Intrauterine and perinatal life are critical periods for programming of cardiometabolic diseases. However, their relative role remains controversial. We aimed to assess, at weaning, sexdependent alterations induced by fetal or postnatal nutritional interventions on key organs for metabolic and cardiovascular control. Fetal undernutrition was induced by dam food restriction (50 % from mid-gestation to delivery) returning to ad libitum throughout lactation (Maternal Undernutrition, MUN, 12 pups/litter). Postnatal overfeeding (POF) was induced by litter size reduction from normally fed dams (4 pups/litter). Compared to control, female and male MUN offspring exhibited: 1) low birth weight and accelerated growth, reaching similar weight and tibial length by weaning, 2) increased glycemia, liver and white fat weights; 3) increased ventricular weight and tendency to reduced kidney weight (males only). Female and male POF offspring showed: 1) accelerated growth; 2) increased glycemia, liver and white fat weights; 3) unchanged heart and kidney weights. In conclusion, postnatal accelerated growth, with or without fetal undernutrition, induces early alterations relevant for metabolic disease programming, while fetal undernutrition is required for heart abnormalities. The progression of cardiac alterations and their role on hypertension development needs to be evaluated.The similarities between sexes in pre-pubertal rats suggest a role of sex-hormones in female protection against programming.

Background and aimsLeft ventricular hypertrophy (LVH) in hypertension is associated with a greater risk of sustained supraventricular/atrial arrhythmias. Dronedarone is an antiarrhythmic agent that was recently approved for the treatment of atrial fibrillation. However, its effect on early regression of LVH has not been reported. We tested the hypothesis that short-term administration of dronedarone induces early regression of LVH in spontaneously hypertensive rats (SHRs).MethodsTen-month-old male SHRs were randomly assigned to an intervention group (SHR-D), where animals received dronedarone treatment (100 mg/kg) for a period of 14 days, or to a control group (SHR) where rats were given vehicle. A third group with normotensive control rats (WKY) was also added. At the end of the treatment with dronedarone we studied the cardiac anatomy and function in all the rats using transthoracic echocardiogram, cardiac metabolism using the PET/CT study (2-deoxy-2[18F]fluoro-D-glucose) and cardiac structure by histological analysis of myocyte size and collagen content.ResultsThe hypertensive vehicle treated SHR rats developed the classic cardiac pattern of hypertensive cardiomyopathy as expected for the experimental model, with increases in left ventricular wall thickness, a metabolic shift towards an increase in glucose use and increases in myocyte and collagen content. However, the SHR-D rats showed statistically significant lower values in comparison to SHR group for septal wall thickness, posterior wall thickness, ventricular mass, glucose myocardial uptake, size of left ventricular cardiomyocytes and collagen content. All these values obtained in SHR-D rats were similar to the values measured in the normotensive WKY control group.ConclusionThe results suggest by three alternative and complementary ways (analysis of anatomy and cardiac function, metabolism and histological structure) that dronedarone has the potential to reverse the LVH induced by arterial hypertension in the SHR model of compensated ventricular hypertrophy.

Drug safety and efficacy studies frequently use oral gavage, but repetitive usage may cause problems. Administration through voluntary ingestion represents an opportunity for refinement. We aimed to develop a protocol for voluntary ingestion of gelatin-based supplements in rats, assessing the influence of age, sex, fasting (4 h), and additives (vanilla, VF; sucralose, S), and to test it in lactating dams. Three-week-old and 5-month-old Sprague-Dawley rats were placed individually in an empty cage containing a gelatin cube and trained daily (5 days/week), recording the day the whole cube was consumed (latency). Rats trained prior to gestation were offered a gelatin containing 250 mg/kg cocoa shell extract (CSE) during lactation. Rats that did not eat the cube after 8 training days were considered non-habituated, with a proportion similar in young males (7.1%), young females (11.1%), and adult females (10.3%), but significantly higher in adult males (39.3%). Excluding non-habituated rats, latency was 2–3 days, without differences between young and adult rats (p = 0.657) or between males and females (p = 0.189). VF or VF + S in the gelatin did not modify latency, while fasting significantly reduced it in females (p = 0.007) but not in males (p = 0.501). During lactation, trained females ate the CSE-gelatin within 1–5 min without litter problems. Conclusions: Acceptance of a gelatin-based supplement is negatively influenced by male sex, facilitated by fasting, and not modified by additives. Training is remembered after 2 months and does not interfere with lactation. Gelatin-based voluntary ingestion is suitable to administer drugs that need to pass through the digestive system, ensuring adequate dosage, and is important to detect non-habituated rats prior to the study. The current protocol may be implemented by training the rats in their own cage.

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