Background and purpose: Vascular 'denervation' hyper-reactivity has generally been investigated 1-2 weeks after administration of chemicals that temporarily prevent transmitter release, but do not necessarily inactivate the neuronal noradrenaline transporters (NETs). We have investigated the reactivity of rat tail arteries over longer periods after removing the terminals by surgical denervation. Experimental approach: Two and 7 weeks after denervation, myography was used to assess contractions of isolated arterial segments to phenylephrine, methoxamine, clonidine, vasopressin and angiotensin II (AII). Denervation was confirmed by lack of tyrosine hydroxylase immunoreactive nerve terminals. Key results: The NET inhibitor, desmethylimipramine, increased the pEC50 for phenylephrine in control, but not denervated arteries after both 2 and 7 weeks. Relative to controls, pEC50s for phenylephrine (with desmethylimipramine), methoxamine, clonidine and vasopressin were increased at 2 but not 7 weeks after denervation. The pEC50 for phenylephrine in the absence of desmethylimipramine was greater than control after both 2 and 7 weeks' denervation. The maximum contraction to vasopressin was larger than in controls at 2 but not 7 weeks after denervation, whereas contractions to AII were markedly enhanced at both time points. Conclusions and implications:Increased vascular reactivity to a1-and a2-adrenoceptor agonists, and vasopressin is transient following denervation. After 7 weeks, increased reactivity to phenylephrine can be entirely accounted for by the loss of NETs. Maintained supersensitivity to AII indicates that denervation differentially and selectively affects vascular reactivity to circulating vasoconstrictor agents. This might explain persistent vasoconstriction in denervated skin of humans after nerve injuries.

Sympathetic nerve-mediated contractions of mesenteric and tail arteries controlled by preganglionic neurones decentralized by a spinal cord injury (SCI) are potentiated, and likely contribute to autonomic dysreflexia. However, reactivity to the α(1)-adrenoceptor agonist phenylephrine has been reported to be enhanced in vascular beds controlled by preganglionic neurones lying both rostral and caudal to an SCI in vivo. Here responses of isometrically-mounted median and saphenous arteries isolated from rats 2 and 8 weeks after transection of the T4 spinal cord have been compared with those from sham-operated rats. After SCI, contractions of median arteries to perivascular nerve stimulation, to α-adrenoceptor agonists (phenylephrine and clonidine), to the P2X-purinoceptor agonist α,β-methylene ATP, and to 60 mM K(+) were unchanged. Blockade of nerve-evoked contractions by α-adrenoceptor antagonists (prazosin and idazoxan) was not affected by SCI in either the median or saphenous arteries. In contrast, at 2 and 8 weeks after SCI, nerve-evoked contractions of saphenous arteries were potentiated. Saphenous arteries were less sensitive to phenylephrine 8 weeks after SCI, and their contractions to 60 mM K(+) were reduced. However, the sensitivity of saphenous arteries to clonidine was unchanged by SCI. Eight weeks after SCI, the reactivity of saphenous arteries to α,β-methylene ATP was unchanged, but the P2-antagonist suramin produced more blockade of nerve-evoked contractions. These findings demonstrate that neurovascular transmission is enhanced in arteries located caudal, but not rostral, to a spinal transection. In the saphenous artery, the most likely explanation seems to be an increase in neurotransmitter release, as may occur in other inactive sympathetic pathways caudal to the lesion.

