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₁-Adrenergic Hypothesis for Pulmonary Hypertension^*

* From the Department of Medicine, Southampton General Hospital, Southampton, UK.

	Abstract

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Pulmonary hypertension (PH) is a chronic and disabling condition that affects the pulmonary vasculature. Once PH is diagnosed, the prognosis is generally poor with a rapid downhill course. PH management is largely empirical because the underlying pathophysiologic mechanisms that are responsible for the excessive vasoconstrictor and vascular smooth muscle proliferative responses are poorly understood. Based on new information concerning the role of adrenergic receptors in regulating various cellular functions, a new perspective on the genesis of PH has emerged, along with a unifying hypothesis for the role of ₁-adrenergic receptors present in the pulmonary vasculature as the major contributor to the pathophysiologic changes associated with PH. Adrenergic receptors that are present on vascular smooth muscle cells regulate vascular tone and growth. The ₁-adrenergic receptors that are present on the small- and medium-sized pulmonary arteries have a unique and greatly enhanced affinity and activity to ₁-adrenergic agonists. Under physiologic conditions, this helps in regulating vascular tone and maintains an adequate ventilation/perfusion matching. However, the excessive stimulation of ₁-adrenergic receptors produces not only smooth muscle contraction but also proliferation and growth. The conditions that produce an increase in ₁-adrenoreceptor gene synthesis, density, and activity (such as hypoxia or changes in vessel wall pressure) or increase the levels of its agonists (such as norepinephrine, appetite suppressants, or cocaine) greatly enhance pulmonary vascular smooth muscle contractile and proliferative responses and lead to the development of PH. An understanding of the role played by these receptors in the pathophysiology of PH would not only help to avoid the use of ₁-agonists for appetite suppression and other disease states, but also would help in developing new drugs to block these receptors. A further understanding of the ₁-adrenoreceptor subtypes present in the pulmonary vasculature, the factors that regulate their expression, and their intracellular signaling pathways would help researchers to devise newer therapeutic strategies and, hopefully, to find a cure for this crippling condition.

Key Words: ₁-adrenoreceptor • appetite suppressants • hypothesis • hypoxia • norepinephrine • pulmonary hypertension

	Introduction

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Pulmonary hypertension (PH) is a severe disabling condition that affects the pulmonary vasculature. When untreated, PH results in decreased vascular compliance, progressive elevation in pulmonary artery pressure, and, eventually, right heart failure and death. Once PH is diagnosed, the general prognosis is poor with a rapid downhill course. Heart-lung transplantation is usually the only therapeutic modality available. Vasoconstriction of the small- and medium-sized pulmonary arteries plays an important role in the pathogenesis of PH during the early stages of the disease; progressive PH is characterized by vascular remodeling and structural changes that result from smooth muscle proliferation and migration leading to occlusive arterial lesions.¹ Although much is known about the pathologic and molecular changes associated with PH, its management is largely empirical because the underlying pathogenic mechanisms that are responsible for increased smooth muscle contractile and proliferative responses remain poorly understood. Several possible underlying mechanisms have been suggested to explain the pathogenesis of PH: pulmonary artery endothelial cell dysfunction; abnormal smooth muscle phenotype; abnormal vascular remodeling in response to hemodynamic changes; abnormal oxygen-sensing apparatus in the pulmonary artery smooth muscles; abnormal expressions of ion channels on cell surface membranes; increased levels of vasoconstrictor mediators, such as serotonin and endothelin-1 (ET-1); and reduced production of vasodilators, such as nitric oxide and prostacyclin. However, these mechanisms do not explain the entire pathogenic features noted in the different types of PH. Based on new information concerning the role of adrenergic receptors in regulating various cellular functions, the present analysis offers a new perspective and insight into the genesis of PH. I also propose a unifying hypothesis for the role of ₁-adrenoreceptors that are present in the pulmonary vasculature as the major contributor to the pathophysiologic changes that are associated with PH.

