CARDIAC AND REGIONAL HEMODYNAMICS, INDUCIBLE NITRIC-OXIDE SYNTHASE (NOS) ACTIVITY, AND THE EFFECTS OF NOS INHIBITORS IN CONSCIOUS, ENDOTOXAEMIC RATS

1 A reproducible model of the hyperdynamic circulatory sequelae of end otoxaemia in conscious, chronically-instrumented Long Evans rats, was achieved with a continuous infusion of lipopolysaccharide (LPS, 150 mu g kg(-1) h(-1)) for 32 h. Over the first 2 h of LPS infusion, there w as a transient hypotension and tachycardia, accompanied by a marked in crease in renal flow and vascular conductance, although there were red uctions in cardiac and stroke index. Between 4-8 h after the start of LPS infusion, there was slight hypotension and tachycardia, and a tran sient rise in mesenteric flow and conductance, but reductions in the h indquarters vascular bed; the hyperaemic vasodilatation in the renal v ascular bed was maintained. At this stage, all cardiac haemodynamic va riables 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 ha emodynamic variables were not different from baseline. At this stage, cardiac and stroke index were substantially elevated, in association w ith marked increases in peak aortic how, dF/dt(max) and total peripher al 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 lu ng inducible nitric oxide synthase (iNOS) activity was increased, but at 6 h there were significant increases in iNOS activity in lung, live r, 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(-1) mg(-1) protein, respectively). However , by 24 h after the start of LPS infusion, iNOS activity was not eleva ted 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 mu mol l(-1)), and further by 6 h (228.10 +/- 29.20 mu mol l(-1)), but were less 24 h after onset of LPS infusion (74.96 +/- 11.34 mu mol l(-1)). Hence, the progressive hypotension, increasing c ardiac function and developing hyperaemic vasodilatation in renal and hindquarters vascular beds between 8-24 h after the onset of LPS infus ion, occurred when tissue iNOS activity and plasma nitrite/nitrate lev els were falling. 3 Pretreatment with NG-monomethyl-L-arginine (L-NMMA , 30 mg kg(-1) bolus, 30 mg kg(-1) h(-1) infusion) Ih before LPS infus ion did not prevent the early hypotension, but abolished the initial r enal vasodilatation and the later (6-8 h) fall in mean arterial pressu re (MAP), and the additional renal vasodilatation. However, under thes e conditions, mesenteric and hindquarters hows and conductances were s ubstantially decreased. Similar, but less marked, effects were seen wi th L-NMMA pretreatment at 10 mg kg(-1) bolus, 10 mg kg(-1) h(-1) infus ion, whereas at a lower dose of 3 mg kg(-1) bolus, 3 mg kg(-1) h(-1) i nfusion, L-NMMA pretreatment had little effect on responses to LPS. 4 Delaying treatment with L-NMMA (10 mg kg(-1) bolus, 10 mg kg(-1) h(-1) infusion) until 4 h after the start of LPS infusion prevented the lat e hindquarters vasodilatation and attenuated the late renal vasodilata tion, but still reduced mesenteric flow. When treatment with L-NMMA wa s delayed until 24 h after the start of LPS infusion, renal and hindqu arters vasodilatations were only slightly affected, but mesenteric flo w was still compromised. Delayed treatment with L-NAME (3 mg kg(-1) h( -1) starting 24 h after onset of LPS infusion) caused substantial inhi bition of the renal vasodilatation, but also caused marked reduction i n mesenteric and hindquarters hows and indices of cardiac performance. 5 These findings indicate that iNOS activity is not directly responsib le for the widespread vasodilatation seen after 24 h infusion of LPS i n conscious rats. If our observations can be extrapolated to the clini cal situation, they indicate that non-selective NOS inhibition could h ave detrimental effects in endotoxaemic patients with signs of a hyper dynamic circulation.