PULMONARY HYPERTENSION AND HYPOXIA IN THE NORMAL PULMONARY CIRCULATION Hypoxic vasoconstriction involves mostly small arterioles with an internal diameter of 200 – 600 mm (1) and is predominantly caused by alveolar hypoxia rather than hypoxemia (2) Hypoxic pulmonary vasoconstriction is a disadvantageous physiological response at high altitude. When the whole lung is exposed to hypoxia, hypoxic pulmonary vasoconstriction results in a substantial increase in pulmonary vascular resistance and pulmonary arterial pressure. In lowlanders a vigorous vasoconstrictor response to hypoxia may result in two conditions which may be lethal: high altitude pulmonary oedema (HAPE) and subacute mountain sickness. First described in highlanders in Peru who descended to the seaboard for several days before returning home above 4000 m (3), HAPE is a consequence of a pulmonary capillary leak into the interstitial and alveolar spaces (4). Since the pulmonary capillaries lie downstream of the small pulmonary arteries which vasoconstrict, high pressure in the capillaries could not occur were it not for uneven vasoconstriction resulting in patchy high pressure overperfusion of areas of lung tissue. The condition is rapidly reversible on descent. Subacute mountain sickness is a condition in which chronic hypoxic pulmonary vasoconstriction leads to right heart failure in children in Tibet (5). It has also been reported in soldiers who engaged in strenuous exercise at 5800 – 6700 m for several months (6). PULMONARY HYPERTENSION: PATHOPHYSIOLOGY IN THE DISEASED PULMONARY CIRCULATION PH exists when the mean pulmonary arterial pressure is greater than 25 mm Hg (7). This may as a consequence of increased resistance to blood flow in the pulmonary circulation, increased downstream pressures in the left side of the heart requiring an increased pulmonary arterial pressure to maintain forward flow in the pulmonary circulation, a high cardiac output or a combination of these haemodynamic situations. The clinical consequence of maintaining a high pulmonary arterial pressure is to increase the afterload on the right ventricle resulting in uncoupling of the right ventricle and pulmonary circulation. The right ventricle progressively dilates and undergoes hypertrophy. Ultimately myocardial failure supervenes with a progressive fall in cardiac output resulting in death. For many of its causes pulmonary hypertension has a poor prognosis. Increased vascular resistance in the pulmonary circulation may be a consequence of hypoxic pulmonary vasoconstriction, pulmonary arterial hypertension, parenchymal lung disease, myocardial and / or valve diseases of the left side of the heart, chronic thromboembolic disease as well as a variety of unknown mechanisms. Chronic hypoxic pulmonary vasoconstriction results in medial hypertrophy of the pulmonary arteries. In contrast pulmonary arterial hypertension may result in vasoconstriction not associated with hypoxia, intimal proliferation into the vessel lumen causing obstruction to blood flow as well as the formation of vascular plexiform lesions and thrombosis. Progression of pulmonary arterial hypertension is associated with the development of hypoxaemia as a consequence of ventilation perfusion mismatch and low cardiac output. Parenchymal lung disease such as chronic obstructive pulmonary disease (COPD) may cause pulmonary hypertension as a consequence of hypoxic pulmonary vasoconstriction but as lung parenchyma is lost as in emphysema or becomes fibrosed so too do its blood vessels, and the overall cross-sectional area of the pulmonary circulation is reduced. Other proposed mechanisms of pulmonary hypertension in lung disease include inflammation of blood vessels, and vasoconstriction caused by mechanical hyperinflation. DRUG THERAPY FOR PULMONARY HYPERTENSION: WHO BENEFITS AND WHO DOES NOT? It is clear that long-term oxygen therapy is the treatment of choice for patients with chronic hypoxic pulmonary vasoconstriction. In particular long-term oxygen may reduce progression of pulmonary hypertension in COPD although structural changes in the blood vessels remain unchanged. Disease specific targeted drug therapies for pulmonary arterial hypertension fall into three groups: prostacyclin and its analogues, endothelin receptor antagonists and phosphodiesterase 5 inhibitors. Drug therapies used in pulmonary arterial hypertension may worsen gas exchange in patients with chronic parenchymal lung disease due to inhibition of pulmonary vasoconstriction. Vasodilators have not been shown to improve long-term outcomes and no trials of drug therapies for pulmonary arterial hypertension have shown these drugs to be effective.