Key points are not available for this paper at this time.
Circulating 5-hydroxytryptamine (5-HT) is produced mainly in the enterochromaffin cells of the intestine. 5-HT is also, however, locally released from pulmonary neuroendocrine cells and neuroepithelial bodies distributed throughout the airways. Secretion of large amounts of 5-HT from these cells occurs in response to airway hypoxia and increased local 5-HT may contribute to secondary pulmonary arterial hypertension PAH (Johnson Barer et al., 1993; MacLean, 1999b). Initial vascular tone is extremely low in the normal lung unlike in the systemic circulation where basal tone is maintained by tonic activity of the sympathetic nervous system. Sympathetic innervation of the pulmonary circulation does exist and its activation has similar effects as in the systemic circulation but this does not contribute to basal vasomotor tone. Pulmonary arteries exhibit a vasoconstrictor response to hypoxic conditions (Von Euler Weir McCulloch et al., 1996). Hence there are many differences between the normal pulmonary and systemic arterial ciculations which should predict differential pharmacology and vascular reactivity. Changes occur in the pulmonary hypertensive lung which further alters pulmonary arterial pharmacology and reactivity. Primary PAH (PPH) is the clinical term used to describe a rare condition associated with progressive elevation in pulmonary arterial pressure (by 10–15 mmHg), associated with pulmonary vascular remodelling, for which no underlying cause can be found. PAH occurs more commonly secondary to collagen vascular disease, congenical systemic to pulmonary shunt, portal hypertension, human immunodeficiency virus infection, chronic obstructive lung diseases, interstitial fibrosis and high left-sided filling pressures. A familial form of PAH has also been described and characterized with linkage to chromosome 2q31-q32. It is an autosomal dominant disease with incomplete penetrance and genetic anticipation (Nichols et al., 1997). Both secondary PAH and PPH share common pathobiologies. The earliest change is the muscularization of the terminal portion of the pulmonary arterial vascular tree (Figures 1 and 2). This is caused by hyperplasia of smooth muscle cells (SMCs) which extend distally in a layer to the original elastic lamina (Heath et al., 1987). The chronic hypoxic rat is a commonly studied model of pulmonary hypertension where rats are maintained in hypoxic conditions for, typically, up to 3 weeks. Figure 2 demonstrates muscularization of small pulmonary arteries in the chronic hypoxic rat lung. It should be noted, however, that the pattern of SMC migration observed in hypoxic PAH is different from that observed in plexogenic PAH (characteristic of PPH; Heath, 1992). In PPH, the migration is more widespread and plexogenic lesions occlude the vascular lumen. In hypoxic PAH, there is more limited migration and occlusive lesions are rare. However cellular intimal proliferation exists in both hypoxic PAH and PPH. Importantly, regardless of the aetiology, the vascular changes render the pulmonary circulation resistant to standard vasodilators relative to the systemic circulation. Hence, the use of these for PAH is limited by systemic hypotension. Diagrammatic representation of the pulmonary arteries within the lung. (A) In the normal lung there is an uneven distribution of smooth muscle phenotypes and numerous non-muscular precapillary vessels (see Figure 2). (B) In the pulmonary hypertensive lung there is progression of muscularization into the non-muscular terminal portion of the arterial tree. This is due to hyperplasia and redistribution of smooth muscle cell phenotypes (see text and Figure 2 for details). Remodelling of precapillary pulmonary arterioles (PAs) in rat lung following development of pulmonary hypertension. (A) Normal rat lung. Note absence of medial layer. (B) In rats exposed to 2 weeks of hypobaric hypoxia with associated pulmonary hypertension. *Note two elastic laminae separated by distinct medial layer. PAH exhibits a very complex pathobiology with many other factors influencing both vascular remodelling and reactivity. Inactivation of voltage regulated potassium channels (KV) by hypoxia or anorexigens can cause vasoconstriction and defects in KV channels have been implicated in PAH (Yuan et al., 1998). Altered endothelial cell function is also thought to play a role in PAH. For example, there is a loss in the prostacyclin synthase enzyme in PAH patients (Tuder et al., 1999) and there may also be a decreased production of nitric oxide in severe PAH (Giaid MacLean, 1999a). The increase in vascular tone observed in PAH may be due to decreased levels of cyclic GMP and cyclic AMP caused by increased phosphodiesterase activity (MacLean et