Mechanisms of direct peritoneal resuscitation-mediated splanchnic hyperperfusion following hemorrhagic shock.

Conventional resuscitation (CR) from hemorrhagic shock causes a persistent and progressive splanchnic vasoconstriction and hypoperfusion despite hemodynamic restoration with intravenous fluid therapy. Adjunctive direct peritoneal resuscitation (DPR) with a clinical peritoneal dialysis solution instilled into the peritoneal cavity has been shown to restore splanchnic tissue perfusion, down-regulate the gut-derived exaggerated systemic inflammatory response, promote early fluid mobilization, and improve overall outcome. This study was conducted to define the molecular mechanisms of DPR-induced gut hyperperfusion after hemorrhagic shock. Male rats were bled to 50% baseline mean arterial pressure and resuscitated with the shed blood plus two volumes of saline (CR). In vivo videomicroscopy and Doppler velocimetry were used to assess terminal ileal microvascular diameters and blood flow. Direct peritoneal resuscitation animals received CR and topical application of a clinical glucose-based peritoneal dialysis solution (Delflex). Inhibitors, glibenclamide (K(+)ATP channels), N-monomethyl-L-arginine (L-NMMA) (nitric oxide synthase), 8-cyclopentyl-1,3-diprophylxanthine (DPCPX) (A1 adenosine receptor), tetrabutylammonium (K(+)Ca2+ channels), and mefenamic acid (cyclooxygenase) were topically applied (individually or in combination) with DPR according to protocol; BQ-123 (endothelin A receptor antagonist) and BQ-788 (endothelin B receptor antagonist) were used topically with CR to define the mechanism of post-CR vasoconstriction and hypoperfusion. Conventional resuscitation caused a persistent progressive intestinal vasoconstriction and hypoperfusion that can be abolished with endothelin antagonists. In contrast, adjunctive DPR caused an instantaneous sustained vasodilation and hyperperfusion. Glibenclamide or L-NMMA partially attenuated DPR-induced vasodilation, whereas the addition of DPCPX to the two inhibitors eliminated the dilation. Cyclooxygenase and K(+)Ca2+channels were not active in DPR-mediated microvascular effects. In conclusion, DPR improves splanchnic tissue perfusion by endothelium-dependent mechanisms mediated by activations of glibenclamide-sensitive K(+) channels (KATP), adenosine A1 receptor subtype activation, and nitric oxide release. Direct peritoneal resuscitation preserves endothelial dilatory functions, thereby overriding any endothelium-derived constrictor response triggered by hemorrhagic shock and CR.