Induction of ET‐1‐ and non‐ET‐1‐mediated endothelium‐dependent vasoconstriction in endotoxemic hypotensive shock

Effective managements of refractory hypotension to vasoconstrictors in severe sepsis are limited. A new strategy to ameliorate endotoxemic hypotension by inducing endothelium‐dependent constriction of endotoxemic large arteries was examined. In lipopolysaccharide (LPS)‐induced endotoxemic rats, oroxylin‐A (OroA, 15 mg/kg, iv) administered 6 hours after LPS‐challenge promptly reversed/normalized diminished mean arterial pressure and heart rate. OroA (1–10 μM), which did not constrict isolated normal arteries, repeatedly induced exclusive endothelium‐dependent sustained‐constriction without tachyphylaxis of isolated endotoxemic aortic and tail arteries. OroA‐induced constriction of mesenteric arteries with intact‐endothelium (EC+) was blocked by endothelin‐1 (ET‐1)‐receptor antagonists which, did not affect that of tail or aortic arteries, suggesting ET‐1‐mediated and non‐ET‐1‐substance(s)‐mediated vasoconstrictions, respectively. In parallel, repeated applications of ET‐1 to mesenteric arteries lead to significant tachyphylaxis, OroA, however, induced repeated constriction of tail arteries without tachyphylaxis, Moreover, OroA significantly decreased LPS‐induced expression of ET‐1 mRNA and proteins in tail arteries, while OroA increased those in the mesenteric arteries, suggesting the heterogeneities of the endothelial cells. OroA‐induced ET‐1‐mediated and non‐ET‐1‐substance(s)‐mediated constrictions of all isolated arteries (EC+) were blocked exclusively by ROCK inhibitors. OroA reversed LPS‐induced suppression of RhoA‐activities and enhanced ROCK‐phosphorylation only in arteries with endothelium. Activated muscle ROCK‐activities in mesenteric arteries (EC+) but not those in tail or aortic arteries (EC+) were blocked by ET‐1‐receptor antagonists. Moreover, OroA‐post‐treatment suppressed, via inhibiting NF‐κB, inducible‐NOS expression and circulating NO. LPS induces region‐dependent expression of endothelial ET‐1‐ and/or non‐ET‐1‐vasoconstrictors. Both ET‐1 and non‐ET‐1 were released specifically by OroA‐activated muscle RhoA/ROCK‐pathway, causing prompt‐and‐sustained vasoconstriction that partly is due to OroA‐induced decrease of circulating NO. Simultaneous preservation of endothelial functions, induction of endothelium‐dependent constriction of large arteries, and suppression of systemic inflammation, as shown by OroA, offer new strategies for acute management of endotoxemic‐hypotensive shock. Support or Funding Information supported by MOST & Tzu Chi Foundation This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .