PHYSIOLOGICAL SOCIETY SYMPOSIUM: CONTOL OF THE PULMONARY CIRCULATION

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1 Experimental Physiology (1995), 80, Printed in Great Britain PHYSIOLOGICAL SOCIETY SYMPOSIUM: CONTOL OF THE PULMONARY CIRCULATION CLINICAL ASPECTS OF HYPOXIC PULMONARY VASOCONSTRICTION R. M. LEACH AND D. F. TREACHER Department of Intensive Care Medicine, Guy's and St Thomas' Hospital Trust, London SE] 7EH, UK (MANUSCRIPT RECEIVED 20JUNE 1995, ACCEPTED 11 JULY 1995) SUMMARY Although frequently unrecognized, hypoxic pulmonary vascular disease is an important cofactor in the morbidity and mortality of a wide spectrum of disease processes. The hypoxic response incorporates two distinct phases, the acute hypoxic vasoconstrictor response and vascular remodelling associated with prolonged alveolar hypoxia. Understanding of the mechanisms causing both processes has increased rapidly and may result in the near future in specific treatment aimed at correcting underlying physiological abnormalities. However, currently available therapies remain limited to correction of the hypoxaemia and generalized non-specific pulmonary vasodilatation. The recent development of inhaled NO therapy represents a significant advance in the management of the acute hypoxic pulmonary vasoconstriction occurring during critical illness. INTRODUCTION Teleologically, acute hypoxic pulmonary vasoconstriction (AHPV) is an inherent property of the lung that developed as a protective mechanism designed to divert blood from poorly ventilated alveoli and maintain or improve ventilation: perfusion relationships. When generalized, this physiological process may become pathological and result in significant and detrimental increases in pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR) and right ventricular workload (Harris & Heath, 1986 a, c). In the clinical situation, hypoxic pulmonary vasoconstriction (HPV) may occur as an acute episode during rapidly progressive critical illness or as a sustained response with pulmonary hypertension (PHT) in progressive lung disease. Widespread alveolar hypoxia occurs during many acute medical illnesses, including those causing airways obstruction (asthma and inhalation of foreign objects), failure of ventilation (acute spinal and neurological disease) or acute lung damage (pneumonia and acute respiratory distress syndrome). The resulting AHPV may have profound haemodynamic consequences, including a reduction in cardiac output, increased pulmonary vascular permeability and right ventricular failure, but it is immediately reversible if adequate alveolar oxygenation can be re-established. Increased PAP and PVR may encourage the recruitment of low-pressure pulmonary vascular shunts with a subsequent reduction in systemic arterial oxygenation. Recurrent episodes of AHPV in patients with normal lungs but episodes of hypoventilation and severe arterial desaturation, as in obstructive sleep apnoea, may result in the development of chronic pulmonary hypertension despite a normal arterial partial pressure of oxygen (Pa,o2) Presented at the Oxford Meeting of the Society in July 1995.

