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Reactive gas which has a large number of functions in many different tissues.
Acts as a signalling molecule in blood vessels, has a role in the immune system,
modulates platelet function, acts as a neurotransmitter.
Metabolism
- synthesized from L-arginine by nitric oxide synthase (NOS)
- several forms of NOS: can be broadly classified into constitutive and
inducible types
- iNOS is responsible for the toxic effects of intrinsic NO. Causes a sustained
release of larger amounts of NO from activated neutrophils, vascular endothelium
and microglial cells. Chief inducers are endotoxin and many cytokines.
Can be down-regulated by corticosteroids, IL-4, platelet-derived growth factor
and transforming growth factor b. In the intravascular space combines with haemoglobin to form
nitrosyl-haemoglobin. This forms methaemoglobin which is broken down into
haemoglobin and nitrate by the action of methaemoglobin reductase
Pulmonary circulation
Physiological effects
- transition from fetal circulation involves an increase in nitric oxide and prostacyclin. These are thought to mediate the fall in pulmonary vascular
resistance and consequent rise in pulmonary blood flow
- also thought to be involved in regulation of pulmonary vascular bed in later
life. however role under normoxic conditions may be minimal. Majority of this
effect may come from inhalation of NO from the upper airways
- has been demonstrated that there is little or no expression of cNOS in the
vascular endothelium of pulmonary arteries with severe histologic abnormalities
in patients with chronic pulmonary hypertension
Therapeutic effects of inhaled nitric oxide
- ARDS: in concentrations <40 ppm causes selective vasodilatation in
ventilated lung regions causing a reduction in pulmonary artery pressure. Latter
is not reduced to normal, probably because pulmonary hypertension is due in part
to pulmonary vascular occlusion by microthrombosis and by compression. Results
in improved VQ matching as well as decreased RV afterload. However 3 studies of
the effects of NO on mortality have failed to show a benefit.
- high dose (100 ppm) may decrease
PaO2. Possibly because high concentrations penetrate poorly
ventilated areas and increase shunting.
- may increase left atrial
pressure causing pulmonary oedema in patients with poor LV
function and pulmonary hypertension associated with LV dysfunction
- persistent pulmonary hypertension of the newborn. Unlike intravenous
vasodilators which also cause systemic vasodilatation with a concomitant
increase in R to L shunting, NO causes selective pulmonary vasodilatation (binds
avidly to Hb and is inactivated before it reaches the systemic circulation).
Improves oxygenation in most babies with PPHN. However recent reports suggest
that responsiveness to NO is less when PPHN is associated with lung hypoplasia
or congenital diaphragmatic hernia
- used to test pulmonary vasodilatory capacity in patients with congenital heart
disease or patients referred for cardiac transplantation prior to surgery
- has been used to relieve severe pulmonary hypertension after surgical
correction of congenital heart disease: transient endothelial dysfunction
with lack of endogenous NO production may result from cardiopulmonary bypass
- methaemoglobinaemia and nitrogen dioxide toxicity are
potential hazards. In order to minimize the latter NO and O2
concentrations should be kept as low as possible with minimum contact time
between the two. MetHb, nitric oxide and nitrogen dioxide concentrations should
be monitored when NO is being administered
Pharmacological aspects
- mediates the action of some common vasodilators eg GTN, nitroprusside
- NO synthetase inhibition: may underlie the immunosuppressive and
anti-inflammatory actions of steroids
- L-arginine analogues eg N-nitro-L-arginine methyl ester (L-NAME),
N-mono-methyl-L-arginine (L-NMMA) competitively inhibit both cNOS and iNOS. In
experimental animals and humans increase arterial BP and SVR. Effect on outcome
unknown
- methylene blue oxidises the haem moiety of soluble guanylate cyclase and
inhibits the actions of NO. Improves haemodynamics in septic shock. Again effect
on outcome unknown
– NO present in compressed medical air
Further reading
Kam PCA, Govender G. Nitric oxide: basic science and clinical applications.
Anaesthesia, 1994; 49:515-521
Rossaint R, Pappert D, Falke K. Nitric oxide and pulmonary circulation. Curr
Opinion Crit Care, 1996; 2:29-34
Zimmerman JL, Hanania NA. Vasodilators in mechanical ventilation. Critical
Care Clinics, 1998, 14(4):611-627
© Charles Gomersall December 1999
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