Transient supersensitivity to α‐adrenoceptor agonists, and distinct hyper‐reactivity to vasopressin and angiotensin II after denervation of rat tail artery

Abstract

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.

Autonomic Consequences of Spinal Cord Injury

“…Interestingly, some studies have challenged the concept of α-AR hypersensitivity by reporting no change in pressor response to norepinephrine in rats with complete cervical SCI (216,268), suggesting that apparent enhanced sympathetic response may be caused by periodic episodes of SPN hyperactivity rather than denervation-related hypersensitivity. Other studies have otherwise shown that arterial and venous blood vessels from rats with more chronic SCI markedly increase nerve-evoked constrictions (290,337), and the arterial vascular muscle is transiently supersensitive to α 1 and α 2 -AR agonists (338).…”

A Novel Model of Dexamethasone-Induced Hypertension: Use in Investigating the Role of Tyrosine Hydroxylase

“…As mentioned above, this could also be associated with a-MPT central effects. More importantly, HR maintenance could be due to opposing responses of the parasympathetic nervous system to reduced sympathetic activity (Dickson et al, 1981;Levy, 1984;Lacroix et al, 1990), in addition to potential cardiovascular supersensitivity to catecholamines that may occur immediately after a-MPT administration (Brus et al, 1970;Tripovic et al, 2010). In contrast, decreased HR upon DEX administration is probably a reflex central response to the elevated blood pressure.…”

Upregulation of α1-adrenoceptors on cutaneous nerve fibres after partial sciatic nerve ligation and in complex regional pain syndrome type II

“…Nevertheless, in the present study, vascular expression of α 1 -ARs did not change after PSL, and was similar in patients with CRPS type II and controls. Loss of neuronal noradrenaline transporters or other changes (e.g., in gap-junction proteins, angiotensin II receptor expression or intracellular signalling to contractile stimuli) may contribute to denervation supersensitivity [53].…”