Increased α2-adrenergic constriction of isolated arterioles in diffuse scleroderma

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Abstract
Objective Vasospasm and ischemic organ injury are important in the pathogenesis of systemic sclerosis (SSc; scleroderma). The present study was performed to determine whether SSc arterioles have an intrinsic disturbance in vasoconstrictor activity. Methods Skin biopsy samples were obtained from the upper arm of 11 patients with diffuse SSc (clinically uninvolved skin) and 8 age- and sex-matched control subjects. Dermal arterioles were dissected from the biopsy sample and mounted in a myograph for continuous monitoring of arteriolar diameter. The resting internal diameter of control and SSc arterioles was similar (mean ± SEM 164 ± 15μ and 166 ± 18μ, respectively). Results Dermal arterioles displayed no spontaneous constrictor activity in the absence of stimulation. Vasoconstriction in response to KCl, a receptor-independent activator of smooth muscle, or to phenylephrine, a selective α1-adrenergic receptor (α1-AR) agonist, was similar in control and SSc arterioles. However, constrictor responses to UK 14,304, a selective α2-AR agonist, were increased in SSc compared with control arterioles (maximal constriction responses of 25 ± 5% and 67 ± 4% [mean ± SEM] in control and SSc arterioles, respectively; P = 0.000014). Mechanical denudation of the endothelium did not alter reactivity to α2-AR activation, indicating that the enhanced constriction in SSc was not mediated by changes in endothelial dilator activity. Indeed, in arterioles constricted with phenylephrine, the endothelial stimuli acetylcholine or bradykinin evoked endothelium-dependent relaxation that was similar in control and SSc arterioles. Conclusions Vascular smooth muscle in SSc arterioles displayed a selective increase in α2-AR reactivity. The endothelial dilator function appeared normal. Altered activity of smooth muscle α2-ARs may contribute to the vasospastic activity that is a prominent feature of the SSc disease process.