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

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 pEC(50) for phenylephrine in control, but not denervated arteries after both 2 and 7 weeks. Relative to controls, pEC(50)s for phenylephrine (with desmethylimipramine), methoxamine, clonidine and vasopressin were increased at 2 but not 7 weeks after denervation. The pEC(50) 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 alpha(1)- and alpha(2)-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. British Journal of Pharmacology (2010) 159, 142-153; doi:10.1111/j.1476-5381.2009.00520.x; published online 4 December 2009