ACE inhibition reverses hypertension response sensitization (HTRS) and improves heart function in severe food-restricted (sFR) refed rats

Background: Acute periods of severe food restriction can impair cardiovascular function. Less understood are the long-term effects on cardiovascular function after the sFR period has ended. We previously found months after the sFR period ended and body weight (BW) recovered due to refeeding, that sFR-Refed rats exhibited increased angiotensin-converting enzyme (ACE) activity, larger increases in blood pressure (BP) after angiotensin (Ang)-[1-8] infusion (i.e., HTRS) and increased frequencies of ischemia-induced cardiac arrhythmias compared to control (Ctrl) rats. Aim: Determine the effect of transiently inhibiting ACE during refeeding on HTRS and cardiac arrhythmias in sFR-Refed rats. Methods: Female Fischer rats (3-months-old) were fed normal chow ad libitum (Ctrl) or a 60% caloric-restricted (sFR) diet for 2 weeks before being maintained on normal chow ad libitum. After 6 weeks of refeeding, these 2 groups were subdivided into vehicle (Veh, drinking water) or Cap (20mg/Kg, drinking water) treatment for 6 weeks (n=8/group). After a 1-week drug washout period, cardiac output (CO) was assessed by precision ultrasound and HTRS was determined by measuring BP responses to Ang-[1-8] infusion into the femoral vein. A separate cohort (n=8/group) was euthanized, and their isolated hearts were subjected to ischemia-reperfusion using a Langendorff preparation to assess the frequency of arrhythmias. Results: After 2 weeks of sFR, rats lost 15% of their initial BW [DFinal/Initial): Ctrl, 1.50±0.80 vs sFR, -15.4±1.1; p<0.001]. After 3 months of refeeding, there were no detectable differences in BW, BP, CO and heart rate among all 4 groups; The Ang-[1-8] pressor response remained higher in sFR-Refed-Veh compared to Ctrl while Cap treatment abolished this effect [DmmHg: Ctrl-Veh, 9.7±0.6; sFR-Refed-Veh, 14±1*; Ctrl+Cap, 11±0.4; sFR-Refed+Cap, 11±0.8; *p<0.02 vs Ctrl, same treatment; n=6-7]. The increased frequency of cardiac arrhythmias in the sFR group remained after 3 months of refeeding, while transient Cap treatment abolished this effect [(% of time in arrhythmia): Ctrl+Veh, 34±8; sFR-Refed+Veh, 68±9*; Ctrl+Cap, 12±2; sFR-Refed+Cap, 13±2, *p<0.02 vs Ctrl, same treatment; n=8]. Conclusion: Transient treatment with Cap abolished the HTRS and higher incidence of arrhythmias in female sFR-Refed rats. This research suggests short term ACE inhibitor treatment after prior exposure to periods of sFR may reduce the risk of long-term cardiovascular disease in women. AHA: 940246 (AS); KL2: KL2TR001432 (AS); Marriott Award: EG400066 (AS). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.