Age-related changes in the sympathetic innervation of cerebral vessels and in carotid vascular responses to norepinephrine in the rat: in vitro and in vivo studies

Abstract

We hypothesized that the density of sympathetic noradrenergic innervation of cerebral arteries and vasoconstrictor responses evoked in carotid circulation by norepinephrine (NE) increase with maturation and age. In rats of 4–5, 10–12, and 42–44 wk of age (juvenile, mature, middle aged), glyoxylic acid applied to stretch preparations showed the density of noradrenergic nerves in basilar and middle cerebral arteries was greater in mature than juvenile or middle-aged rats. In anesthetized rats, infusion of NE (2.5 μg/kg iv) increased mean arterial pressure (ABP) to ∼180 mmHg in mature and middle-aged but to only ∼150 mmHg in juveniles rats. Concomitantly, carotid blood flow (CBF) decreased in mature and middle-aged rats but remained constant in juveniles because carotid vascular conductance (CVC) decreased more in mature and middle-aged than juvenile rats. We also hypothesized that nitric oxide (NO) blunts cerebral vasoconstrictor responses to NE. Inhibition of NO synthase with l-NAME (10 mg/kg iv) induced similar increases in baseline ABP in each group, but larger decreases in CVC and CBF in mature and middle-aged than juvenile rats. Thereafter, the NE-evoked increase in ABP was similar in juvenile and mature but accentuated in middle-aged rats. Concomitantly, NE decreased CVC in juvenile and mature, but not middle-aged rats; in them, CBF increased. Thus, in juvenile rats, sparse noradrenergic innervation of cerebral arteries is associated with weak NE-evoked pressor responses and weak carotid vasoconstriction that allows autoregulation of CBF. Cerebral artery innervation density increases with maturation but lessens by middle age. Meanwhile, NE-evoked pressor responses and carotid vasoconstriction are stronger in mature and middle-aged rats, such that CBF falls despite the evoked increase in ABP. We propose that in juvenile and mature rats, NO does not modulate NE-evoked pressor responses, cerebral vasoconstriction, or CBF autoregulation, but by middle age, NO limits pressor responses and prevents breakthrough of CBF in the upper part of the autoregulatory range.