al., 1996b; 1997), depolarization by inactivation of K+ channels (Osipenko et al., 1998) as well as increased levels of endogenous vasoconstrictors such as angiotensin II (Cargill Liu Fishman, 1999). In the US, dexfenfluramine was widely co-prescribed with phentermine, a combination which became known as ‘fen/phen’. Phentermine can inhibit monoamine oxidase B, an action which could potentially inhibit the metabolism of 5-HT hence increasing local and plasma levels of 5-HT. In addition, phentermine has been shown to prolong the vasoconstrictor effects of 5-HT in rat lung (Seiler et al., 1976). Fenfluramine, in association or not with phentermine, has been shown recently to induce valvular heart disease very similar to those observed after exposure to 5-HT-like drugs such as ergotamine and methysergide, and with increased 5-HT levels associated with carcinoid disease (Connolly et al., 1997). There is certainly evidence suggesting a synergistic interaction between fenfluramine and phentermine to favour PAH and cardiac valve disease (Wellman Buczko et al., 1975). As a consequence circulating free 5-HT concentration increases with fenfluramine treatment (Martin Nemecek et al., 1986; Pitt et al., 1994). The mechanism by which 5-HT causes SMC proliferation varies with cell types and species. Several studies have concluded that the mitogenic action of 5-HT is initiated through its binding to a cell surface receptor, notably the 5-HT2A type (Pitt et al., 1994), whereas evidence has also been provided that it results from an energy-dependent transport of 5-HT into the cell (Lee et al., 1991). 5-HT is a potent inducer of bovine and rat pulmonary artery SMC proliferation and this effect is dose-dependently inhibited by highly selective inhibitors of 5-HT transport such as paroxetine and fluoxetine (Lee et al., 1991; Eddahibi et al., 1999b), but not by the 5-HT2A receptor antagonist ketanserin. In rat vascular SMCs, fluoxetine and paroxetine inhibited 3H5-HT uptake and 5-HT-induced cell proliferation at similar concentrations suggesting that both phenomena are tightly related (Eddahibi et al., 1999b). The proliferative response of bovine pulmonary vascular SMCs to 5-HT is also inhibited by agents that block the transport of 5-HT but not by 5-HT receptor antagonists (Lee et al., 1991). this the mechanisms by which 5-HT its mitogenic effect after SMCs, et observed that 5-HT-induced synthesis is associated with of protein and that both effects are by 5-HT transport or inhibitors (Lee et al., 1997). 5-HT mitogenesis in SMCs cellular through the than binding to a receptor, of protein as a downstream in the of in association with 5-HT transport has also been to play a role in the mitogenic effects of 5-HT (Lee et al., 1998). 5-HT2A receptors have been shown to induce proliferation the activating protein in rat cells & The of these is two are in the of the it can be that hypoxia increases the of the through binding of to of these An increase in levels has also been observed in the lung from rats exposed to chronic studies that the was located in the of pulmonary arteries in pulmonary hypertensive rats (Eddahibi et al., 1999b). expression was in pulmonary arteries of rats whereas could be in the of hypoxic These suggest that in pulmonary artery SMC from large pulmonary arteries not conditions, and that occurs in response to In that that 5-HT may as a mitogenic factor for pulmonary artery SMC only conditions of increased The that 5-HT the development of pulmonary hypertension through activity is by (1) of the 5-HT a exposure to hypoxia pulmonary hypertension in rats (Eddahibi et al., 1997). This aggravating effect of 5-HT on hypoxic pulmonary hypertension is rats are term with an of 5-HT transport (Eddahibi et al., 1998). the mitogenic effects of 5-HT in pulmonary artery SMCs are by inhibitors of 5-HT uptake such as paroxetine and (Eddahibi et al., 1999b). Hence, evidence suggests that of 5-HT through is for its in mitogenic effect in (2) is by a in cell types such as pulmonary vascular endothelial and SMCs et al., 1994). In mice the and exposed to hypoxia for 2 the and the wall thickness of muscularized pulmonary arteries decreased as compared with (Eddahibi et al., 2000a). the pulmonary artery pressure was and the less in hypoxic than in These observations that hypoxic pulmonary hypertension is impaired in mice further evidence that a major role in hypoxia-induced vascular remodelling through its ability to the mitogenic action of 5-HT. dexfenfluramine treatment may lung expression of the 5-HT studies have shown that levels and activity in can be by and pharmacological in high has been shown to in both concentration and uptake of 5-HT in as well as in levels within the et al., 1996). However, the effect of chronic dexfenfluramine