Enteral tranexamic acid attenuates vasopressor resistance and changes in α1-adrenergic receptor expression in hemorrhagic shock

Abstract

BACKGROUND Irreversible hemorrhagic shock is characterized by hyporesponsiveness to vasopressor and fluid therapy. Little is known, however, about the mechanisms that contribute to this phenomenon. Previous studies have shown that decreased intestinal perfusion in hemorrhagic shock leads to proteolytically-mediated increases in gut permeability, with subsequent egress of vasoactive substances systemically. Maintenance of blood pressure is achieved in part by α1 receptor modulation, which may be affected by vasoactive factors; we thus hypothesized that decreases in hemodynamic stability and vasopressor response in shock can be prevented by enteral protease inhibition. METHODS Rats were exposed to experimental hemorrhagic shock (35 mmHg mean arterial blood pressure for 2 hrs, followed by reperfusion for 2 hrs) and challenged with phenylephrine (2 μg/kg) at discrete intervals to measure vasopressor 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 following induction of hemorrhagic shock. RESULTS Blood pressure response (duration and amplitude) to phenylephrine after reperfusion was significantly attenuated in animals subjected to hemorrhagic shock compared to baseline and control non-shocked animals, and was restored to near baseline by enteral TXA. Arteries from shocked animals also displayed decreased α1 receptor density with restoration to baseline following enteral TXA treatment. In vitro, rat shock plasma decreased α1 receptor density in smooth muscle cells, which was also abrogated by enteral TXA treatment. CONCLUSIONS Results from this study demonstrate that experimental hemorrhagic shock leads to decreased response to the α1-selective agonist phenylephrine and decreased α1 receptor density via circulating shock factors. These changes are mitigated by enteral TXA with correspondingly improved hemodynamics. Proteolytic inhibition in the lumen of the small intestine improves hemodynamics in hemorrhagic shock, possibly by restoring α1 adrenergic functionality necessary to maintain systemic blood pressure and perfusion.

Enteral Tranexamic Acid Decreases Proteolytic Activity in the Heart in Acute Experimental Hemorrhagic Shock

“…Data from our laboratory indicate that levels and functionality of the α 1D receptor are decreased in the vasculature in hemorrhagic shock. 26 Therefore, we anticipated a similar decrease in cardiac concentrations of this receptor as well as the β 1 and β 2 adrenergic receptors and additional catecholamine receptors examined for their role in cardiac function. 27 However, these receptor concentrations increased in HS in the heart, mirroring similar increases seen in the other transmembrane receptors studied.…”

Proteolysis in septic shock patients: plasma peptidomic patterns are associated with mortality

“…10 Further, we recently reported the occurrence of systemwide proteolysis and the appearance of a large number of circulating peptides in a rat model of shock. 8 The objectives of this study are: (i) to investigate proteolysis in septic shock patients compared with septic patients without shock and healthy donors by assessment of plasma peptide concentrations from mass spectrometry-based peptidomics, and by in silico analysis of proteolytic activity; and (ii) to determine the association between proteolysis and inhospital mortality in septic shock.…”

Enhanced intestinal permeability and intestinal co-morbidities in heat strain: A review and case for autodigestion

“…One of the consequences of such unchecked protease activity is the cleavage of membrane receptors, a process that compromises the associated cell functions they control. For example, cleavage of the adrenergic receptors may cause a central blood pressure reduction [ 96 ], an elevated permeability to molecules the size of digestive enzymes as interepithelial membrane adhesion molecules (e.g., E-cadherin) are cleaved [ 91 , 97 ], or insulin resistance may arise as the ectodomain of the insulin receptor is cleaved [ 98 ]. While to date, receptor cleavage has not been investigated in heat shock, it is notable that post-exertional heat stroke and even post-exercise controls exhibit hyperglycemia over several hours and days ( Figure 12 ).…”