	Physiologic Role of Adrenoreceptors in the Pulmonary Vasculature

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The pulmonary vasculature expresses both -adrenoceptors and ß-adrenoreceptors, both of which help to regulate pulmonary vascular tone by producing vasoconstriction or vasodilatation, respectively.² These receptors also contribute significantly to the structural development of the vasculature during lung growth by regulating DNA and protein synthesis.^{2 ,3} The stimulation of ₁-adrenoreceptors increases DNA and protein synthesis in vascular smooth muscle cells; the stimulation of ß-adrenoreceptors inhibits this process. In the normal pulmonary circulation, a balance that favors vasodilatation and the inhibition of proliferation is maintained by a predominant ß-adrenergic effect. However, during periods of stress (such as alveolar hypoxemia), the balance tilts in favor of a vasoconstrictor effect mediated by a predominant -adrenergic activity, since this response can be specifically inhibited by -antagonists.⁴ This mechanism helps to divert blood flow away from poorly ventilated alveoli to the regions that are better ventilated, thereby optimizing ventilation/perfusion ratio (/) matching, and maintaining an adequate systemic PO₂.

	Unique Properties of 1-Adrenoreceptors in the Pulmonary Circulation

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The blood vessels that supply the different regions of the body are specialized in many ways, presumably to allow them to serve the requirements of those particular tissues. ₁-Adrenoreceptors are expressed on most vascular smooth muscle cells, and their subtypes are distributed in a pattern that is specific for functionally distinct vessel types.⁵ The population of these receptors and their subtypes vary greatly, not only in different vessels but also at different levels within the same vascular tree, thereby exhibiting regional variations in their reactivity to various agonists.^{5 ,6 ,7} The pharmacologic properties of the different receptors are therefore influenced by their local tissue environment. Bevan et al⁸ studied the variation in sensitivity of ₁-adrenoreceptors to norepinephrine (NE) in 12 different rabbit arteries and showed a difference of > 200-fold between them. When compared to other arteries, the ₁-adrenoreceptors present in the medium-sized pulmonary arteries demonstrated the highest affinity to NE, with the greatest contractile response. The increased sensitivity of ₁-adrenoreceptors to NE in the pulmonary arteries may greatly facilitate the local regulation of vascular tone in response to acute changes in oxygen concentrations, thereby maintaining an adequate / matching.

The stimulation of ₁-adrenoreceptors increases intracellular free calcium levels by at least two different mechanisms: (1) the coupling to specific G proteins on the cell membrane to activate phospholipase C, which generates inositol 1,4,5-triphosphate (IP₃), a second messenger that binds to specific receptors on the endoplasmic reticulum to release stored intracellular calcium into the cytoplasm⁹ ; and (2) the blockade of K⁺ ion channels present on the cell membranes, leading to membrane depolarization and the influx of extracellular calcium through voltage-sensitive Ca²⁺ channels.¹⁰ Among the several pools of intracellular Ca²⁺ ([Ca²⁺]i) stores available, the endoplasmic/sarcoplasmic reticulum forms a major source. The size of this storage pool for releasable Ca²⁺ also determines the efficacy of receptor activity.⁹ Smooth muscle cells of the pulmonary arteries show increased numbers of sarcoplasmic reticuli when compared to other vessels⁹ and, therefore, have greater amounts of intracellular calcium stores. Also, there exists a wide variation in the electrophysiologic properties of smooth muscle cells, not only at different sites, but also at different levels within the same vascular tree.¹¹ Compared to the large pulmonary arteries, the small- and medium-sized pulmonary arteries express greater amounts of K⁺ channels of the delayed rectifier type.¹¹ Basal K⁺ efflux via these channels maintains the small- and medium-sized pulmonary arteries in a relaxed state; inhibition of these channels by pharmacologic stimuli causes rapid membrane depolarization, influx of extracellular calcium, and vasoconstriction.¹¹ ₁-Adrenergic receptors are linked to the K⁺ channels; when stimulated, they block K⁺ efflux and promote a greater influx of extracellular calcium, thereby leading to greater vasoconstriction at these sites. It follows that, when compared to other vessels, medium-sized pulmonary arteries show not only differential ₁-adrenoreceptor subtypes and affinities, but also differential [Ca²⁺]i stores and differential electrophysiologic properties that could explain their greatly enhanced responsiveness to ₁ agonists.