We have investigated the recovery of sympathetic control following reinnervation of denervated rat tail arteries by relating the reappearance of noradrenergic terminals to the amplitude of nerve-evoked contractions of isometrically mounted artery segments in vitro. We have also assessed reactivity to vasoconstrictor agonists. Freezing the collector nerves near the base of the tail in adult rats denervated the artery from ∼40 mm along the tail. Restoration of the perivascular plexus declined along the length of the tail, remaining incomplete for >6 mo. After 4 mo, nerve-evoked contractions were prolonged but of comparable amplitude to control at ∼60 mm along the tail; they were smaller at ∼110 mm. At ∼60 mm, facilitation of contractions to short trains of stimuli by the norepinephrine transporter blocker, desmethylimipramine, and by the α2-adrenoceptor antagonist, idazoxan, was reduced in reinnervated arteries. Blockade of nerve-evoked contractions by the α1-adrenoceptor antagonist, prazosin, was less and by idazoxan greater than control after 8 wk but similar to control after 16 wk. Sensitivity of reinnervated arteries to the α1-adrenoceptor agonist, phenylephrine, was raised in the absence but not in the presence of desmethylimipramine. Sensitivity to the α2-adrenoceptor agonist, clonidine, was maintained in 16-wk reinnervated arteries when it had declined in controls. Thus regenerating sympathetic axons have a limited capacity to reinnervate the rat tail artery, but nerve-evoked contractions match control once a relatively sparse perivascular plexus is reestablished. Functional recovery involves prolongation of contractions and deficits in both clearance of released norepinephrine and autoinhibition of norepinephrine release.

Johansen NJ, Tripovic D, Brock JA. Streptozotocin-induced diabetes differentially affects sympathetic innervation and control of plantar metatarsal and mesenteric arteries in the rat. Am J Physiol Heart Circ Physiol 304: H215-H228, 2013. First published November 16, 2012; doi:10.1152/ajpheart.00661.2012.-In humans neural control of arterial vessels supplying skin in the extremities is particularly vulnerable to the effects of diabetes. Here the streptozotocin (STZ) rat model of type 1 diabetes was used to compare effects on neurovascular function in plantar metatarsal arteries (PMAs), which supply blood to skin of hind paw digits, with those in mesenteric arteries (MAs). Twelve weeks after STZ (60 mg/kg ip), wire myography was used to assess vascular function. In PMAs, lumen dimensions were unchanged but both nerve-evoked contractions and sensitivity to ␣1 (phenylephrine, methoxamine)-and ␣2 (clonidine)-adrenoceptor agonists were reduced. The density of perivascular nerve fibers was also reduced by ϳ25%. These changes were not observed in PMAs from STZ-treated rats receiving either a low dose of insulin that did not greatly reduce blood glucose levels or a high dose of insulin that markedly reduced blood glucose levels. In MAs from STZ-treated rats, nerve-evoked increases in force did not differ from control but, because lumen dimensions were ϳ20% larger, nerveevoked increases in effective transmural pressure were smaller. Increases in effective transmural pressure produced by phenylephrine or ␣,␤-methylene ATP in MAs from STZ-treated rats were not smaller than control, but the density of perivascular nerve fibers was reduced by ϳ10%. In MAs, the increase in vascular dimensions is primarily responsible for reducing effectiveness of nerve-evoked constrictions. By contrast, in PMAs decreases in both the density of perivascular nerve fibers and the reactivity of the vascular muscle appear to explain impairment of neurovascular transmission. diabetes; sympathetic innervation; neurovascular transmission IN HUMANS ABNORMAL CONTROL of the vasculature has been implicated in the etiology of many diabetes-related complications such as neuropathy and diabetic foot ulceration (41). These changes involve endothelium-dysfunction (30) as well as deficits in both sympathetic nerve-mediated vasoconstriction (see below) and sensory nerve-mediated vasodilation (1). However, the mechanisms whereby diabetes affects sympathetic and sensory nerve regulation of the vasculature are not well understood, although it is believed that diabetes causes degeneration of these nerve supplies (34).Many clinical studies have evaluated the effects of diabetes on sympathetic nerve-mediated vasoconstriction of arterial vessels supplying plantar skin of the foot. These studies have demonstrated that both type 1 (insulin dependent) and type 2 (noninsulin dependent) diabetic patients with signs of sensory and/or autonomic neuropathy (e.g., orthostatic hypertension) have increased skin blood flow under basal conditions (2, 33) and attenuated reductions i...