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

• Published in: British journal of pharmacology 1995-10, Vol.116 (3), p.2005-2016
• Main Authors: Gardiner, S.M., Kemp, P.A., March, J.E., Bennett, T.
• Format: Article
• Language: English
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Arginine - analogs & derivatives; Arginine - pharmacology; Biological and medical sciences; cardiac function; Cardiac Output - drug effects; Disease Models, Animal; Emergency and intensive care: infection, septic shock; Enzyme Induction; Hemodynamics - drug effects; Hypotension - enzymology; Hypotension - physiopathology; inducible nitric oxide synthase activity; Intensive care medicine; Lipopolysaccharide; Lipopolysaccharides - toxicity; Lung - drug effects; Lung - enzymology; Medical sciences; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase - metabolism; NOS inhibitors; omega-N-Methylarginine; Rats; regional haemodynamics; Reproducibility of Results; Stroke Volume - drug effects; Tachycardia - enzymology; Tachycardia - physiopathology
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1995.tb16405.x

1 A reproducible model of the hyperdynamic circulatory sequelae of endotoxaemia in conscious, chronically‐instrumented Long Evans rats, was achieved with a continuous infusion of lipopolysaccharide (LPS, 150 μg kg−1 h−1) 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/dtmax 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−1 mg−1 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 μmol l−1), and further by 6 h (228.10 ± 29.20 μmol l−1), but were less 24 h after onset of LPS infusion (74.96 ± 11.34 μmol l−1). 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 NG‐monomethyl‐L‐arginine (l‐NMMA, 30 mg kg−1 bolus, 30 mg kg−1 h−1 infusion) 1 h before LPS infusion did not prev