Evaluation of Maternal Reproductive Outcomes and Biochemical Analysis from Wistar Audiogenic Rats (WAR) and Repercussions in Their Offspring.

The objective of the present study was to evaluate maternal reproductive performance, body weight, and frequency of external and internal anomalies of newborns of Wistar Audiogenic Rat (WAR) females as compared with Wistar rats. The adult WAR and Wistar rats were mated within their respective strains. After confirming the pregnancy, the body weights were weekly evaluated. On day 21 of pregnancy, the female rats were anesthetized and sacrificed to evaluate the maternal reproductive outcomes and biochemical profile, newborn weight, and external and internal anomalies. The WAR strain gained less weight during the pregnancy and presented hyperproteinemia, hypertriglyceridemia, and embryonic losses concerning Wistar rats, suggesting an inadequate intrauterine condition for embryonic development and fetal viability. WAR also presented a higher percentage of newborns classified as small for gestational age related to intrauterine growth restriction, which was confirmed by the lower number of ossification centers. There was a higher percentage of skeletal anomalies compared with fetuses of the Wistar dams, confirming their greater susceptibility during the formation and development of their skeletal system. Thus, the WAR presents physiological alterations compromising the viability of their embryos and fetuses, leading to impaired development of the newborns.

Impaired central respiratory chemoreflex in an experimental genetic model of epilepsy.

KEY POINTS: It is recognized that seizures commonly cause apnoea and oxygen desaturation, but there is still a lack in the literature about the respiratory impairments observed ictally and in the post-ictal period. Respiratory disorders may involve changes in serotonergic transmission at the level of the retrotrapezoid nucleus (RTN). In this study, we evaluated breathing activity and the role of serotonergic transmission in the RTN with a rat model of tonic-clonic seizures, the Wistar audiogenic rat (WAR). We conclude that the respiratory impairment in the WAR could be correlated to an overall decrease in the number of neurons located in the respiratory column. ABSTRACT: Respiratory disorders may involve changes in serotonergic neurotransmission at the level of the chemosensitive neurons located in the retrotrapezoid nucleus (RTN). Here, we investigated the central respiratory chemoreflex and the role of serotonergic neurotransmission in the RTN with a rat model of tonic-clonic seizures, the Wistar audiogenic rat (WAR). We found that naive or kindled WARs have reduced resting ventilation and ventilatory response to hypercapnia (7% CO2 ). The number of chemically coded (Phox2b+ /TH- ) RTN neurons, as well as the serotonergic innervation to the RTN, was reduced in WARs. We detected that the ventilatory response to serotonin (1 mm, 50 nl) within the RTN region was significantly reduced in WARs. Our results uniquely demonstrated a respiratory impairment in a genetic model of tonic-clonic seizures, the WAR strain. More importantly, we demonstrated an overall decrease in the number of neurons located in the ventral respiratory column (VRC), as well as a reduction in serotonergic neurons in the midline medulla. This is an important step forward to demonstrate marked changes in neuronal activity and breathing impairment in the WAR strain, a genetic model of epilepsy.

Angiotensin II-independent angiotensin-(1-7) formation in rat hippocampus: involvement of thimet oligopeptidase.

The involvement and relevance of the renin-angiotensin system have been established clearly in cardiovascular diseases, and renin-angiotensin system involvement has also been investigated extensively in the central nervous system. Angiotensin II acts classically by binding to the AT1 and AT2 receptors. However, other pathways within the renin-angiotensin system have been described more recently, such as one in which angiotensin-(1-7) (Ang-(1-7)) binds to the receptor Mas. In the central nervous system specifically, it has been reported that this heptapeptide is involved in learning and memory processes that occur in central limbic regions, such as the hippocampus. Therefore, this prompted us to investigate the possible role of the Ang-(1-7)-receptor Mas pathway in epileptic seizures, which are also known to recruit limbic areas. In the present study, we show that Ang-(1-7) is the main metabolite of angiotensin I in rat hippocampi, and, strikingly, that thimet oligopeptidase is the main enzyme involved in the generation of Ang-(1-7). Furthermore, elevations in the levels of thimet oligopeptidase, Ang-(1-7), and of receptor Mas transcripts are observed in chronically stimulated epileptic rats, which suggest that the thimet oligopeptidase-Ang-(1-7)-receptor Mas axis may have a functional relevance in the pathophysiology of these animals. In summary, our data, which describe a new preferential biochemical pathway for the generation of Ang-(1-7) in the central nervous system and an increase in the levels of various elements of the related thimet oligopeptidase-Ang-(1-7)-receptor Mas pathway, unveil potential new roles of the renin-angiotensin system in central nervous system pathophysiology.

Changes in autonomic control of the cardiovascular system in the Wistar audiogenic rat (WAR) strain.

We evaluated autonomic cardiovascular modulation and baroreflex control of heart rate (HR) in a particular epileptic rat strain, Wistar audiogenic rats (WARs). We studied spontaneous baroreflex sensitivity as well as reflex changes in HR evoked by phenylephrine/nitroprusside-induced changes in arterial pressure (AP). Atropine and propranolol were used to measure cardiac autonomic tone. AP and pulse interval (PI) variability analysis were performed in the time and frequency domains (FFT spectral analysis) to evaluate cardiovascular sympatovagal modulation in WARs. AP and HR were higher in WARs (109±2 mm Hg and 366±9 bpm) than in Wistar control rats (101±2 mm Hg and 326±10 bpm). The power of the low-frequency band of both AP and PI spectra, a marker of sympathetic modulation, was higher in WARs than in Wistar control rats. The high-frequency power of the PI spectra in normalized units, which is linked to cardiac vagal modulation, was lower in WARs. Both WARs and Wistar control rats had similar vagal tone (91±13 bpm vs 94±11 bpm, respectively), but sympathetic tone was higher in WARs (30±4 bpm vs 14±4 bpm). No differences were detected in the gain of evoked (1.32±0.1 ms/mm Hg vs 1.35±0.2 ms/mm Hg) or spontaneous (1.34±0.2 ms/mm Hg vs 2.04±0.2 ms/mm Hg) baroreflex sensitivity. The higher AP and HR and the autonomic imbalance (sympathetic predominance) in WARs might be associated with an increased risk of life-threatening cardiovascular events in this strain.