ABSTRACT
BACKGROUND: The up-regulation of nitric oxide (NO) and cyclooxgenase-2 (COX-2) has been implicated in the pathophysiology of hemorrhagic shock. We examined the effects of aminoguanidine (AG), which is a known inducible nitric oxide synthase (iNOS) inhibitor, and NS-398, a known COX-2 inhibitor, in our rat model of refractory hemorrhagic shock (RHS). MATERIAL AND METHODS: We measured tissue iNOS and COX-2 protein expression, brain and plasma nitrate/nitrite and prostaglandin E2 (PGE2) levels, plasma creatinine and glutamic oxalacetic transaminase (GOT) levels, quantified the histological damages in kidney, liver, lung, and brain, survival rate, and mean arterial blood pressure (MABP) in RHS rats. RESULTS: Semiquantitative analysis of tissues showed iNOS protein was not detected in AG + RHS rats but was detected in normal saline and NS-398 RHS rats. Tissue COX-2 protein was not detected in AG and NS-398 RHS rats but was detected in normal saline + RHS rats. The levels of brain and plasma nitrate/nitrite and PGE2 and plasma creatinine and GOT were significantly lower in the AG + RHS rat group when compared with the normal saline RHS rat group. Histological examinations also showed a reduction in organ damage for AG + RHS rats when compared with treated RHS rats. AG + RHS rats showed significantly increased survival and MABP level when compared with treated RHS rats. CONCLUSION: Our present findings suggest that NO produced by iNOS might result in organ damages. This in turn might lead to COX-2 up-regulation, and it increases the production of reactive oxygen species and toxic prostanoids. NO-mediated organ damage might be one way in which toxic products of COX-2 might further contribute to NO's deleterious effect in the later stages of RHS. It is therefore suggested that treatment of AG via inhibition of NO might contribute to improved physiological parameters and survival rates following RHS.
Subject(s)
Dinoprostone/blood , Enzyme Inhibitors/pharmacology , Guanidines/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , Nitric Oxide/metabolism , Shock, Hemorrhagic/drug therapy , Animals , Aspartate Aminotransferases/metabolism , Blood Pressure , Brain/pathology , Creatinine/blood , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Cyclooxygenase Inhibitors/pharmacology , Immunoblotting , Kidney/pathology , Liver/pathology , Lung/pathology , Male , Nissl Bodies , Nitrates/blood , Nitric Oxide Synthase/metabolism , Nitric Oxide Synthase Type II , Nitrites/blood , Nitrobenzenes/pharmacology , Prostaglandin-Endoperoxide Synthases/metabolism , Rats , Rats, Sprague-Dawley , Shock, Hemorrhagic/metabolism , Shock, Hemorrhagic/mortality , Sulfonamides/pharmacology , Survival RateABSTRACT
Excessive production of nitric oxide (NO) as result of inducible nitric oxide synthase (iNOS) induction has been implicated in the pathophysiology of hemorrhagic shock. Our aim was to study the effects of NOS inhibitors, aminoguanidine (AG) and NG-nitro-L-arginine methyl ester (L-NAME), on survival rate, mean arterial blood pressure (MABP), temporal evolution of infarct volume, nitric oxide (NO) production and neurological deficit in a model of delayed hemorrhagic shock (DHS) in conscious rats. Our results showed that the NOS inhibitors significantly improved survival rate, MABP, and attenuated brain NO overproduction 24, 48 h and 72 h after DHS. AG reduced brain infarct volume and improved the neurological performance evaluated by the rotameric and grip strength tests while L-NAME did not show protective effect in rats following DHS. These findings suggest that NO formation via iNOS activation may contribute to organ damage and that the selective iNOS inhibitor, AG, may be of interest as a therapeutic agent for neurological recovery following DHS.
Subject(s)
Enzyme Inhibitors/therapeutic use , Nervous System/physiopathology , Nitric Oxide Synthase/antagonists & inhibitors , Shock, Hemorrhagic/drug therapy , Shock, Hemorrhagic/physiopathology , Animals , Blood Pressure/drug effects , Brain Chemistry/drug effects , Cerebral Cortex/physiology , Guanidines/therapeutic use , Male , NG-Nitroarginine Methyl Ester/therapeutic use , Nervous System/pathology , Nitric Oxide Synthase/metabolism , Nitric Oxide Synthase Type II , Nitrites/metabolism , Postural Balance/drug effects , Postural Balance/physiology , Psychomotor Performance/drug effects , Psychomotor Performance/physiology , Rats , Rats, Sprague-Dawley , Shock, Hemorrhagic/pathology , Survival Analysis , Tetrazolium Salts/pharmacologyABSTRACT
Hemorrhagic shock (HS) has been implicated in the induction of inducible nitric oxide synthase (iNOS) that leads to increase production of nitric oxide (NO). Recently, NO has been implicated to cause hyporesponsiveness of blood vessel in vitro towards vasoconstrictors in refractory (decompensated) HS. In our in vivo model, we examined the effects of aminoguanidine (AG), a known iNOS inhibitor, with angiotensin II (ANG II), a vasoconstrictor, following hemorrhagic shock decompensatory phase (HSDP) on percentage survival, vascular responsiveness, mean arterial blood pressure (MABP), heart rate and mean nitrate/nitrite levels in anaesthetized rats. HSDP (3 h) was achieved via constant pressure method (40-45 mmHg). MABP and heart rate was measured via the left carotid artery. Plasma collected from HSDP rats was used to measure nitrate/nitrite levels. Vascular hyporeactivity to ANG II was carried out using HSDP aortic strips, precontracted with KCl and noradrenaline. Sham-operated rats served as controls. HSDP rats decreased percentage survival, vascular contractility to ANG II and noradrenaline, MABP, heart rate while showing increased levels of nitrate/nitrite. Infusion of AG with ANG II, increased percentage survival and had reversed these cardiovascular effects of HSDP rats. This study indicates that excessive NO formation from iNOS activity induces vascular hyporeactivity and decompensation in HSDP. This might suggest that selective NOS inhibitor, AG, when coupled with ANG II, show reduction in NO's effect in HSDP.