2 866 R. M. LEACH AND D. F. TREACHER during much of the day. Chronic generalized alveolar hypoxia occurs in populations living at high altitude or as a result of pulmonary diseases which restrict ventilation (chronic obstructive airways disease (COAD), kyphoscoliosis, polio and sleep apnoea) or cause progressive lung destruction (emphysema and fibrosising alveolitis). In contrast to the immediately reversible AHPV, prolonged alveolar hypoxia results in persistent elevation of PAP, which is not immediately or totally reversible with correction of alveolar oxygen concentrations to normal values (Harris & Heath, 1986c). Persistent HPV and the associated vascular structural remodelling are the principal mechanisms for the sustained increase in PAP and PHT although other factors, including secondary polycythaemia, hypercapnia and increased airways resistance may be involved (Harris & Heath, 1986c). Although the contribution of these mechanisms will vary according to the disease, their combined effect is an established cause of morbidity and mortality resulting from cor pulmonale (Voelkel, 1986). The clinical and therapeutic management of AHPV and chronic PHT must be directed to correcting the vascular and haemodynamic derangements. In this article, the mechanisms, aetiology and pathological processes are briefly discussed with the primary emphasis being directed to current and future therapies. It should be recognized that the clinical and pathological consequences of hypoxic PHT tend to be less severe and are quite distinct from those due to primary PHT and the PHT secondary to cardiac lesions, which are not discussed in this review. ACUTE HYPOXIC PULMONARY VASOCONSTRICTION The mechanism of acute hypoxic pulmonary vascular smooth muscle contraction is complex. The process requires an oxygen sensor to detect hypoxia and a transduction mechanism to transfer this information to the vascular smooth muscle, which finally effects the contractile process. Despite considerable progress over the last 50 years, these physiological mechanisms have not been fully elucidated. Experimental evidence indicates that AHPV occurs at a local level primarily in the pulmonary resistance arterioles and is independent of circulating humoral substances or neural mechanisms (Glazier & Murray, 1971; Harris & Heath, 1986 a; Voelkel, 1986). In addition, it has been suggested that the oxygen sensor, transducer and contractile mechanisms are all intrinsic properties of the pulmonary vascular smooth muscle (Murray, Chen, Marshall & Macarak, 1990). Experimentally, AHPV is associated with pulmonary vascular smooth muscle cell (PVSMC) membrane depolarization and extracellular Ca2+influx through voltage-gated channels sensitive to dihydropyridines (McMurtry, Davidson, Reeves & Grover, 1976). Recent evidence suggests that potassium channel inhibition may have an important role in mediating these effects and, in the isolated PVSMC, hypoxia reduces the amplitude of outwardly directed Ca2k-sensitive potassium currents measured by the patch-clamp technique (Post, Hume, Archer & Weir, 1992). However, there is evidence that endothelium-derived vasoactive factors may be essential in both mediating and modulating AHPV, and studies in isolated human and animal pulmonary arteries have demonstrated that HPV is dependent on an intact endothelium (Demiryurek, Wadsworth, Kane & Peacock, 1993; Leach, Robertson, Twort & Ward, 1994). The oxygen sensor responsible for initiating the contractile response in the PVSMC is unknown, but changes in redox potential, energy state and hydrogen peroxide-mediated activation of smooth muscle guanylate cyclase have all been proposed (Voelkel, 1986; Burke-Wolin & Wolin, 1990). AHPV is observed with expired oxygen concentrations of 8-10 % and in vitro at a P02 of

3 HYPOXIC PULMONARY VASOCONSTRICTION 867 between 30 and 50 mmhg (Harris & Heath, 1986c). Maintained AHPV is associated with progressive waning of the acute pressor effect but following periods of prolonged alveolar hypoxia with vascular remodelling it can be demonstrated that the AHPV response is clearly maintained (Harris & Heath, 1986a; Voelkel, 1986). Thus, in the clinical situation, a sudden acute deterioration of chronic alveolar hypoxia is associated with AHPV of a degree similar to or greater than that seen in the absence of the pre-existing PHT and results in further deterioration in pulmonary haemodynamics, often with catastrophic consequences (Harris & Heath, 1986c). Patients with established PHT who experience periods of hypoxia in the postoperative period following cardiothoracic surgery have been demonstrated to have a very high morbidity and mortality. In the clinical situation, the management of the patient with AHPV revolves around reestablishing adequate alveolar oxygenation and ventilation. Initially the inspired oxygen concentration (F 02) must be increased whilst the underlying pathology is corrected. Upper airways obstruction must be reversed by removing or bypassing obstructing lesions from upper airways (mucous, foreign bodies or epiglottitis). Bronchodilator drugs (salbutamol and ipratropium bromide) and anti-inflammatory agents (steroids) reverse bronchospasm and inflammation in small airways (e.g. in asthma, COAD and bronchiolitis). Failure of alveolar ventilation (e.g. in kyphoscoliosis or neuromuscular weakness) may require ventilatory support using both non-invasive (cuirass and nasal intermittent positive pressure ventilation) and invasive (tracheostomy and mechanical ventilation) techniques. These simple manoeuvres may be all that is required to reverse the hypoxia and AHPV. However, in the presence of widespread acute alveolar damage the situation can be more complex. In pneumonia or the adult respiratory distress syndrome (ARDS) widespread inflammation and epithelial damage may result in widely differing degrees of ventilation :perfusion mismatch in adjacent areas of lung. Arterial hypoxaemia due to large shunt fractions may cause PHT, increase right ventricular workload and eventually result in right heart failure (Rossaint, Falke, Lopez, Slama, Pison & Zapol, 1993). The high PAP and epithelial disruption may further increase alveolar oedema with progressive arterial hypoxaemia. Reducing the abnormally elevated PVR with intravenous pulmonary vasodilators (prostacyclin, nitrates or calcium antagonists) will reduce PAP and the effective pulmonary capillary pressure, thereby promoting reabsorption of pulmonary oedema and improving right ventricular function. However, the efficacy of the vasodilator is limited by the increased pulmonary shunt fraction, which may further reduce the already compromised partial pressure of arterial oxygen. In addition, the concomitant systemic hypotension associated with these vasodilators may cause right ventricular ischaemia and consequent heart failure (Gottlieb, Wood, Hansen & Long, 1987). Inhalation of nitric oxide (NO) has recently been demonstrated to be of value in the management of patients with severe alveolar damage, arterial hypoxaemia and PHT (Rossaint et al. 1993). In vivo, the vascular endothelium synthesizes NO, a powerful local vasodilator, from the terminal guanidino nitrogen atom of the amino acid L-arginine. NO relaxes muscular arteries by activating guanylate cyclase and increasing cyclic guanosine 3',5'-monophosphate (cgmp). In the blood, NO is rapidly bound and inactivated by haemoglobin, preventing systemic side-effects. Theoretically, when inhaled in the respiratory gas mixture, the vasodilatory effects of NO should be limited to vessels in ventilated alveoli, selectively enhancing perfusion of ventilated regions, reducing pulmonary shunting and improving arterial oxygenation (Zapol, Rimar, Gillis, Marletta & Bosken, 1994). In practice, inhalation of NO

4 868 R. M. LEACH AND D. F. TREACHER 120 I- N"kJ '- VP."'-!. IN".' '.'-" I'V"'!Ei100 -o,,%.. *--C>"...o.O e -o 0 m 60- EI\ 0 t Time (min) Fig. 1. inhaled nitric oxide therapy (20 p.p.m.) in a 36-year-old woman with severe acute respiratory distress syndrome. Response of mean pulmonary artery pressure (PAP), mean systemic blood pressure (BP) and Pa,O, to cessation of gas at a concentration of 5-80 p.p.m. dilates the pulmonary circulation of conscious, spontaneously breathing lambs in which acute vasoconstriction has been induced by breathing a hypoxic gas mixture or by infusing a stable thromboxane-endoperoxide analogue (Frostell, Fratacci, Wain, Jones & Zapol, 1991). Similarly, in patients with primary PHT, inhaling NO (40 p.p.m.) produced pulmonary vasodilatation equivalent to that observed with prostacyclin (Pepke-Zaba, Higenbottam, Dinh-Xuan, Stone & Wallwork, 1991). In a recent study of patients with severe ARDS, treatment with inhaled NO (18 p.p.m.) was compared with intravenous prostacyclin (Rossaint et al. 1993). Nitric oxide reduced PAP from to mmhg (P < 0.05), decreased shunt fraction from to % (P < 0.05), reduced pulmonary vascular resistance and significantly increased arterial oxygen tension. The systemic vascular resistance (SVR) and blood pressure (BP) were unaffected. The improvements in pulmonary haemodynamics and arterial oxygenation with NO inhalation were maintained with no evidence of tachyphylaxis. In contrast, although prostacyclin infusion (4 ng kg-' min-1) reduced PAP and PVR, intrapulmonary shunt increased and arterial oxygen tensions, SVR and systemic BP fell. A typical response to NO inhalation in a patient with severe ARDS is illustrated