Sympathetic reactivity of cerebral arteries in developing fetal lamb and adult sheep

Abstract

The response of cerebral arteries to norepinephrine was examined in vivo in six dated preterm fetal (94-121 days gestation), eight term fetal (127-141 days gestation), five newborn (7-14 days), and five adult sheep, anesthetized and equipped with a closed cranial window. Norepinephrine (10(-8)-10(-4) M in cerebrospinal fluid) caused a dose-dependent decrease in pial arteriolar diameter in fetal and newborn lambs; however, preterm fetuses were 7- and 14-fold more sensitive to norepinephrine than term fetuses and newborn lambs, respectively. The effective concentration of norepinephrine inducing a 15% decrease in diameter (EC15) was 4.6 +/- 1.8, 33 +/- 11, and 64 +/- 23 microM, for the respective ages. Adult cerebral arterioles did not contract to norepinephrine. In preterm and term fetuses, the contractile response to norepinephrine was blocked by alpha 1-antagonist, prazosin (3 mg iv), and was enhanced by cocaine (10(-5) M; EC15 = 0.086 +/- 0.04 and 1.84 +/- 1.20 microM, respectively) indicating that alpha 1-adrenoceptors mediate the response and that the decrease in sensitivity is not caused by development of neuronal uptake processes. In seven fetuses (111-141 days; mean 123 days gestation), electrical stimulation of the superior cervical sympathetic ganglion constricted pial arterioles by 21 +/- 5%; this contractile response was also blocked by prazosin. The cerebral arterioles of the fetus in utero possess a functional sympathetic innervation capable of influencing cerebrovascular resistance. There is a loss of responsiveness of cerebral arterioles to norepinephrine during fetal and postnatal development, suggesting that the contribution of neuroadrenergic mechanisms to cerebrovascular regulation may be relatively unique to the immature brain.

Cerebrovascular effects of intravenous dopamine infusions in fetal sheep

“…The latter is supported by data from chronic pial window studies in developing sheep, in which NE caused a dose-dependent arteriolar vasoconstriction mediated by ␣ 1 -adrenergic receptors. This response was most significant in preterm fetuses (94-121 days) and was not present in adult sheep (34). In adults and children, ϳ20% of infused dopamine is converted to NE, and dopamine also triggers release of stored NE from nerve endings (27), although sick preterm infants may not exhibit dose-dependent increases in NE during dopamine infusion (20).…”

“…Ontogenic changes in the sensitivity of vascular beds to catecholamines have been described in several species, all of which suggest that ␣-adrenergic receptor development occurs first, followed by ␤-adrenergic and, finally, dopaminergic receptors. Wagerle et al (34) used the closed cranial window technique in developing sheep to demonstrate dose-dependent decreases in pial arteriolar diameter in response to NE. They showed that preterm fetuses are significantly more sensitive to NE than full-term fetuses and newborn lambs and that adult cerebral arterioles do not constrict at all (34).…”

“…Wagerle et al (34) used the closed cranial window technique in developing sheep to demonstrate dose-dependent decreases in pial arteriolar diameter in response to NE. They showed that preterm fetuses are significantly more sensitive to NE than full-term fetuses and newborn lambs and that adult cerebral arterioles do not constrict at all (34). Vasodilatory dopaminergic receptor activity may thus be incompletely developed in newborns compared with ␣-adrenergic receptor activity, supporting our hypothesis that dopamine stimulates vasoconstrictive ␣-adrenergic receptors and has minimal vasodilatory dopaminergic effects in the immature brain.…”

Nitric Oxide and β-Adrenergic Mechanisms Modify Contractile Responses to Norepinephrine in Ovine Fetal and Newborn Cerebral Arteries

“…'l'he absence of endothelium-dependent relaxation in the immature cerebral circulation might effect an enhanced response to contractile stimuli. However, the fact that a functional cholinergic vasodilator capability was expressed in fetal early in fetal life (16). In addition to NO, alterations in P-adrenoceptor density and/or function in various vascular beds can changc significantly during aging (17)(18)(19)(20) and possibly modulate cerebrovascular reactivity to NE (21).…”

Effects of Maturation on Cyclic GMP-Dependent Vasodilation in Ovine Basilar and Carotid Arteries

“…In the cerebral circulation, this immaturity may be particularly important, because it may contribute to the high incidence of cerebrovascular complications observed in neonates (2,3). Among the few studies that have directly examined maturational changes in cerebral arteries, however, most have found that vasoconstrictor reactivity is generally higher in immature than in mature cerebral arteries (1,(4)(5)(6). Thus, the high incidence of neonatal cerebrovascular complications seems not to be a consequence of a deficit in the ability of cerebral arteries to respond to vasoconstrictor stimuli.…”