Abstract 1301: Improved Endothelium-Dependent Vasodilation After Endothelin Receptor Blockade in Patients With Systemic Sclerosis
Severe vascular damage related predominantly to injury of endothelial cells is a common feature in patients with systemic sclerosis (SSc). We tested the hypothesis that endothelial dysfunction in these patients might involve activation of the endothelin (ET-1) system, whose vasoconstrictor and profibrotic properties are known to play a relevant role in the pathophys-iology of organ damage in SSc. To this purpose, endothelium-dependent and -independent forearm blood flow responses to intra-arterial infusion of graded doses of acetylcholine (ACh; 7.5, 15, and 30 μg/min) and sodium nitroprusside (SNP; 0.8, 1.6, and 3.2 μg/min), respectively, were assessed by strain-gauge plethysmography during concurrent infusion of saline in 12 patients with SSc (11 females) and in a group of matched controls. Vascular activity of the ET-1 system was evaluated in both groups by intra-arterial infusion of BQ-123 (a selective antagonist of ETA receptors, at the dose of 10 nmol/min for 60 min); in patients with SSc, dose-response curves to ACh and SNP were repeated during administration of BQ-123. Before ETA receptor blockade, the vasodilator response to ACh was significantly blunted in patients with SSc compared to controls (14.6 ± 1.6 [mean ± SEM] vs. 23.3 ± 2.3 mL/min per dL at the highest dose; P<0.001), whereas the response to SNP was not different between the 2 groups (13.9 ± 1.3 vs. 15.1 ± 0.5; P = 0.27). Infusion of BQ-123 resulted in a greater vasodilator response in patients (45 ± 9% from baseline at 60 min) than in controls (18 ± 9%; P < 0.001), thereby indicating enhanced ET-1 vasoconstrictor activity in SSc. Of note, in patients with SSc, ETA receptor blockade induced a significant potentiation of the vasodilator response to ACh (20.7 ± 3.9 mL/min per dL; P < 0.001 vs. saline); the response to SNP, by contrast, was not significantly modified by administration of BQ-123 (P = 0.31 vs. saline). Our findings indicate that activation of the ET-1 system in arterial vessels of patients with SSc importantly contributes to their decreased endothelium-dependent vasodilator responsiveness. This observation, therefore, suggests that ET-1 receptor antagonists may represent a useful therapeutic tool to prevent vascular dysfunction and subsequent organ damage in SSc.