Central angiotensin II AT1 receptors mediate fetal swallowing and pressor responses in the near-term ovine fetus

Abstract

Swallowed volumes in the fetus are greater than adult values (per body weight) and serve to regulate amniotic fluid volume. Central ANG II stimulates swallowing, and nonspecific ANG II receptor antagonists inhibit both spontaneous and ANG II-stimulated swallowing. In the adult rat, AT1 receptors mediate both stimulated drinking and pressor activities, while the role of AT2 receptors is controversial. As fetal brain contains increased ANG II receptors compared with the adult brain, we sought to investigate the role of both AT1 and AT2 receptors in mediating fetal swallowing and pressor activities. Five pregnant ewes with singleton fetuses (130 +/- 1 days) were prepared with fetal vascular and lateral ventricle (LV) catheters and electrocorticogram and esophageal electromyogram electrodes and received three studies over 5 days. On day 1 (ANG II), following a 2-h basal period, 1 ml artificial cerebrospinal fluid (aCSF) was injected in the LV. At time 4 h, ANG II (6.4 microg) was injected in the LV, and the fetus was monitored for a final 2 h. On day 3, AT1 receptor blocker (losartan 0.5 mg) was administered at 2 h, and ANG II plus losartan was administered at 4 h. On day 5, AT2 receptor blocker (PD-123319; 0.8 mg was administered at 2 h and ANG II plus PD-123319 at 4 h. In the ANG II study, LV injection of ANG II significantly increased fetal swallowing (0.9 +/- 0.1 to 1.4 +/- 0.1 swallows/min; P < 0.05). In the losartan study, basal fetal swallowing significantly decreased in response to blockade of AT1 receptors (0.9 +/- 0.1 to 0.4 +/- 0.1 swallows/min; P < 0.05), while central injection of ANG II in the presence of AT1 receptor antagonism did not increase fetal swallowing (0.6 +/- 0.1 swallows/min). In the PD-123319 study, basal fetal swallowing did not change in response to blockade of AT2 receptor (0.9 +/- 0.1 swallows/min), while central injection of ANG II in the presence of AT2 blockade significantly increased fetal swallowing (1.5 +/- 0.1 swallows/min; P < 0.05). ANG II caused significant pressor responses in the control and PD-123319 studies but no pressor response in the presence of AT1 blockade. These data demonstrate that in the near-term ovine fetus, AT1 receptor but not AT2 receptors accessible via CSF contribute to dipsogenic and pressor responses.

Development of fetal brain renin–angiotensin system and hypertension programmed in fetal origins

“…In rat fetuses at GD 20, Ang II was formed and released from primary cultures in brain cells such as neurons (Weyhenmeyer et al, 1980; Gadbut et al, 1991). During the past decade, a series of studies, including ours, have demonstrated physiological functions of Ang II in the ovine fetal brain, at both near-term and pre-term (El-Haddad et al, 2000, 2001, 2002, 2005; Shi et al, 2004a,c; Xu et al, 2003, 2004, 2005). These studies strongly support the hypothesis that the fetal local RAS in the brain is relatively mature and plays an important role in physiological functions, including the central regulation of cardiovascular and neuroendocrine responses.…”

“…Intracerebroventricular Ang II injection in the chronically catheterized sheep fetuses-induced vigorous swallowing associated with low voltage ECoG high frequency in late gestation (Ross et al, 1994; Xu et al, 2001; El-Haddad et al, 2000, 2001, 2002, 2005). In addition, icv Ang II-induced fetal swallowing activity could be blocked by an angiotensin receptor antagonist (El-Haddad et al, 2001, 2005). These physiological experiments provide evidence that the fetal brain RAS is active at late gestation and appear to play an important role in the control of fetal dipsogenic responses during development.…”

Fetal development of regulatory mechanisms for body fluid homeostasis

“…This indicates that the central RAS and AT1, but not AT2 receptor, are critically involved in the regulation of arterial pressure in the near-term fetal sheep (18). In the near-term ovine fetus, AT1 receptors but not AT2 receptors (19) contribute to dipsogenic and pressor responses, as well as arginine vasopressin (AVP) release. Although little is known about the role of the AT2 receptor in the regulation of cardiovascular functions and body fluid balance, the high expression of AT2 receptors during fetal and early postnatal life implies an important role in cellular differentiation and organ development.…”

“…Several studies explored the neuronal mechanisms underlying the high rate of in utero fetal swallowing. In chronically prepared nearterm ovine fetuses, icv injection of Ang II or neuronal nitric oxide synthase (nNOS) blocker or N-methyl-D-aspartate (NMDA) receptor antagonists, which block either central Ang II receptors (19), nNOS, or NMDA receptors (58)(59)(60), markedly reduced spontaneous fetal swallowing. These J. Guan et al…”