Enteral protease inhibition mitigates impaired Windkessel function in experimental trauma/hemorrhagic shock

Abstract

Introduction: Trauma/hemorrhagic shock (T/HS) is characterized by systemic hypotension and poor organ perfusion, but despite efforts to improve hemodynamic stability via blood product/fluid therapy and vasopressor interventions, diastolic blood pressure (DBP) and thus, mean arterial pressure (MAP) is often recalcitrant to interventions. Large artery compliance is an important determinant of the Windkessel model of vascular hemodynamics, but its functional status remains unresolved in T/HS. We have previously demonstrated that enteral protease inhibition restores blood pressure (BP) and improves autonomic function and vascular resistance after T/HS. Here, we were interested in determining the impact of enteral protease inhibition on arterial compliance in T/HS. Methods: Male Wistar rats (~400g) were randomly assigned to three groups, corresponding to administered resuscitation: shed whole blood (WB), lactated Ringer’s (LR), and LR with enteral gabexate mesilate treatment (LR+GM). Under anesthesia, animals were subjected to experimental T/HS, established by midline laparotomy and controlled hemorrhage to maintain MAP at 35-40 mmHg for 90 min. Animals were then fluid resuscitated with WB or LR over 120 min to achieve a goal MAP of 65 mmHg. Carotid-femoral pulse wave velocities (PWV) and diastolic decay time constants (τ) were estimated from BP waveforms as measures of arterial compliance. Pressure myography was conducted on excised femoral arteries from T/HS animals and healthy donors to assess passive biomechanical properties, i.e., tissue energy loss. Results: PWV increased by ~15% in all T/HS animals at the end of shock compared to baseline. During and at the end of reperfusion, the untreated LR group continued to display elevated PWV, while the PWV of LR+GM and WB animals decreased significantly and returned closer to baseline values (LR: 12.4% vs LR+GM: 6.43%, p<0.05; vs WB: 5.03%, p<0.01). Diastolic τ was reduced by ~34% by the end of shock in all groups but was improved in WB and LR+GM groups by 2 hours after reperfusion. In contrast, this decrease in τ was exacerbated in the LR-only group (p<0.01 vs LR+GM & WB) through the end of the experiment. Biomechanical biaxial testing revealed pronounced leftward shifts in circumferential tension-strain curves in all T/HS groups, especially in the untreated LR group, as compared to healthy animals. Untreated LR vessels demonstrated significantly greater energy loss compared to those of healthy control vessels (31.5% vs 19.7%, p<0.05). Conclusions: Enteral GM infusion attenuated both the marked increases in PWV and vascular energy loss seen after T/HS, suggesting that impairment in arterial compliance after T/HS may be mediated, in part, by serine proteases. By targeting the modulators of large artery Windkessel function, organ perfusion during diastole can be maintained to improve hemodynamic stability and clinical outcomes in T/HS. Department of Defense Award W81XWH-17-2-0047 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.