Other factors affecting pulmonary vascular tone

In the early 1970s, it became apparent that the pulmonary endothelium metabolised circulating vasoactive substances. Some, such as bradykinin, were removed, whereas others, such as angiotensin II were produced.

During the next decade it was shown that kinins, peptides, catecholamines, lipoproteins, and many other substances were metabolised in the lung. With the discovery and characterisation of the vasodilator, prostacyclin (PGI2), and the vasoconstrictor, thromboxane, it became apparent that the endothelium played an important role in controlling the pulmonary circulation itself.32 In the 1980s it was shown that pulmonary and systemic vessels release a labile endothelium derived relaxing factor (EDRF) which modifies the vasopressor response to various pharmacological agents and to acute hypoxia. It is now clear that EDRF is nitric oxide (NO). The NO is synthesised from L-arginine by nitric oxide synthase. It then diffuses within the cell, or to another cell, where it stimulates soluble guanylyl cyclase or other haem containing proteins. This results in an increase in cyclic guanosine monophosphate (GMP) which produces the physiological effect. For example, in smooth muscle cells cyclic GMP decreases cell calcium which leads to relaxation of the muscle cell and vasodilation. As nitric oxide has a high affinity for haemoglobin with the formation of methaemoglobin, it has a half life measured in seconds. It is also rapidly oxidised to nitrite and nitrate by superoxide radical in the blood vessel wall or by oxygen in free solution.

Vascular tone is controlled by opposing factors which cause constriction or dilatation. Dilatation is induced by acetylcholine, bradykinin, angiotensin converting enzyme inhibitors, and adenine nucleotides, all of which stimulate NO production. It seems likely that pulsatile flow and local shear stress may play an important role in the control of NO release in vivo. There is, however, now evidence that NO may also influence blood pressure by regulating sympathetic nerve activity. Nitric oxide decreases hypoxic vasoconstriction in the lung, and there is evidence that there is either decreased production or increased destruction of NO in systemic and pulmonary hypertension and in ischaemic heart disease. Excessive production of NO may be the cause of the profound vasodilation in septic shock. Nitric oxide also inhibits platelet aggregation. It modulates tubuloglomerular feedback in the kidney, inhibits insulin release, controls the relaxation of sphincters along the gastrointestinal tract, and may also function as a neurotransmitter.33

The NO synthase which subserves intercellular communication is Ca and cadmodulin

dependent, but there is another inducible, Ca independent synthase which releases larger quantities of NO over longer periods from activated macrophages, thus causing NO to act as a cytotoxic agent. More recently other NO synthases have been discovered in tissues other than the reticuloendothelial system, so raising the possibility that NO may be implicated in the causation of other types of cell damage.

The rapid inactivation of NO by haemoglobin and the ability to administer the gas by inhalation has enabled NO to be used as a selective pulmonary vasodilator (see page 203).

In 1988 an endothelially derived vasoconstrictor substance termed endothelin was isolated. Subsequently, three peptides have been identified (ET-1, ET-2, and ET-3). These do not appear to be stored in the endothelium but may be released by such diverse factors as shear stress, hypoxia, endotoxin, tumour necrosis factor (TNFa), interferon, adrenaline, angiotensin, thrombin, activated platelets, and some prostanoids. ET-1 is increased in sepsis but it is not yet clear what role these substances play in the mediation of normal vascular tone.

Arachidonic acid metabolites are also released in sepsis. The cyclo-oxygenase system leads to the formation of prostaglandins, thromboxanes, and PGI2, whereas the lipo-

oxygenase system produces leukotrienes.32

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