	Intracellular Signaling Pathways Used by 1-Adrenergic Receptors

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₁-Adrenergic receptors couple to G proteins (Gq, G11, and G13) present on cell membranes. On stimulation, ₁-adrenergic receptors activate the enzyme phospholipase C (Fig 1 ), which metabolizes phosphatidylinositol 4,5-biphosphate to produce IP₃ and diacylglycerol.⁵ The primary function of IP₃ is to mobilize calcium from the intracellular stores by binding to specific receptors that are present on the endoplasmic reticulum. diacylglycerol activates protein kinase C (PKC), which in turn phosphorylates several membrane-bound intracellular enzymes to produce tonic contraction of smooth muscle.⁵ The activation of PKC via ₁-adrenergic stimulation activates the Na+/H+ exchanger,¹² which maintains increased [Ca²⁺]i levels. In addition, PKC phosphorylates several proteins, and it activates transcription factors, such as mitogen-activated protein kinase and nuclear factor B, which induce DNA synthesis and cell proliferation.¹³ By increasing the levels of oncoprotein Bcl-2, which inhibits apoptosis, PKC promotes the survival of vascular smooth muscle cells.¹⁴ ₁-Adrenergic receptors also couple to membrane K⁺ ion channels via PKC which, on stimulation with specific agonists, can block these channels,^{10 ,15} leading to membrane depolarization and the entry of Ca²⁺ from extracellular sources through voltage-dependent Ca²⁺ channels.

View larger version (16K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Signal transduction pathways of 1-adrenergic receptors in smooth muscle cells. MAP Kinase = mitogen-activated protein kinase; NFB = nuclear factor B.

The Hypoxic Model for PH
In the late 1890s, Francois Frank and Bradford Dean demonstrated that asphyxia elicited pulmonary vasoconstriction and that the sympathetic nervous system was involved in this pressor response.¹⁷ Similarly, it has been observed that hypoxic contraction and oxygen relaxation develops much more readily in pulmonary vascular smooth muscle than in systemic vascular smooth muscle.¹⁸ This constrictor response to hypoxia is unique to the pulmonary circulation because hypoxia in other vessels normally causes vasodilatation.

The lung serves as a portal for oxygen delivery to the body, and the physiologic mechanisms it adopts in response to hypoxia regulate the quantity of oxygen that is delivered to the other organs. Alveolar hypoxia (secondary to high altitude), hypoventilation syndromes, and COPD are, by far, the most common causes of PH. Oxygen, the final acceptor of electrons in the respiratory chain, has become an evolutionary advantage, by allowing a more complete utilization of energy sources. Organisms have developed complex regulatory systems to secure adequate oxygen homeostasis, particularly in circumstances of reduced availability. Mammalian cells are able to sense reduced oxygen tension in their environment and to respond to it by producing a series of systemic, local, and metabolic changes that try not only to limit hypoxia, but also to produce cellular changes that ameliorate the damaging effects of oxygen deprivation. Central to these responses is the induction of a specific hypoxia responsive element, described by Semenza¹⁹ as hypoxia-inducible factor 1 (HIF-1). HIF-1 induces the transcription of various genes, such as erythropoietin, to stimulate RBC production (and improve their oxygen-carrying capacity) and various growth factors, such as vascular endothelial growth factor (VEGF), ET-1, and platelet-derived growth factor (PDGF) to stimulate the growth of new capillaries in order to improve local oxygen delivery (Fig 2 ).²⁰ In the absence of adequate oxygen, the cells have to rely solely on excessive glycolysis for energy production; for this to take place, efficient glucose entry inside the cell and the presence of various glycolytic enzymes are critical. HIF-1 induces the transcription of glucose transporter (GLUT) molecules (to facilitate glucose entry inside cells) and various enzymes of the glycolytic pathway: lactic dehydrogenase, aldolase A, enolase 1, phosphofructokinase L, and phosphoglycerate (Fig 2 ).²⁰ These changes, therefore, help the cell to mount an adaptive response to low oxygen concentrations.

