Skip to main content
Open Access Publications from the University of California

UC San Diego

UC San Diego Electronic Theses and Dissertations bannerUC San Diego

Enteral protease inhibition preserves vasopressor resistance and vascular α1-adrenergic receptor expression in hemorrhagic shock


Hemorrhagic shock is characterized by hyporesponsiveness to vasopressor and fluid therapy. Little is known about the contributing mechanisms. We hypothesize that decreased intestinal perfusion in hemorrhagic shock leads to proteolytically-mediated increases in gut permeability, with egress of vasoactive substances. Failure to maintain blood pressure is partially mediated by α1 adrenergic receptor modulation; we thus hypothesized that decreases in hemodynamic stability and vasopressor response can be prevented by enteral protease inhibition. Rats were exposed to hemorrhagic shock (35 mmHg mean arterial blood pressure for 2 hrs, followed by 2 hour reperfusion) and challenged with phenylephrine (2 µg/kg) at intervals to measure responsiveness. A second group of animals received enteral injections with the protease inhibitor tranexamic acid (TXA) (127 mM) along the small intestine and cecum one hour into shock. Blood pressure response to phenylephrine after reperfusion was attenuated in animals subjected to hemorrhagic shock compared to baseline and non-shocked animals, and was restored by TXA. Arteries from shocked animals displayed decreased α1 receptor density with restoration to baseline density following enteral treatment. This finding was replicated in vitro, as rat shock plasma decreased α1 receptor density of incubated smooth muscle cells, which was also abrogated by TXA treatment. Results demonstrate that hemorrhagic shock leads to decreased vasopressor response to phenylephrine as well as decreased α1 receptor density via circulating factors. Changes are prevented by enteral TXA with correspondingly improved hemodynamics. Proteolytic inhibition of the small intestine improves outcomes in hemorrhagic shock, partially by restoring α1 adrenergic activity and maintaining blood pressure.

Main Content
For improved accessibility of PDF content, download the file to your device.
Current View