Emmanuel K. Dayao

Endogenous neuropeptide Y mediates vasoconstriction during endotoxic and hemorrhagic shock.

Neuropeptide Y (1-36), NPY, is a sympathetic vasoconstrictor whose activities in blood vessels is determined by the presence of vasoconstrictive Y1 receptors and the enzyme dipeptidyl peptidase IV (DPPIV), which converts NPY to non-vasoconstrictive peptides. While the role of the NPY system has been established during cold water stress, its role in hypotensive conditions has not; yet, exogenous NPY improves hemodynamics and survival in rats with endotoxic shock. We used a new selective non-peptidergic Y1 receptor antagonist, BIBP-3226, to determine the role of the endogenous NPY/Y1 system in endotoxic shock (induced by i.v. injection of 10 mg/kg of Escherichia coli lipopolysaccharide 0127:B8, LPS) and hemorrhagic shock (bleeding of 15 ml/kg over 1.5 min). Conscious rats received a bolus of BIBP-3226 or the vehicle 5 min before endotoxin challenge or induction of hemorrhage, followed by continuous infusion. Mean arterial pressure (MAP) at 5 min after LPS administration dropped in the control group by 15%, compared to 36% in the BIBP-3226-treated group (p < 0.01). Similarly, the hemorrhage-induced drop in MAP in the control group was 32% at 5 min, compared to 53% in the BIBP-treated rats (p < 0.01). Plasma NPY levels were unchanged in the endotoxic shock group, but were significantly elevated in the hemorrhagic shock group. BIBP-3226 pretreatment abrogated the increased plasma NPY levels after hemorrhagic shock. Endogenous NPY contributes to blood pressure recovery during endotoxic and hemorrhagic shock.

Effect of neuropeptide Y on endotoxin-induced suppression of the response to various agonists in conscious rats☆

Hypotension during endotoxic shock is related to reduced vascular responsiveness to vasoconstrictors. Neuropeptide Y (NPY) is known to potentiate the pressor response to some agonists, and NPY infusion has been shown to improve hemodynamics and survival in endotoxemic rats. We therefore studied the effect of NPY infusion on the suppressed pressor effect of norepinephrine (NE), angiotensin II (AII), vasopressin (VP), and endothelin (ET) in conscious endotoxemic rats. Chronically cannulated conscious rats were infused with a non-hypotensive dose of endotoxin (LPS, 10 micrograms/10 microliters/min) throughout the experiment. Infusion of NPY, 40 pmol/10 microliters/min was started 15 minutes before the LPS infusion, and continued for 65 minutes. Five minutes after the termination of NPY infusion, increasing agonist doses were administered i.v. to construct dose-response curves. Each experiment included one control group where saline replaced LPS, and one control group where saline replaced NPY. LPS infusion caused suppression of the pressor responses to all four agonists, as expressed by ED50 and by decreased pressor response to the individual agonist doses. In addition, LPS infusion altered the bradycardic response to AII and ET. NPY infusion prior to the administration of NE, AII and VP resulted in partial reversal of the LPS-induced suppressed responsiveness to these agonists. NPY infusion had no effect on the response to ET in either control or endotoxemic rats. Partial reversal of the suppressed responsiveness to the three agonists by NPY infusion may contribute to the observed NPY-induced improvement of blood pressure and survival rate during endotoxic shock.

Effect of sodium arsenite on iNOS expression and vascular hyporeactivity associated with cecal ligation and puncture in the rat.

Induction of the heat shock response protects animals from either endotoxemia or peritonitis. In endotoxemia, heat shock protein (HSP) induction is associated with reversal of vascular hyporeactivity and inhibition of iNOS expression. Recent studies suggest differences in the inflammatory mechanisms during endotoxemia and peritonitis animal models and their response to therapeutic interventions. We therefore studied the effect of the HSP inducer sodium arsenite (SA) on vascular reactivity and iNOS expression in rats undergoing cecal ligation and puncture (CLP). CLP resulted in suppression of the pressor effect of norepinephrine (NE) in vivo (measured by changes in blood pressure in response to NE boluses) and ex vivo (changes in contraction force in isolated mesenteric arteries in response to NE concentrations), and in the expression of iNOS protein. Pretreatment of the rats with SA resulted in reversal of CLP-induced vascular hyporeactivity in vivo and ex vivo, and inhibition of iNOS expression after 22 h. SA pretreatment improved 7-day survival after CLP from 18.2% to 70% (P < 0.005). Glucocorticoid receptor inhibition did not affect the effect of HSP induction on iNOS expression. The similarity of the effect of HSP on vascular reactivity and iNOS expression in two distinct sepsis models suggests that this effect may be clinically important and that a causative relationship between HSP induction, iNOS inhibition, and reversal of vascular reactivity is likely.

Effect of tyrosine kinase inhibition on sepsis-induced vascular hyporesponsiveness, iNOS mRNA expression and NF-κB nuclear translocation in rats

The dependence of the critical steps in the sepsis cascade on the transcription factor NF-kappaB andation to nitric oxide (NO) production are controversial. Tyrosine kinase (TK) is involved in several of the steps, and TK inhibitors (TKI) inhibit lipopolysaccharide (LPS)-induced vascular hyporesponsiveness in septic animals. We studied the relationship of TK inhibition, hemodynamics, vascular contraction, iNOS mRNA expression and NF-kappaB translocation in anesthetized endotoxic rats. The TKI AG556 (2.5 mg/kg i.p.), given 1 h before i.v. endotoxin (LPS) resulted in attenuation of early (<60 min) and late (60-120 min) hypotension, improved contraction of mesenteric arteries to norepinephrine 4 h after LPS, and attenuated tissue iNOS mRNA expression. LPS-induced NF-kappaB translocation was unaffected. The observed dissociation between NF-kappaB translocation and the salutary effect of TKI in vivo and ex vivo and its effect on iNOS mRNA expression suggest that although NF-kappaB may be involved in the sepsis cascade, it may not be essential for some of the molecular and vascular consequences of septic shock.