Cardiac and regional haemodynamics, inducible nitric oxide synthase (NOS) activity, and the effects of NOS inhibitors in conscious, endotoxaemic rats

Abstract

1 A reproducible model of the hyperdynamic circulatory sequelae of endotoxaemia in conscious, chronically-instrumnted Long Evans rats, was achieved with a continuous infusion of lipopolysaccharide (LPS, 150 pg kg-' h'l) for 32 h. Over the first 2 h of LPS infusion, there was a transient hypotension and tachycardia, accompanied by a marked increase in renal flow and vascular conductance, although there were reductions in cardiac and stroke index. Between 4-8 h after the start of LPS infusion, there was slight hypotension and tachycardia, and a transient rise in mesenteric flow and conductance, but reductions in the hindquarters vascular bed; the hyperaemic vasodilatation in the renal vascular bed was maintained. At this stage, all cardiac haemodynamic variables and total peripheral conductance, were increased, but central venous pressure was reduced. By 24 h after the onset of LPS infusion, there was clear hypotension and tachycardia, accompanied by increases in renal and hindquarters flow and conductance, although mesenteric haemodynamic variables were not different from baseline. At this stage, cardiac and stroke index were substantially elevated, in association with marked increases in peak aortic flow, dF/dtm. and total peripheral conductance; these changes were well-maintained over the following 8 h of LPS infusion. 2 By 2 h after the start of LPS infusion, only lung inducible nitric oxide synthase (iNOS) activity was increased, but at 6 h there were significant increases in iNOS activity in lung, liver, spleen, heart and aorta (43.3±7.8, 28.8±3.3, 50.8±7.2, 3.04±0.29, 3.76±0.94 pmol min' mg -' protein, respectively). However, by 24 h after the start of LPS infusion, iNOS activity was not elevated significantly in any tissue examined, and kidney iNOS activity did not change significantly during LPS infusion. Plasma nitrite/nitrate levels were increased after 2 h infusion of LPS (from 6.07 ± 1.23 to 29.44± 7.08 pmol 1-1), and further by 6 h (228.10±29.20 pmol I-'), but were less 24 h after onset of LPS infusion (74.96±11.34 pmol I-'). Hence, the progressive hypotension, increasing cardiac function and developing hyperaemic vasodilatation in renal and hindquarters vascular beds between 8-24 h after the onset of LPS infusion, occurred when tissue iNOS activity and plasma nitrite/nitrate levels were falling.3 Pretreatment with N0-monomethyl-L-arginine (L-NMMA, 30 mg kg-' bolus, 30mg kg7' h-' infusion) 1 11 before LPS infusion did not prevent the early hypotension, but abolished the initial renal vasodilatation and the later (6-8 h) fall in mean arterial pressure (MAP), and the additional renal vasodilatation. However, under these conditions, mesenteric and hindquarters flows and conductances were substantially decreased. Similar, but less marked, effects were seen with L-NMMA pretreatment at 10 mg kg' bolus, 10 mg kg-' h-' infusion, whereas at a lower dose of 3 mg kg-' bolus, 3 mg kg' h-' infusion, L-NMMA pretreatment had little effect on responses to LPS.4 Delaying treatment with L-NMMA (10 mg kg-' bolus, 10 mg...

Maintenance of Renal Vascular Reactivity Contributes to Acute Renal Failure during Endotoxemic Shock

“…Using a selective iNOS inhibitor, iNOS knockout mice, or global NOS inhibition, it has been clearly shown that iNOS/NO production mediates most, if not all, of the weakened responsiveness to constrictor substances (7,25,34). However, measurements during endotoxemic shock reveal a relatively low to absent stimulation of iNOS and NO production in the kidney compared with other tissues (35,36).…”

Comparison of Effects of Nitric Oxide Synthase (NOS) Inhibitors on Plasma Nitrite/Nitrate Levels and Tissue NOS Activity in Septic Organs

“…This discrepancy between iNOS activity and protein expression in the liver cannot be easily explained. Probable causes may include 1) differences in NOS assay conditions, 2) differences in the routes through which the LPS was administered, and 3) differences in species used (7,19,21). These might explain why iNOS activity was only slightly upregulated in the liver after LPS injection.…”

Complex regional haemodynamic effects of anandamide in conscious rats

“…saline infusion) there was a fall in mesenteric vascular conductance (Table 1) which we have noted on previous occasions (e.g., Gardiner et al, 1995), and which is probably due to the waning of postprandial hyperaemia. The cardiovascular responses to anandamide were as described above, and were reproducible, following repeated administration in the presence of saline (Figure 3).…”