Extracellular superoxide dismutase (EC‐SOD) modulates endothelin 1 contractions in resistance vessels: roles of endothelium, ET receptor, ROS and TP receptor

EC‐SOD is effective antioxidant, but its role in vascular contractility is unknown. We investigated this in isolated mesenteric arterioles (MAs) from 10 EC‐SOD −/ − (−/ −) and 10 EC‐SOD +/+ (+/+) mice by using a myograph. Contractions to phenylephrine were similar in two groups, but contractions to endothelin 1 (ET‐1) were increased in −/ − mice (100±3% vs 66±5%, p<0.01). ET‐1 contractions can be 75% abolished by BQ123 (an ET‐ A antagonist) and 25% by BQ788 (an ET‐ B antagonist) in two groups. Endothelium removal decreased ET‐1 contractions in −/ − mice, but unchanged ET‐1 contractions in +/+ mice, indicates an endothelium‐derived contracting factor (EDCF) released by ET‐1in −/ − mice. After intact MAs were incubated with antagonists of O 2 ·− (PEG‐SOD), thromboxane prostanoid receptors (TP‐Rs, SQ29548), thromboxane A 2 synthase (TxA 2 ‐S, OKY‐046NA), COX‐1 (SC‐560) or COX‐2 (Paracoxib), the augmented ET contraction in−/ − mice were significantly reduced (p<0.01) by PEG‐SOD (−64 ± 14%),SC‐560 (−61 ± 3%), OKY‐046NA (−56 ± 3%), or SQ‐29,548 (−71 ± 16%)but notby paracoxib, whereas these agents unaffected ET contractions in +/+ mice. The expression of ET‐ A , ET‐ B and COX‐1 were increased in MAs from −/ − mice. In conclusion, −/ − mice have selectively enhanced microvascular contractions to ET‐1, which duo to O 2 ·− and enhanced ET receptors activating an EDCF that requires COX‐1 with generation of TxA 2 ‐S activating TP‐Rs on the smooth muscle cells. Thus, EC‐SOD is a major defense against vascular ET contractility and may defend against hypertension and vasculopathy.