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Nitric oxide

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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

 

©Charles Gomersall, April, 2014 unless otherwise stated. The author, editor and The Chinese University of Hong Kong take no responsibility for any adverse event resulting from the use of this webpage.
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