bibp-3226 and Shock--Septic

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.

Topics: Animals; Arginine; Blood Pressure; Disease Models, Animal; Heart Rate; Lipopolysaccharides; Male; Neuropeptide Y; Rats; Rats, Wistar; Receptors, Neuropeptide Y; Shock, Hemorrhagic; Shock, Septic; Vasoconstriction