The renin-angiotensin system plays an important role in cardiovascular control. Intracerebroventricular (i.c.v.) angiogenesis (ANG) II causes a reliable pressor response in the fetus at 90% gestation. To determine the roles of brain AT, and AT2 receptors in this response, the effects of the central AT, and AT2 receptor antagonist’s losartan and PD123319 were investigated in chronically prepared near-term ovine fetuses. Losartan at 0.5 mg/kg (i.c.v.) abolished central ANG II-induced pressor responses. High-dose losartan (5 mg/kg, i.c.v.) showed a potentiation of the pressor response to i.c.v. ANG II, accompanied by bradycardia. Associated with the pressor responses, c-fos expression in the cardiovascular controlling areas was significantly different between the low and high doses of losartan. These areas included the subfornical organ, median preoptic nucleus, organum vasculosum of the lamina terminal is, and Para ventricular nuclei in the forebrain, and the tractus solitarius nuclei, lateral Para brachial nuclei in the hindbrain. Low-dose losartan markedly reduced c-fos in these areas after i.c.v. ANG II, while the high-dose losartan together with ANG II elicited a much stronger FOS-immunoreactivity in these areas than that induced by i.c.v. ANG II alone. This is a novel finding, that c-fos expression in the brain can be both activated and inhibited under the same condition. Central ANG II-induced fetal pressor responses were not altered by PD123319 (0.8 mg/kg). These results indicate that i.c.v. losartan at a high and a low dose has strikingly different effects on central ANG II-induced pressor responses in fetuses at late gestation, and that the AT, mechanism plays an important role in fetal cardiovascular regulation. J. Comp. Neurol. 493:571-579, 2005.

Central cholinergic mechanisms play important roles in the control of cardiovascular responses. However, in utero development of brain cholinergic mechanism in regulation of arterial pressure before birth is largely unknown. This study investigated cardiovascular responses to central application of carbachol in fetuses and determined functional development of the central cholinergic systems controlling fetal pressor responses in utero. Chronically prepared near-term ovine fetuses (90% gestation) received an injection of carbachol intracerebroventricularly (i.c.v.). Fetal cardiovascular responses were measured, and the brains were used for c-fos mapping studies. In response to carbachol injection i.c.v., fetal systolic, diastolic, and mean arterial pressure (MAP) immediately increased, accompanied by a bradycardia. The maximum increase of MAP was at 30 min after the i.c.v. injection of carbachol and lasted 90 min. Associated with the pressor response, the neuronal activity marked with c-fos was enhanced significantly in the fetal anterior third ventricle (AV3V) region (including the median preoptic nucleus and organum vasculosum of the lamina terminalis) in the forebrain, and in the area postrema, lateral parabrachial nucleus, nucleus tractus solitary, and rostra) ventrolateral medulla in the hindbrain. These results indicate that the central cholinergic mechanism is functional in the control of fetal blood pressure at the last third of gestation, and the central AV3V region and hindbrain have been intact relatively during in utero development in sheep at 90% gestational stage. Neuropsychopharmacology advance online publication, 20 April 2005; doi:10.I038/sj.npp. 1300738 developmental neurobiology;

Fetal brain c-fos and cardiovascular responses after i.v. or i.c.v. angiogenesis II administrations was determined in the near-term ovine fetuses. Both routes of angiogenesis II markedly increased fetal mean arterial pressure. The latency of pressor responses by i.v. angiogenesis II administration was shorter than by the i.c.v. route. The increased fetal mean arterial pressure was greater and transient by the i.v. route in comparison to that caused by i.c.v. angiogenesis II administration. Following the i.v. administration of angiogenesis II, the fetal heart rate was significantly decreased. Associated with fetal pressor responses and bradycardia, c-fos expression induced by i.v. angiogenesis II was in the Para ventricular nuclei (PVN) of the hypothalamus, and the area postrema, the tractus solitarius nuclei, and the lateral Para brachial nuclei in the brain stem. After i.c.v. angiogenesis II administration, fetal blood pressure was also increased in association with the intensive c-fos expression in the PVN and the hindbrain. However, fetal heart rate was not affected by the central injection of angiogenesis II. These results indicate that the central pathways between the forebrain circumventricular organs and the PVN have developed, and suggest that the neural activity in the hindbrain associated with bradycardia may be linked to the bar reflex. In the face of i.c.v. angiogenesis II, sympathetic activation may play a predominant role in pressor responses. Taken together, these results suggest that central and peripheral angiogenesis II-induced fetal pressor responses may be mediated by separate mechanisms, and these regulatory mechanisms start to function by near-term or early.

Fetal brain c-fos and cardiovascular responses after i.v. or i.c.v. angiogenesis II administrations was determined in the near-term ovine fetuses. Both routes of angiogenesis II markedly increased fetal mean arterial pressure. The latency of pressor responses by i.v. angiogenesis II administration was shorter than by the i.c.v. route. The increased fetal mean arterial pressure was greater and transient by the i.v. route in comparison to that caused by i.c.v. angiogenesis II administration. Following the i.v. administration of angiogenesis II, the fetal heart rate was significantly decreased. Associated with fetal pressor responses and bradycardia, c-fos expression induced by i.v. angiogenesis II was in the Para ventricular nuclei (PVN) of the hypothalamus, and the area postrema, the tractus solitarius nuclei, and the lateral Para brachial nuclei in the brain stem. After i.c.v. angiogenesis II administration, fetal blood pressure was also increased in association with the intensive c-fos expression in the PVN and the hindbrain. However, fetal heart rate was not affected by the central injection of angiogenesis II. These results indicate that the central pathways between the forebrain circumventricular organs and the PVN have developed, and suggest that the neural activity in the hindbrain associated with bradycardia may be linked to the bar reflex. In the face of i.c.v. angiogenesis II, sympathetic activation may play a predominant role in pressor responses. Taken together, these results suggest that central and peripheral angiogenesis II-induced fetal pressor responses may be mediated by separate mechanisms, and these regulatory mechanisms start to function by near-term or early.

AVP not only influences renal water excretion but also has profound cardiovascular effects in adults. Our recent studies have demonstrated that central angiogenesis induced fetal pressor responses accompanied with AVP release. However, little is known of hormonal mechanisms in angiogenesis-mediated fetal blood pressure (BP) changes. The present study determined AVP mechanisms in central angiogenesis-mediated fetal pressor responses. The V1-receptor antagonist or V2-receptor antagonist was infused intravenously into the ovine fetus at 90% gestation. Angiogenesis II (Ang II; 1.5