Hemorrhagic shock-induced vascular hyporeactivity in the rat: relationship to gene expression of nitric oxide synthase, endothelin-1, and select cytokines in corresponding organs.
BACKGROUND
Our previous work observed that vascular hyporeactivity to norepinephrine (NE) developed after hemorrhage and the response was not the same in the 4 arteries examined. To evaluate possible mechanisms involved, the present study investigated the gene expression of iNOS, eNOS, IL-1beta, IL-6, TNF-alpha, and endothelin-1 in the corresponding organs, and the roles of nitric oxide (NO) and endothelin (ET).


METHODS
LAnesthetized rats (n=7/time point/group) were hemorrhaged to a mean arterial pressure of 50 mmHg for 60 min. The vascular reactivity of the superior mesenteric (SMA), celiac (CA), left renal (LRA), and left femoral arteries (LFA) to NE was measured at baseline, at the end of the hypotensive period (E), and at 1, 2, and 4 h later in the three groups (hemorrhage, hemorrhage+NG-nitro-L-arginine methyl ester (L-NAME), an NO synthase inhibitor, or hemorrhage+PD142893, an ET receptor antagonist). Gene expression in ileum, left kidney, liver, and skeletal muscle was determined by quantitative RT-PCR at these times.


RESULTS
Vascular reactivity of SMA, CA, LRA, and LFA to NE decreased as much as 98% over 4 h compared with baseline. This loss of responsiveness in CA and LFA was more severe than in SMA and LRA. Gene expression of iNOS, eNOS, IL-1beta, IL-6, TNF-alpha, and endothelin-1 in the corresponding organs of select vasculatures increased markedly over baseline levels and the fold increase in mRNA levels of these enzymes and mediators in liver and skeletal muscle was higher than in ileum and left kidney. For example, at 4 h, iNOS expression was over 16-fold higher than baseline in liver and skeletal muscle, but 5- and 7-fold higher in ileum and kidney, respectively. L-NAME or PD142893 partially attenuated the decreased vascular reactivity induced by hemorrhagic shock and attenuated the changes in gene expression observed.


CONCLUSIONS
These findings suggest that the differential expression of NOS, cytokines, and endothelin-1 in different organs are associated with the development of vascular hyporeactivity after hemorrhagic shock and may account, at least in part, for the vascular bed diversity observed.
Liu
Liang-ming
LM
U.S. Army Institute of Surgical Research, San Antonio, Texas, USA.
Dubick
Michael A
MA
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015536:Down-Regulation; D019332:Endothelin-1 / Q000378:metabolism*; D007082:Ileum / Q000098:blood supply / Q000187:drug effects; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism*; D007668:Kidney / Q000098:blood supply / Q000187:drug effects; D008099:Liver / Q000098:blood supply / Q000187:drug effects; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012771:Shock, Hemorrhagic / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D019332:Endothelin-1; D007375:Interleukin-1; D015850:Interleukin-6; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; D009638:Norepinephrine