Unexpected consequences of damage to the sympathetic innervation on neurovascular transmission

Nerve injuries that cause loss of vascular sympathetic innervation produce changes in blood flow that are believed to be associated with denervation and reinnervation of the vasculature. Denervation of arteries renders them hyperreactive to circulating vasoconstrictor agents. It is assumed that this hypersensitivity is lost when the blood vessels become reinnervated. However, the mechanisms underlying the recovery of vascular function following nerve injuries are not understood. To investigate these mechanisms we have assessed changes that follow denervation and reinnervation of the rat tail artery. These studies demonstrate that: (1) hyperreactivity of denervated vascular muscle to α-adrenoceptor agonists lasts <2 weeks and, in the longer term, loss of neuronal norepinephrine transporters (NETs) alone explains the increased reactivity to agonists like phenylephrine that are substrates of this amine uptake pump; (2) sympathetic reinnervation of denervated arteries is incomplete for many months and they remain hyperreactive to agonists that are substrates of the NET; (3) nerve-evoked contractions of reinnervated arteries are restored to control amplitude despite the lower density of noradrenergic axons. In addition to overturning widely held views of denervation hypersensitivity and rapid sympathetic regeneration, the last finding is most unexpected. Apparently either the effectiveness of neurotransmitter(s) released from the regenerated axon terminals is enhanced or there is substantial redundancy in the normal vascular innervation. In support of the latter suggestion, removal of half the sympathetic innervation of the tail artery also did not reduce the size of nerve-evoked contractions measured after 3 or 7 days. These findings demonstrate that vasoconstriction to sympathetic nerve stimulation does not scale with the number of innervating axons and suggest that the mechanisms activated by nerve released neurotransmitters are normally saturated.