in Fig. 1. A marked variation has been reported for the haemodynamic and respiratory effects of NO inhalation between patients with ARDS and within the same patient at different times in the course of the disease (Zapol et al. 1994). In general, those patients with the most severe PHT respond most effectively (Zapol et al. 1994). Almitrine, a pulmonary vasoconstrictor drug, further reduced shunt fraction during NO inhalation, possibly by increasing vasoconstriction in the shunting lung regions (Zapol et al. 1994). The well-recognized harmful effects of high concentrations of NO are due to the formation of nitrogen dioxide (Zapol et al. 1994). It is therefore essential that the treatment is delivered through the appropriate equipment and is adequately monitored. The most recent studies suggest that NO concentrations even as low as p.p.b. can achieve an effective response

5 HYPOXIC PULMONARY VASOCONSTRICTION 869 Table 1. Nocturnal pulmonary artery catherization in a patient with severe COAD, SAS and nocturnal hypoxaemia Baseline, h Nadir, h Morning after, h Pa,02 PAP Pao, PAP Pa02 PAP (mmhg) (mmhg) (mmhg) (mmhg) (mmhg) (mmhg) Control, night Verapamil, night Study performed on consecutive nights: night 1, control; night 2, patient treated with an intravenous verapamil infusion (2 mg h-' following 5 mg stat dose from to h). Pulmonary artery pressure (PAP) was measured continuously. in some patients with ARDS (Zapol et al. 1994). Discontinuation of NO therapy is associated with a rapid return of PAP and PaO02 to baseline levels (Fig. 1) and can, on occasions, produce severe vasoconstriction requiring slower weaning of therapy (Zapol et al. 1994). However, the recent advent of NO therapy represents a valuable therapeutic strategy in the management of AHPV. The recurrent AHPV observed due to alveolar hypoventilation in sleep apnoea syndrome (SAS) represents another interesting clinical challenge. The conditions associated with SAS include primary hypoventilation, central neurological lesions, Pickwickian syndrome (obesity-hypoventilation syndrome) and structural obstruction of the upper airways (Harris & Heath, 1986c). The majority of apnoeic attacks are caused by obstruction in the pharynx and may last up to 2 min (Harris & Heath, 1986c). During these episodes severe arterial hypoxaemia causes a marked elevation in PAP (Table 1). In a severe case, over half the night may be occupied by apnoea. The recurrent AHPV eventually results in the development of PHT and right heart failure (Harris & Heath, 1986c). Therapy is aimed at relieving nocturnal laryngeal obstruction and improving alveolar oxygenation. Loss of weight, supplemental oxygen and nocturnal nasal intermittent positive pressure ventilation (NIPPV) have been demonstrated to be beneficial. Pulmonary vasodilators may have dramatic effects on reversing HPV (Table 1) but the long-term therapeutic use of vasodilators to reverse PHT has been limited by systemic hypotension and increased pulmonary shunting, which cause further deterioration in the arterial oxygen tension. Increased shunting is unlikely in the presence of uniform alveolar hypoventilation, but most patients with SAS have associated lung disease and pure alveolar hypoventilation is relatively uncommon. However, long-term vasodilator therapy may be beneficial in some patients unable to tolerate currently available ventilatory techniques. CHRONIC HYPOXIC PULMONARY VASOCONSTRICTION AND HYPERTENSION Investigation of the pulmonary vascular response to chronic alveolar hypoxia has proved difficult. The response differs between and within species and is influenced by anatomical, biochemical and physiological factors (Harris & Heath, 1986c; Voelkel, 1986; Palevsky & Fishman, 1990). Nevertheless, a sustained increase in pulmonary vascular tone, which is mediated through contraction of muscular arteries and resistance arterioles, has been demonstrated in experimental animals maintained under prolonged hypoxic conditions, in humans dwelling at high altitudes and in human disease states associated with chronic alveolar hypoxia (Harris & Heath, 1986b; Palevsky & Fishman, 1990). This prolonged vasospastic

