Differential Responses to Systemic and Local Angiotensin II Infusions in Conscious Postnatal Sheep

Abstract

vascular smooth muscle until 2 wk postnatal when they are replaced by AT 1 . Thus, the mechanisms whereby ANG II increases MAP after birth are unclear. We examined the effects of ANG II on femoral vascular resistance (FmVR) and blood flow (FmBF) in serial studies of newborn sheep (n ϭ 7) at 7-14 d, 15-21 d, and 22-35 d. Animals had femoral catheters implanted for systemic ANG II infusions and cardiovascular monitoring, and a flow probe was implanted on the contralateral artery proximal to the superficial saphenous artery, which contained a catheter for intra-arterial ANG II infusions. Studies were performed using a range of systemic and intra-arterial ANG II doses. Systemic ANG II increased MAP dose-dependently at all ages (p Ͻ 0.001); however, responses were not age dependent. FmBF rose dose dependently at 7-14 d (p Ͻ 0.001) and was unchanged at older ages. The transition from fetal to newborn life is associated with numerous hemodynamic changes, including alterations in HR, blood pressure, PVR, and the distribution of cardiac output (1-4). The autonomic nervous system and the reninangiotensin system (RAS) are considered important modulators of the cardiovascular changes in the perinatal period. This is supported by evidence of increased circulating levels of catecholamines and ANG II during and after parturition (1, 4 -6). ANG II is the predominant vasoactive agent associated with the RAS and is believed to be an important regulator of blood pressure in fetal, neonatal, and adult sheep (7-9). The effects of ANG II on blood pressure may reflect its direct action on VSM through increases in PVR or on cardiac output by increasing venous return or HR (4, 10 -13). Indirect effects on VSM also may occur through activation of central autonomic nervous system activity or the release of other vasoactive mediators (11, 14 -16).ANG II mediates its actions by binding to specific AT. At least two AT subtypes have been identified, AT 1 and AT 2 , and their expression is developmentally regulated (17)(18)(19). In the adult, the AT 1 is the primary subtype expressed in most tissues, including VSM, and accounts for most biologic actions of ANG II (20,21). However, AT 2 are found in selective adult tissues, e.g. adrenal, myometrium, and uterine arteries from pregnant and nonpregnant women and sheep (9,(21)(22)(23)

Vessel-Specific Regulation of Angiotensin II Receptor Subtypes During Ovine Development

“…We previously reported that AT 2 receptor binding predominated in ovine peripheral VSM until~4 wk postnatal, whereas only umbilical VSM had predominant AT 1 binding in the last 2-3 wk of gestation (9,19). Thus, increases in umbilicoplacental resistance seemed to be a major determinate of Ang II-mediated increases in fetal blood pressure at term, whereas changes in peripheral resistance played a minor role in the fetus and neonate (9,40). The RAS may have other effects on VSM development, e.g.…”

Effects of Systemic and Local Phenylephrine and Arginine Vasopressin Infusions in Conscious Postnatal Sheep

“…Although systemic infusions of ANG II in conscious postnatal sheep increase MAP and PVR, as reflected by increases in FmVR, arterial infusions directly into the hindlimb do not alter FmBF or FmVR (21). Furthermore, these responses are similar throughout the first postnatal month (21,22), mirroring the prevalence of the nonvasoconstricting type-2 ANG II receptor subtype (AT2 ) in peripheral VSM until 3-4 wk postnatal (13,23). Thus, the rise in basal MAP after birth is unlikely due to increases in vascular sensitivity to ANG II.…”

“…Six newborn sheep were serially studied between 7 and 35 d postnatal. Surgery was performed at 3-5 d of life using procedures previously described (21). Briefly, each animal received preoperative subcutaneous atropine (0.088 mg/kg) followed by sodium pentobarbital (7.5-10 mg/kg i.v.)…”

“…To determine the effects of each agent on PVR independent of systemic effects and changes in MAP or perfusion pressure, we examined the responses to local arterial infusions of each agent via the superficial saphenous artery catheter (21). To more accurately compare the effects of systemic and local infusions of each agent, the hindlimb should be exposed to similar plasma concentrations of the agent.…”

“…To compare responses by hemodynamic parameters with different units, e.g. MAP, FmBF, and FmVR, and changes across postnatal age, data are presented as the relative or percentage change (%⌬) from baseline (21,29). One-way ANOVA for repeated measures was used to analyze the changes in hemodynamic parameters across postnatal ages and across doses within each age group.…”