs. HF). The increase in aldosterone was accompanied by a 2-fold increase in adrenal aldosterone synthase mRNA expression and zona glomerulosa hypertrophy. Rats were also studied after 8 wk of HF diet, a time when MAP, but not body weight, was increased. At this time plasma aldosterone was unchanged but plasma renin activity was increased (4.4 ± 0.5 vs. 8.1 ± 1.3 ng/ml/h; control vs. HF, P < 0.05). These studies suggest that rats fed a HF diet from weaning may be a useful model for studying obesity-associated hyperaldosteronism.

Fig. 1.

Feeding rats a HF diet from 3 wk of age increased body weight (A), MAP (B), and HR (C). Blood pressure and HR were measured by telemetry (n = 6 for HF and n = 7 for control; * indicates a significant difference from control).

Fig. 2.

Plasma aldosterone (A), PRA (B), and the aldosterone- PRA ratio (C) differ temporally with the development of obesity. Aldosterone and PRA were measured by RIA (n = 5 for 8-wk control, n = 6 for 8-wk HF, and n = 7 for 17 week HF and control; * indicates a significant difference from the appropriate age-matched control).

Fig. 3.

Rats fed a HF diet exhibit ZG hypertrophy. A, Representative slices of adrenal glands from rats fed the HF and control diets. B, Areas of the individual regions of the adrenal. C, Those regions expressed as a percentage of the adrenal area (n = 7 for controls and 8 for the HF; * indicates a significant difference from control).

Fig. 4.

MR antagonism with canrenoic acid had no effect on MAP (A) or HR (B) in rats fed the HF diet. MAP and HR were measured by telemetry, the results shown are for the last week of the study. Results were analyzed by one-way ANOVA (P = 0.03 for MAP and 0.03 for HR) (n = 7 for control, n = 6 for HF, and n = 7 for HF+CAN; * indicates a significant difference from control after Bonferroni correction).

Fig. 5.

Rats fed the HF diet exhibited MRA remodeling as evidenced by an increase in the vessel wall thickness (A) and the wall-lumen ratio (B). Canrenoic acid treatment prevented the vessel remodeling as assessed by pressure myography under zero flow and calcium-free conditions (n = 7 for control, n = 7 for HF, and n = 8 for HF+CAN; * indicates a significant difference by two-way repeated-measures ANOVA).