6 870 R. M. LEACH AND D. F. TREACHER response is associated with a complex pathological structural remodelling throughout the pulmonary circulation and in all components of the vascular wall (Harris & Heath, 1986c). Although many factors, including acidosis and raised Pco2, may potentiate HPV it is clear that the primary influence is the prolonged alveolar hypoxia (Harris & Heath, 1986a). Thus, in high-altitude dwellers with a low PCo, and patients with chronic lung disease with a high Pco02 the PHT and pathological changes are identical (Harris & Heath, 1986b,c). The increased vascular tone. is at least partially reversible, but whether the prolonged HPV observed is mechanistically' the same as AHPV has not been established. Several secondary factors play a minor role in the development of hypoxic PHT. Blood viscosity is increased owing to hypoxiainduced polycythaemia and raises PVR according to the Poiseuille equation (Harris & Heath, 1986 c). Repeated, phlebotomy to reduce blood viscosity and packed cell volume in patients with COAD effectively reduces PAP and PVR but not to normal values. Cardiac output and Pa 2 are unaffected. In chronic lung disease, increased airways resistance and destruction of alveolar blood vessels may contribute to PHT (Palevsky & Fishman, 1990). Experimental and theoretical evidence suggests that the increased alveolar pressure during expiration compresses pulmonary blood vessels, increasing mean PVR. However, morphometry has shown no correlation between total alveolar surface area (hence blood vessels) and right ventricular hypertrophy (Harris & Heath, 1986 c). Basal tone in PVSMC results from a balance between vasodilator and vasoconstrictor influences (Dinh-Xuan, Higenbottam, Clelland, Pepke-Zaba, Cremona & Butt, 1991; Rodman, 1992). Recent studies suggest that a defect in pulmonary vasodilatation and, in particular, a failure of endothelium-mediated PVSMC relaxation may be the primary factor responsible for PHT associated with chronic hypoxia (Dinh-Xuan et al. 1991; Crawley, Zhao, Giembycz, Liu, Barnes, Winter & Evans, 1992). Nitric oxide has been established as the major mediator of endothelium-dependent vascular relaxation by stimulating soluble guanylate cyclase and increasing cgmp production in PVSMC (Zapol et al. 1994). Hypoxia reduces soluble guanylate cyclase activity, but early data suggest that L-arginine, a precursor of NO, may reverse this endothelial dysfunction (Palevsky & Fishman, 1990; Crawley et al. 1992). The structural pulmonary vascular changes seen with chronic alveolar hypoxia are independent of the underlying cause (Harris & Heath, 1986c). Collagen and elastin are deposited in the adventitia, longitudinal muscle appears in the intima, smooth muscle hypertrophy and hyperplasia occurs in the media and new muscle develops in distal arterioles (Harris & Heath, 1986c; Palevsky & Fishman, 1990). Cultured smooth muscle cells from hypoxic animals produce an elastogenic factor not found in the cellular media from control animals (Mecham, Whitehouse, Wrenn, Parks, Griffin, Senior, Crouch, Stenmark & Voelkel, 1987). However, cultured smooth muscle cells exposed to hypoxia alone do not produce this factor and r6cent evidence from intact vessels suggests that stretch and endothelial function are required in addition to hypoxia to stimulate matrix production (Tozzi, Poiani, Harangozo, Boyd & Riley, 1989). Inhibition of collagen formation with cis-hydroxyproline substantially reverses structural remodelling and decreases PVR in experimental models of hypoxic PHT (Poiani, Tozzi, Choe, Yohn & Riley, 1990). Potential cellular mitogens that may stimulate smooth muscle cell DNA synthesis have been demonstrated to increase in hypoxic lungs. These include endothelin, the polyamines (spermine) and platelet-derived growth factors (Katayose, Ohe, Yamauchi, Ogata, Shirato, Fujita, Shibahara & Takishima, 1993). Primarily therapy must be directed at preventing the development of recurrent or persistent alveolar hypoxia and the progression of chronic lung disease. In experimental animals and SAS it has been demonstrated that even short periods of daily hypoxia result in maintained

7 HYPOXIC PULMONARY VASOCONSTRICTION PHT (Harris & Heath, 1986 c). Similarly, inhomogeneity of ventilation: perfusion ratios in chronic lung disease may initiate the pathophysiological conditions for the development of PHT at a local level, with progressive generalization as the disease deteriorates. Essential therapeutic measures include smoking cessation and bronchodilator therapy to improve alveolar oxygenation in COAD, continuous positive airways pressure in obstructive sleep apnoea and mechanical ventilatory assistance in patients with respiratory muscle weakness. Only when therapy aimed at preventing and controlling the primary disease has been optimized should specific effort be directed to the control of PHT. In established PHT, therapy aims to reverse the mechanisms responsible for the prolonged vasospastic response and structural remodelling. Current options include the use of supplemental oxygen and vasodilator therapy. Treatment aimed at reversing the HPV is at least partially effective, but rarely returns PAP and PVR to normal values (Harris & Heath, 1986c). Even relatively high concentrations of supplemental oxygen (Fio,2 > 