Lipopolysaccharide alters vasodilation to atrial natriuretic peptide via nitric oxide and endothelin-1: Time-dependent effects

Abstract

Nitric oxide (NO) induces vascular relaxation via cGMP in vascular smooth muscle (VSM) and is an important mediator of vascular tone during sepsis, as endothelial NO synthase (eNOS) may be upregulated during the early stages. Atrial natriuretic peptide (ANP) also stimulates cGMP via eNOS hence, this study aimed to investigate the role of NO in time-dependent altered vascular responses to ANP during the first 4 h of exposure to bacterial lipopolysaccharide (LPS). We used male rat saphenous arteries [internal relaxed diameter 63–152 µm, n = 48], mounted on a wire myograph and pre-constricted with phenylephrine. At 2 h in the presence of LPS, there was increased relaxation to ANP in arteries exposed to LPS [16.3 ± 2.4%, P < 0.05]. However the response to ANP was not altered by the NOS inhibitor Nω-nitro- l-arginine methyl ester (L-NAME, 10 − 4 M) and following denudation (vessels without endothelium). At 4 h there was no longer increased relaxation to ANP in the presence of LPS. Moreover the vasodilator response to ANP was significantly reduced following L-NAME or denudation [4.4 ± 1.0% and 4.3 ± 1.1% respectively, P < 0.05]. However, the non-specific endothelin-1 (ET-1) receptor antagonist Bosentan [10 − 5 M] increased dilatation in LPS exposed arteries at 1 and 2 h, reaching significance at 4 h [14.0 ± 3.4%, P < 0.05]. In summary, an endothelial and NO dependent mechanism is responsible for increased relaxation to ANP following 2 h exposure to LPS. However after 4 h an endothelial and NO independent process involving ET-1 is responsible for decreased relaxation to ANP. The enhanced response to ANP may exacerbate early systemic vasodilatation during early sepsis.