Increased alpha(2)-adrenergic constriction of isolated arterioles in diffuse scleroderma

Objective. Vasospasm and ischemic organ injury are important in the pathoge nesis of systemic sclerosis (SSc; scleroderma). The present study was perfo rmed to determine whether SSc arterioles have an intrinsic disturbance in v asoconstrictor activity. Methods. Skin biopsy samples were obtained from the upper arm of 11 patient s with diffuse SSc (clinically uninvolved skin) and 8 age- and sex-matched control subjects. Dermal arterioles were dissected from the biopsy sample a nd mounted in a myograph for continuous monitoring of arteriolar diameter. The resting internal diameter of control and SSc arterioles was similar (me an +/- SEM 164 +/- 15 mu and 166 +/- 18 mu, respectively), Results. Dermal arterioles displayed no spontaneous constrictor activity in the absence of stimulation. Vasoconstriction in response to KCl, a recepto r-independent activator of smooth muscle, or to phenylephrine, a selective alpha(1)-adrenergic receptor (alpha(1)-AR) agonist, was similar in control and SSc arterioles. However, constrictor responses to UK 14,304, a selectiv e alpha(2)-AR agonist, were increased in SSc compared with control arteriol es (maximal constriction responses of 25 +/- 5% and 67 +/- 4% [mean +/- SEM ] in control and SSc arterioles, respectively; P = 0.000014). Mechanical de nudation of the endothelium did not alter reactivity to alpha(2)-AR activat ion, indicating that the enhanced constriction in SSc was not mediated by c hanges in endothelial dilator activity, Indeed, in arterioles constricted w ith phenylephrine, the endothelial stimuli acetylcholine or bradykinin evok ed endothelium-dependent relaxation that was similar in control and SSc art erioles. Conclusions. Vascular smooth muscle in SSc arterioles displayed a selective increase in alpha(2)-AR reactivity, The endothelial dilator function appea red normal. Altered activity of smooth muscle alpha(2)-ARs may contribute t o the vasospastic activity that is a prominent feature of the SSc disease p rocess.