80 %) fail to achieve significant improvements in pulmonary haemodynamics despite increased arterial oxygenation (Harris & Heath, 1986c). The results of trials of long-term oxygen therapy (LTOT) for severe COAD also indicate that reversal of PHT is incomplete. In the Medical Research Council (1981) study, PAP increased by 3 mmhg per year in control patients surviving 500 days, whilst in patients treated with oxygen there was no change. In the Nocturnal Oxygen Therapy Trial (1980) there was a 7 % increase in PVR over 6 months in patients receiving nocturnal oxygen therapy compared with an 11 % decrease in patients on continuous oxygen therapy. Patients with less severe PHT in this study demonstrated improved survival. A small beneficial effect on pulmonary haemodynamics, but incomplete reversal of pre-existing PHT was also reported in the Sheffield LTOT study (Cooper, Waterhouse & Howard, 1987). Despite these disappointing haemodynamic results, arterial oxygenation improved and LTOT was associated with considerable benefit in terms of morbidity and mortality. Although these results suggest that hypoxaemia may be the critical factor in determining prognosis, there is considerable evidence that PHT is of prognostic significance and that correcting haemodynamic factors may have additional benefit (Voelkel, 1986). The efficacy of vasodilator therapy in terms of prognosis and reversal of chronic hypoxic PHT has not been established. A variety of mechanistically distinct vasodilators have been demonstrated to partially correct the increased PVR associated with hypoxia-induced PHT in experimental animals and clinically stable patients with chronic alveolar hypoxia. This suggests a partially reversible component to the vasospasm in this situation (Agostoni, Doria, Galli, Tamborini & Guazzi, 1984). The benefit is greater during acute exacerbations of chronic disease. However, most of these agents lack specificity for the pulmonary circulation and cause clinically significant systemic hypotension at doses required to improve PVR. In addition, vasodilator therapy may increase perfusion through unventilated lung, increasing the shunt fraction and decreasing arterial oxygenation (Harris & Heath, 1986c). The therapeutic value of long-term vasodilator therapy has not been closely studied. It has been reported that the short-term benefit of nifedipine in reducing PAP and PVR was not maintained with long-term therapy (Agostoni et al. 1984). However, in a recent study the effect of long-term therapy (8-12 weeks) with verapamil (160 mg b.i.d. orally; n - 5) was compared with placebo (n = 6) in clinically stable patients (age years old) with severe COAD (FEVy (forced expiratory volume in 1 s), ), stable hypoxaemia over a 6 week period (Pa,o *9 kpa; Pa Co2, kpa) and no systemic cardiovascular disease. At the start and on completion of 8-12 weeks of therapy the right atrial, PAP and pulmonary arterial occlusion pressures were measured by pulmonary artery catheterization. Cardiac output was 871

8 872 R. M. LEACH AND D. F. TREACHER Verapamil Placebo E 25 < Before After Before After Eu > Before After Before After Fig. 2. Comparison of the mean pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) in patients with severe COAD, before and after 8-12 weeks therapy with verapamil (n = 5; 160 mg b.i.d. orally) or placebo (n = 6). 0, individual data for each patient; 0, mean and standard error for each group. * P < determined by standard thermodilution techniques. A significant reduction in PAP and PVR (P < 0 05; Student's paired t test) was observed in patients treated with oral verapamil for 8-12 weeks (Fig. 2) without clinically significant systemic hypotension. The PVR decreased by % and PAP by % in the treatment group compared with and %, respectively, in the placebo group (P < 0.05). No significant change was observed in cardiac output, Pa02') oxygen delivery or carboxyhaemoglobin in the verapamil or placebo groups (Table 2). The decrease in PVR and PAP seen with long-term verapamil treatment is similar to that described during short-term treatment with a variety of vasodilators in stable hypoxic PHT (Voelkel, 1986). These results suggest that prolonged vasodilator therapy is effective at reducing PAP and PVR. The mechanism by which verapamil improved the pulmonary haemodynamics during long-term therapy cannot be determined from this study. Both reversal of the vasospastic component of hypoxia-induced PHT and regression of pulmonary vascular remodelling due to the decrease in HPV may have a role. Although previous studies of long-term vasodilator therapy have not demonstrated a clear survival benefit, further investigation of the benefit of combined LTOT and vasodilator therapy may be justified.

