Topiramate treatment in Wistar rats during childhood induces sex-specific vascular dysfunction in adulthood.

The present study determined whether treatment during childhood with topiramate (TPM), a new generation antiepileptic drug, results in altered aortic reactivity in adult male and female rats. We also sought to understand the role of endothelium-derived contractile factors in TPM-induced vascular dysfunction. Male and female Wistar rats were treated with TPM (41 mg/kg/day) or water (TPM vehicle) by gavage during childhood (postnatal day, 16-28). In adulthood, thoracic aorta reactivity to phenylephrine (phenyl), as well as aortic thickness and expression of cyclooxygenases (COX-1 and COX-2), NOX2, and p47phox were evaluated. The aortic response to phenyl was increased in male and female rats from the TPM group when compared with the control group. In TPM male rats, the hyperreactivity to phenyl was abrogated by the inhibition of NADPH oxidase and COX-2, while in female rats, responses were restored only by inhibition of COX-2. In addition, TPM male rats presented aortic hypertrophy and increased expression of NOX-2 and p47phox, while TPM female rats showed increased COX-2 aortic expression. Taken together, for the first-time, the present study provides evidence that treatment with TPM during childhood causes vascular dysfunction in adulthood, and that the mechanism underlying the vascular effects of TPM is sex-specific.

Intrauterine and Lactational Exposure to Paracetamol: Cardiometabolic Evaluation in Adult Female and Male Offspring.

ABSTRACT: Paracetamol (PAR) is the most common over-the-counter drug recommended by physicians for treatment of pain and fever during gestation. This drug is not teratogenic, being considered safe for fetus; however, PAR crosses the blood-placental barrier. Considering that, the present study aimed to evaluate the vascular and metabolic safety of PAR exposure during intrauterine and neonatal development in adult male and female-exposed offspring. Wistar female rats were gavaged, with PAR (350 mg/kg/d), from gestational day 6-21 or from gestational day 6 until postnatal day 21. Control dams received water by gavage at the same periods. The male and female offspring were evaluated at adulthood (80 days of life). The thoracic aorta reactivity to acetylcholine, sodium nitroprusside, and phenylephrine was evaluated in male and female adult offspring. It was observed that aortic relaxation was similar between the PAR and control offspring. In addition, the contraction to phenylephrine was similar between the groups. Further, the insulin sensitivity, adipose tissue deposition and blood pressure were not different between PAR and control adult offspring. These results suggest that the protocol of PAR exposure used in the present study did not program vascular and metabolic alterations that would contribute to the development of cardiometabolic diseases in adult life, being safe for the exposed offspring.

Can maternal treatment with metformin during gestation and lactation cause metabolic and cardiovascular disorders in rat offspring?

Objective: The aim was to evaluate if maternal treatment with metformin (MET) during pregnancy and lactation could be safe for metabolic and cardiovascular parameters of adult male and female offspring.Materials and methods: Wistar female rats were treated with MET (293 mg/kg/d) or tap water, by gavage during gestation (METG or CTRG) or gestation and lactation (METGL or CTRGL).Results: At 75 days of life, male and female MET offspring presented similar blood pressure when compared with their CTR. The heart rate of female METGL was higher than in the CTRGL. The insulin sensitivity, basal glycaemia, body weight, Lee index of obesity, plasmatic concentration of triglycerides, total cholesterol and fat acid of male and female MET were similar to CTR groups. Lower fat pad deposition was observed in female METG and METGL.Conclusion: MET exposure during gestational and lactation does not program cardiovascular and metabolic alterations in adult offspring life.

Intrauterine exposure to metformin: Evaluation of endothelial and perivascular adipose tissue function in abdominal aorta of adult offspring.

The biguanide metformin (MET) has been used during pregnancy for treatment of polycystic ovary syndrome and gestational diabetes. MET crosses the placenta and maternal treatment can expose the progeny to this drug during important phases of body development. Direct vascular protective effects have been described with the treatment of metformin. Nevertheless, it is unclear whether intrauterine exposure to metformin is safe for the vascular system of offspring. Thus, the present study aimed to investigate the intrinsic effects of metformin exposure in utero in the offspring abdominal aorta reactivity, in the presence and absence of perivascular adipose tissue (PVAT) and endothelium. For this, Wistar rats were treated with metformin 293 mg/kg/day (MET) or water (CTR) by gavage during the gestational period. The abdominal aorta reactivity to phenylephrine, acetylcholine, and sodium nitroprusside was evaluated in male adult offspring. It was observed that abdominal aorta relaxation was similar between MET and CTR groups in the presence or absence of PVAT. In addition, the contraction to phenylephrine was similar between MET and CTR groups in the presence and absence of PVAT and endothelium. Therefore, metformin exposure during pregnancy had no intrinsic effect on the offspring abdominal aorta PVAT and endothelial function, demonstrating it to be safe to the vascular system of the offspring.

Metformin Exposure During Pregnancy and Lactation Did Not Cause Vascular Reactivity Alteration in Adult Male Offsprings.

Metformin has been used for the treatment of some metabolic diseases during gestation and the beneficial effects of metformin to the vascular system have been described in diabetic and obese animal models. Nevertheless, the long-term consequences to the vascular system of offsprings maternally exposed to metformin have not yet been characterized. Therefore, we want to test the hypothesis that gestational and lactational exposure to metformin would be safe for the vascular reactivity of male adult offsprings. Wistar female rats were treated with metformin 293 mg·kg·d, by gavage, from gestational day (GD) 0 to GD 21 (METG) or GD 0 until postnatal day 21 (METGL). Control dams received water by gavage in the same periods (CTRG and CTRGL). In male offsprings (75 days), the aortic reactivity to phenylephrine, acetylcholine, and sodium nitroprusside in the presence or absence of endothelium were evaluated. The results demonstrated that aortic contraction and relaxation were similar between groups. These data showed that metformin exposure during pregnancy and lactation did not interfere with aortic reactivity, suggesting that metformin exposure during gestational and lactation are safe for the offsprings' vascular system.