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NO synthesis and in so doing blocked paw swelling and histopathological changes in the joint
(Stefanovic-Racic, Meyers et al. 1994).
Sepsis is a special picture. Sepsis begins with the exposure to an infectious agent which
induces a cascade of events that initially tries to compensate for the problem with tachycardia,
peripheral vasoconstriction, fever (usually) and increased polymorphonuclear cells. This is
followed by progressive vasodilatation with a high cardiac output and decreased vascular
resistance resulting in hypovolaemic shock and decreased venous return to the heart. This can
progress to a state which is resistant to vasopressor agents and is often combined with a pro-
coagulant state. Increased levels of serum nitrates were found to be correlated with the degree
of systemic vasodilatation (Ochoa, Udekwu et al. 1991; Yoshizumi, Perrella et al. 1993). In
animal studies, NOS inhibitors were used to treat induced sepsis but this was far from
universally successful. The studies did not show improved haemodynamic parameters such as
mean arterial pressure, but there was a further derangement of local blood flow @ooke,
Meyer et al. 1995) resulting in worsened renal (Schwartz, Mendonca et al. 1997) and liver
impairment (Gundersen, Corso et al. 1997) and worsened inflammation generally (Aaron,
Valenza et al. 1998). The timing and dosage were found to be critical, as their use
preventatively or early in shock resulted in worse outcomes (Cohen, Huberfeld et al. 1996;
Strand, Leone et al. 1998). In one study of 12 patients with severe sepsis and hypotension,
low doses of L-NMMA (NOS inhibitor) did result in an increase in pulmonary vascular
resistance but also led to a decrease in cardiac output causing concern that this would result in
poorer tissue perfusion @etros, Lamb et al. 1994). In a further pilot study involving 32
patients with septic shock, the infusion of L-NMMA also resulted in an increase in vascular
tone and a decrease in cardiac index within the first hour of therapy. The infusion continued
for up to eight hours and mean arterial pressure was sustained with a 6O-8OVo reduction of
noradrenaline use (Grover, Zaccardelli et al. 1999). However a much larger multi-centre trial
was then undertaken enrolling 797 patients with septic shock allocated to receive the NOS
inhibitor or placebo for up to 7 days or 14 days in addition to standard therapy. It was
terminated early because of a trend to higher mortality in the treated group by day 28 from
multiple organ failure (Serrano, Casas et al.2004).
2.4
Chapter summary
The idea for doing research into NO in the lung in human adult subjects; in healthy subjects
and in those with respiratory disease, in particular asthma, came at a time when the areas of
environmental pollution and mediator research were rapidly developing. The first area
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