Persistent Renin‐Angiotensin System Sensitization Months After Body Weight Recovery From Severe Food Restriction in Female Fischer Rats

BACKGROUND: Prior exposure to periods of severe food restriction (sFR) is associated with increased risk of developing hypertension and cardiovascular disease later in life. METHODS AND RESULTS: To investigate the mechanism of these long‐term adverse effects of sFR, 4‐month‐old female Fischer rats were divided in 2 groups and maintained on a normal diet ad libitum (control) or on an sFR diet with 60% reduction in daily food intake for 2 weeks that resulted in a 15% reduction in body weight. After the 2‐week sFR period ended, both groups received normal chow ad libitum for 3 months. Within 2 weeks after refeeding was initiated in the sFR group, body weight was restored to control levels; however, plasma angiotensinogen (1.3‐fold; P<0.05), Ang‐[1‐8] (2.0‐fold; P<0.05), and angiotensin‐converting enzyme activity (1.1‐fold; P<0.01) were all elevated 3 months after refeeding. Angiotensin type 1 receptor activity was also increased as evidenced by augmented pressor responses to angiotensin‐[1‐8] (P<0.01) and depressor responses to the angiotensin type 1 receptor antagonist, losartan (P<0.01) in the sFR group. CONCLUSIONS: These results indicate that sensitization of the renin‐angiotensin system persisted months after the sFR period ended. These findings may have implications for women who voluntarily or involuntarily experience an extended period of sFR and thus may be at increased risk of developing cardiovascular disease through sensitization of the renin‐angiotensin system even though their body weight, mean arterial pressure, and heart rate appear normal.