title: Impairment of endothelium-dependent dilation response after resuscitation from hemorrhagic shock involved postreceptor mechanisms.
abstract: Resuscitation from hemorrhagic shock is associated with impairment of the endothelium-dependent dilation response, whereas the dilation response induced by the endothelium-independent pathway, which is mediated by nitroprusside, a nitric oxide (NO) donor and a direct activator of guanylate cyclase, remains unaltered. Whether the impairment of the endothelium-dependent dilation response is caused by a specific receptor alteration or generally a defect in signal transduction pathway remains undetermined. Anesthetized rats were monitored for hemodynamics, and the terminal ileum was prepared for intravital videomicroscopy. Hemorrhage was 50% of mean arterial pressure for 60 min followed by resuscitation with the shed blood returned plus 2 volumes of normal saline. Intestinal microvascular reactivity to the endothelium-dependent receptor-dependent agonists acetylcholine or substance P (10(-8) or 10(-6) M), as well as the endothelium-dependent receptor-independent calcium ionophore, was determined at baseline and at 2 h postresuscitation from hemorrhagic shock. Measured vascular diameters for premucosal A3 arterioles (pA3 and dA3) were normalized and expressed as percentage of the maximal dilation capacity, as obtained from the response to the endothelium-independent NO donor sodium nitroprusside (10(-4) M). At 2 h postresuscitation, there was a marked constriction of pA3 (-70.1 +/- 20) and dA3 (-61.5 +/- 11.6) from maximal dilation capacity. Baseline premucosal arteriolar response to substance P (10(-8) M) was 30.68 +/- 4.19% and 34.66 +/- 5.82% for pA3 and dA3 arterioles, respectively. This was significantly reduced to 20.97 +/- 2.41% and 17.94 +/- 3.60% at 2 h postresuscitation. However, no significant difference between baseline and postresuscitation arteriolar responses was observed at the higher dose of substance P (10(-6) M). Postresuscitation premucosal arteriolar response to the endothelium-dependent receptor-independent calcium ionophore (10(-9) to 10(-5) M) is characterized by a marked decrease in sensitivity and an enhanced threshold for calcium ionophore-mediated dilation. The logEC50 was -7.62 +/- 0.39 and -7.75 +/- 0.32 for the pA3 and dA3 at baseline, respectively. This was significantly (P < 0.01) reduced to -5.15 +/- 0.14 and -4.39 +/- 0.71 at 2 h postresuscitation. These data suggest that impairment of the endothelium-dependent dilation response after resuscitation from hemorrhagic shock is not mediated by specific receptor alteration. Cellular mechanisms that participate in or are part of oxygen free radical formation after resuscitation from hemorrhagic shock such as Ca2+ and leukocytes, appear to have a pivotal role in the mechanism of cellular dysfunction.
authors.affiliation: Department of Physiology and Biophysics, University of Louisville, Louisville, Kentucky 40292, USA. drelzak@aol.com
authors.forename: El Rasheid
authors.initials: el R
authors.lastname: Zakaria
authors.forename: R Neal
authors.initials: RN
authors.lastname: Garrison
authors.forename: David A
authors.initials: DA
authors.lastname: Spain
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Harris
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D004727:Endothelium / Q000378:metabolism / Q000473:pathology*; D005609:Free Radicals; D006470:Hemorrhage; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D008833:Microcirculation; D008853:Microscopy; D009092:Mucous Membrane / Q000473:pathology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism; D011312:Pressure; D051381:Rats; D017207:Rats, Sprague-Dawley; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000473:pathology*; D013373:Substance P / Q000378:metabolism; D013997:Time Factors; D014661:Vasoconstriction
chemical_list: D005609:Free Radicals; D020030:Nitric Oxide Donors; D009599:Nitroprusside; D013373:Substance P; D010100:Oxygen; D002118:Calcium