9 HYPOXIC PULMONARY VASOCONSTRICTION 873 Table 2. Cardiac output, oxygen delivery, Pa O2 and carboxyhaemoglobin before and after 8-12 weeks therapy with verapamil (n = 5) or placebo (n = 6) in patients with severe COAD Cardiac output Oxygen delivery Pao2 Carboxyhaemoglobin (1 min-') (ml min-') (mmhg) (%) Verapamil (160 mg b.i.d. orally) Before After Placebo Before After All changes were not statistically significant. Recent studies have demonstrated selective endothelial dysfunction with a reduction in production of endothelium-derived relaxing factor (NO) in conditions causing prolonged alveolar hypoxia (Crawley et al. 1992). The value of inhaled NO to reduce PVR and increase arterial oxygenation by improving ventilation: perfusion characteristics of the pulmonary circulation has been described in the therapy of AHPV. Although NO therapy may improve pulmonary haemodynamics in hypoxia-induced PHT, it is unlikely to be of practical therapeutic benefit because the extremely short biological activity of this substance necessitates continuous inhalational therapy, which may be expensive. In addition, the long-term effects of NO on other organ systems have not been defined (Zapol et al. 1994). Alternative strategies aimed at augmenting NO production in the pulmonary circulation require further investigation. At present, therapy aimed at reversing the structural remodelling and matrix deposition in pulmonary arteries remains experimental. Specific therapy directed at preventing and reversing the pathological changes associated with hypoxia-induced PHT may be expected with improved understanding of the aetiological and developmental mechanisms involved in the progression of the disease process. HYPOXIC PULMONARY VASOCONSTRICTION AT HIGH ALTITUDE The PHT existing in indigenous populations living at high altitude is well documented (Harris & Heath, 1986b). Comparative examination of the pathological processes in the pulmonary circulation has demonstrated that changes observed in high-altitude dwellers are similar to those in patients with chronic lung disease (Harris & Heath, 1986b; Palevsky & Fishman, 1990). The increased PVR in highlanders is well tolerated, with a normal physical capacity capable of sustaining heavy labour. On returning to sea level there is an immediate decrease in PAP, presumably due to the release of HPV (Harris & Heath, 1986b). This is followed by a more gradual return of PAP to normal over 6 weeks, thought to be related to reversal of the structural remodelling of the pulmonary vessels. Clinical problems related to living at high altitude are infrequent (Harris & Heath, 1986b). Chronic mountain sickness (Monge's disease) is characterized by alveolar hypoventilation, PHT and severe polycythaemia. The condition presents with lethargy and progressively severe

10 874 R. M. LEACH AND D. F. TREACHER neuropsychiatric symptoms. The effective treatment is immediate transport to sea level. Highaltitude pulmonary oedema (HAPO) occurs in highlanders returning to high altitude after even short periods at low levels and in unacclimatized subjects exposed to rapid reductions in barometric pressure (skiers and mountain climbers). The illness develops within 2-7 days and is associated with the typical clinical and radiological features of pulmonary oedema. Cardiac output is often reduced and both PAP and PVR are considerably increased. Treatment with oxygen or descent to a