treatment on expression in lung has not been results in rats that of a dexfenfluramine treatment is by a increase in levels in lung whereas no alterations in the levels of this the treatment (Eddahibi et al., hypothesis is that of may from chronic treatment with or pulmonary artery SMC proliferation in response to increases in binding and activity in platelets from patients with primary and secondary forms of pulmonary hypertension as well as in patients with chronic obstructive lung disease have been observed (Eddahibi et al., 1999a). increased observed in lung from patients with primary PAH lung these results to be by further suggest that human pulmonary hypertension is associated with platelets and/or pulmonary artery SMC recently it was that the 5-HT2A receptor pulmonary arterial Indeed, conditions, the 5-HT2A receptor in the rat, and pulmonary arteries & et al., However, the of studies in human evidence suggests that the receptor in human pulmonary arteries. The receptor demonstrates a potent response in the pulmonary circulation in et al., and human large isolated pulmonary arteries where vasoconstriction is mediated by the receptor (MacLean et al., it has also been shown that the receptor that a major role in vasoconstriction in the human isolated small muscular pulmonary arteries et al., 1999). These the 5-HT2A receptor has been of limited use in the treatment of PAH. For in PAH secondary to platelet storage pool disease or chronic obstructive pulmonary disease is or its use limited due to the of systemic et al., et al., et al., 1997). receptor antagonists may to be more pulmonary selective as it is the 5-HT2A receptor that vasoconstriction in most systemic arteries. Pulmonary arterial to 5-HT are enhanced in the chronic hypoxic rat model of PAH (MacLean et al., Pulmonary vasoconstriction to 5-HT is normally mediated by the 5-HT2A receptor in the However, in chronic hypoxic the increased vasoconstriction to 5-HT is mediated by both the 5-HT2A and receptor (MacLean et al., Indeed, the for the receptor is increased in the pulmonary arteries from these rats et al., 1998). treatment with the antagonist the development of hypertrophy in these chronic hypoxic rats et al., 2000). evidence from both rat and human studies suggests that the receptor is important in pulmonary vasoconstriction and it may contribute to the increased vasoconstrictor response to 5-HT observed in PAH. to receptor are only observed in the of vascular tone or decreased cyclic GMP levels, a phenomenon (MacLean et al., et al., 1995). This phenomenon may contribute to the increased vasoconstrictor response to in PAH where the increased endogenous and decreased cyclic GMP levels This has been described recently in a review 1999b). studies therefore suggest that selective antagonists may be in the pulmonary vasoconstriction associated with PAH, the systemic which vasodilator In and evidence suggests that there are changes in platelet of 5-HT, and of platelets by the lung, with changes in the pulmonary vascular smooth muscle response to 5-HT, which can lead to PAH. In PPH, PAH, or after anorexigen intake, there may be in 5-HT into platelets which lead to increased circulating or local 5-HT 5-HT release from platelets is in the of or monoamine activity is this effect may be local levels of 5-HT, by platelet release or increased of platelets in the lung, pulmonary vascular SMCs to levels of 5-HT. The effect of this be to increase vascular pulmonary smooth muscle and from increased of the receptor, an effect which be in PAH by increased vascular increased protein and decreased cyclic GMP evidence suggests that 5-HT-induced proliferation occurs through 5-HT uptake by the In after anorexigen intake, and in PPH patients and in secondary PAH, increased expression of may lead to further increases in the transport of 5-HT into the SMCs and increased This hypothesis is in Figure The 5-HT of pulmonary arterial hypertension. (A) Platelet of 5-HT. 5-HT uptake by platelets through the may be after anorexigen intake, in primary and secondary pulmonary arterial hypertension, in chronic obstructive lung disease and in the fawn-hooded rat which is to pulmonary arterial hypertension. of platelet 5-HT may be enhanced by and increased of platelets in the lung, lead to increased exposure of pulmonary vascular smooth muscle cells to 5-HT. (B) 5-HT and human pulmonary vascular smooth muscle 5-HT can cause pulmonary vascular smooth muscle cell and occurs through 5-HT uptake by the and of and increased of 5-HT exposure with increased these activity may be secondary to increased by hypoxia and in PPH and secondary PAH. occurs through receptor activation which can be enhanced by decreased cyclic GMP levels and through with receptor
MacLean et al. (Fri,) studied this question.