Resistance to endotoxic shock in mice lacking natriuretic peptide receptor-A

摘要: Background and purpose:  Excessive production of nitric oxide (NO) by inducible NO synthase (iNOS) is thought to underlie the vascular dysfunction, systemic hypotension organ failure that characterize endotoxic shock. Plasma levels atrial natriuretic peptide (ANP), brain (BNP) C-type (CNP) are raised in animal models humans with shock correlate associated cardiovascular dysfunction. Since both peptides play important roles homeostasis via activation guanylate cyclase-linked receptors, we used mice lacking receptor (NPR)-A (NPR1) establish if contribute dysfunction present shock. Experimental approach:  Wild-type (WT) NPR-A knockout (KO) were exposed lipopolysaccharide (LPS) (in vitro vivo), pro-inflammatory cytokines, iNOS expression activity evaluated. Key results:  LPS-treated WT animals exhibited a marked fall mean arterial blood pressure (MABP) whereas KO maintained MABP throughout. LPS administration caused greater suppression responses thromboxane-mimetic U46619, ANP, acetylcholine NO-donor spermine-NONOate versus mice. This differential effect on function was paralleled reduced cytokine production, (plasma [NOx] cyclic GMP). Conclusions implications:  These observations suggest facilitates contributes characteristic Pharmacological interventions target system may represent novel approach treat this life-threatening condition.