lower altitude usually reduces PAP and reverses the pulmonary oedema but does not always prevent a fatal outcome. Diuretics and morphine are frequently administered, but their efficacy is unproven and they may even be harmful. In contrast, nifedipine has proven benefit in the prevention and treatment of HAPO (Bartsch, Maggiorini, Ritter, Noti, Vock & Oelz, 1991). REFERENCES AGOSTONI, P., DORIA, E., GALLI, C., TAMBORINI, G. & GUAZZI, M. D. (1984). Nifedipine reduced pulmonary pressure and vascular tone during short- but not long-term treatment of pulmonary hypertension in patients with chronic obstructive pulmonary disease. American Review of Respiratory Disease 139, BARTSCH, P., MAGGIORINI, M., RITTER, M., NOTI, C., VOCK, P. & OELZ, 0. (1991). Prevention of high altitude pulmonary edema by nifedipine. New England Journal of Medicine 325, BURKE-WOLIN, T. M. & WOLIN, M. S. (1990). Inhibition of cgmp-associated pulmonary arterial relaxation to H202 and 02 by ethanol. American Journal of Physiology 258, H COOPER, C. B., WATERHOUSE, J. & HOWARD, P. (1987). Twelve year clinical study of patients with hypoxic cor pulmonale given long term domiciliary oxygen therapy. Thorax 42, CRAWLEY, D. E., ZHAO, L., GIEMBYCZ, M. A., Liu, S., BARNES, P. J., WINTER, R. J. D. & EVANS, T. W. (1992). Chronic hypoxia impairs soluble guanylyl cyclase-mediated pulmonary arterial relaxation in the rat. American Journal of Physiology 263, L DEMIRYUREK, A. T., WADSWORTH, R. M., KANE, K. A. & PEACOCK, A. J. (1993). The role of endothelium in hypoxic constriction of human pulmonary artery rings. American Review of Respiratory Disease 147, DINH-XUAN, A.T., HIGENBOTTAM, T. W., CLELLAND, C. A., PEPKE-ZABA, J., CREMONA, G. & BuTT, A. Y. (1991). Impairment of endothelium-dependent pulmonary artery relaxation in chronic obstructive lung disease. New England Journal ofmedicine 324, FROSTELL, C., FRATACCI, M. D., WAIN, J. C., JONES, R. & ZAPOL, W. M. (1991). Inhaled nitric oxide: a selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation 83, GLAZIER, J. B. & MURRAY, J. F. (1971). Sites of pulmonary vasomotor reactivity in the dog during alveolar hypoxia and serotonin and histamine infusion. Journal of Clinical Investigation 50, GOTTLIEB, S. S., WOOD, L. D., HANSEN, D. E. & LONG, G. R. (1987). The effect of nitroprusside on pulmonary edema, oxygen exchange, and blood flow in hydrochloric acid aspiration. Anesthesiology 67, HARRIS, P. & HEATH, D. (1986 a). Influence of respiratory gases. In The Human Pulmonary Circulation, ed. HARRIS, P. & HEATH, D., pp Churchill Livingstone, London. HARRIS, P. & HEATH, D. (1986b). The pulmonary circulation at high altitude. In The Human Pulmonary Circulation, ed. HARRIS, P. & HEATH, D., pp Churchill Livingstone, London. HARRIS, P. & HEATH, D. (1986c). Pulmonary haemodynamics in chronic bronchitis and emphysema. In The Human Pulmonary Circulation, ed. HARRIS, P. & HEATH, D., pp Churchill Livingstone, London. KATAYOSE, D., OHE, M., YAMAUCHI, K., OGATA, M., SHIRATO, K., FUJITA, H., SHIBAHARA, S. & TAKISHIMA, T. (1993). Increased expression of PDGF A- and B-chain genes in rat lungs with hypoxic pulmonary hypertension. American Journal of Physiology 264, L LEACH, R. M., ROBERTSON, T. P., TWORT, C. H. C. & WARD, J. P. T. (1994). Hypoxic vasoconstriction in rat pulmonary and mesenteric arteries. American Journal of Physiology 266, L

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