Nitric oxide was formerly known as endothelium-derived relaxing factor (EDRF). It is one of the nitrogen oxides ("NOx") and is synthesized within cells by an enzyme NO synthase (NOS). This enzyme catalyses the oxidation of L-arginine to L-citrulline, producing NO, which diffuses into vascular smooth muscle, activating guanylate cyclase which in turn converts guanosine triphosphate into cyclic guanosine monophosphate (cGMP), causing vascular relaxation.
NOS is present in two forms:
The constitutive form (eNOS)
Present in vascular, neuronal, cardiac tissue, skeletal muscle and platelets, producing small quantities of NO continuously. Here NOS is Ca2+/calmodulin dependant and is stimulated by cGMP.
The inducible form (iNOS)
Present in endothelium, myocytes, macrophages and neutrophils, which produces relatively large quatities of NO after exposure to endotoxins in sepsis. Following induction high levels of NO produced may form cytotoxic radicals and cause capillary leakage.
Nitric oxide acts as a biological mediator throughout the body but especially in:
• Vascular endothelium: responsible for vascular relaxation.
• Platelets: involved in aggregation and adhesion.
• Brain tissue: acts as a neurotransmitter.
• Macrophages: involved in the response to infection.
PGH2 = prostaglandin H2; TBA2 = thromboxane; O2 - = superoxide anion; EDRF = endothelium-derived relaxing factor; EDCF = endothelium-derived contracting factors; K sup + = potassium ion; cGMP = cyclic guanosine monophosphate; cAMP = cyclic adenosine monophosphate.
Nitric oxide (NO) increases the permeability of the potassium channels, leading to a hyperpolarization of the plasma membrane that prevents subsequent contraction. NO and prostacyclin (PGI2 ) inhibit platelet aggregation and platelet or monocyte adhesion to the endothelium, and stimulate platelet disaggregation.
Nitric oxide is a potent vasodilator. Shear stresses in vessels increase NO production and may account for flow dependant vasodilatation. Endothelial NO inhibits platelet aggregation. In septic shock the overproduction of NO results in hypotension and capillary leak. NOS inhibitors have been investigated experimentally in the treatment of sepsis.
Important basal vasodilatation in pulmonary vessels is provided by endogenous NO and this may be reversed in hypoxia. Nitric oxide inhibits hypoxic pulmonary vasoconstriction and preferentially increases blood flow through well-ventilated areas of the lung, thereby improving ventilation: perfusion relationships.
Nitric oxide appears to have a physiological role as a neurotransmitter within the autonomic and central nervous system. Proposed roles include modulation of the state of arousal, pain perception, apoptosis and long term neuronal depression and excitation whereby neurones may “remember” previous signals. Peripheral neurones containing NO control regional blood flow in the corpus cavernosum.
NO is a determinant of gastrointestinal motility and appears to modulate morphine-induced constipation.
Nitric oxide may play a role in sodium homeostasis in the kidney. It is the physiological mediator of penile erection.
Macrophages and neutrophils synthesize NO which can be toxic to certain pathogens and may be important in host defence mechanisms.
Platelet aggregation is inhibited by NO
In neonatal, paediatric or adult pulmonary hypertension, inhaled NO (1-150 ppm) has been used to produce selective pulmonary vasodilatation. Its use in ARDS is increasing although clear effects on outcome have not been conclusively demonstrated.
NO is stored in aluminium or stainless steel cylinders which are typically 40 litres. These contain 100/1000/2000 p.p.m. nitric oxide in nitrogen. Pure NO is corrosive and toxic.
The drug is injected via the patient limb of the inspiratory circuit of a ventilator. The delivery system is designed to minimise the oxidation of nitric oxide to nitrogen dioxide.
Inhaled NO readily reacts with oxidised haemoglobin to yield methaemoglobin. NO has a half-life of less than 5 seconds.
Chemiluminescence and electrochemical analysers should be used and are accurate to 1 ppm.
Exposure to 500-2000 ppm of NO results in methaemoglobinaemia and pulmonary oedema. Methaemoglobinaemia is only rarely significant and is more common in paediatric patients or those with methaemoglobinaemia reductase deficiency. Contamination by nitrogen dioxide can similarly lead to pneumonitis and pulmonary oedema. Environmental levels should not exceed 25 ppm for 8 hours (time-weighted average).