View larger version (21K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Cellular response to hypoxia in pulmonary artery smooth muscle cells. 1 AR = 1-adrenergic receptor.

What Could Be the Physiologic Role of ₁-Adrenoreceptor Upregulation in Response to Hypoxia?:During oxygen deprivation, the energy stores of smooth muscles are quickly depleted. In order to maintain or develop tension, a continuous supply of energy is required. During hypoxic states, anaerobic glycolysis will be the only source of energy available for vascular smooth muscles, and the cells have to depend on an efficient glucose entry mechanism inside the cell. Catecholamines have long been known to independently stimulate glucose transport inside cells.³⁰ Previous studies^{31 ,32} have demonstrated that tissue extraction of glucose from the blood can be greatly enhanced by specific -adrenergic stimulation; however, the underlying signaling mechanisms have only become clear recently. ₁-Adrenergic stimulation greatly enhances glucose entry into cells in a dose-dependent manner by translocating the GLUT molecules GLUT-1 and GLUT-4 from the cytoplasm to the cell surface.^{33 ,34} In addition to increasing glucose levels inside the cell, the activation of ₁-adrenoreceptors further enhances anaerobic glycolysis by inducing lactate production.³⁵ The upregulation of these receptors on oxygen-starved cells may greatly enhance glucose entry into cells and facilitate energy production; therefore, this could be a cellular adaptation in response to the crisis of hypoxia. Interestingly, it has been demonstrated that pulmonary vascular smooth muscle cells undergo hypoxic contraction in glucose-free environments,³⁶ and that the addition of glucose to blood-perfused lungs inhibits the pulmonary vasoconstrictor response to hypoxia.³⁷

Pathophysiologic Changes in ₁-Adrenergic System in Response to Chronic Hypoxia:The upregulation of ₁-adrenoreceptors in pulmonary arteries following hypoxia serves two important roles: (1) improved glucose entry into oxygen-starved smooth muscle cells; and (2) induced vasoconstriction of resistance-sized pulmonary arteries, thereby redistributing blood flow to regions of the lung that are better ventilated (Fig 3 ). Alveolar hypoxia is a potent stimulus for pulmonary vasoconstriction that is likely mediated by ₁-adrenoreceptors because this response can be reversed by ₁-antagonists^{4 ,38 ,39 ,40} ; this is further supported by the observation that in vitro contractile responses to ₁-adrenergic agonists are significantly greater in pulmonary artery rings from patients with PH due to chronic hypoxia than in pulmonary artery rings from control subjects.⁴¹ Prolonged hypoxia has been shown to dramatically increase and prolong pulmonary vascular cell proliferation, increase pulmonary vascular resistance, and induce right ventricular hypertrophy, all of which are associated with an increase in ₁-adrenoreceptors in the lung.²² Recent studies^{42 ,43 ,44} have demonstrated that the prolonged stimulation of ₁-adrenoreceptors in vascular smooth muscle cells greatly increases DNA and protein synthesis both in vivo and in vitro, thereby producing excessive proliferation and growth. The prolonged stimulation of ₁-adrenergic receptors also increases fibronectin production and promotes fibroblast proliferation⁴⁵ that could further contribute to vascular smooth muscle hypertrophy. In addition to upregulating ₁-adrenoreceptors, hy-poxia produces a concomitant downregulation of ß-adrenoreceptor density on pulmonary vessels,²² shifting the balance further in favor of vasoconstrictive and proliferative responses.

View larger version (30K): [in this window] [in a new window] [Download PPT slide]   Figure 3. Signaling pathways of 1-adrenoreceptors leading to PH. PIP2 = phosphatidylinositol 4,5-biphosphate; PLC = phospholipase C; 5HT = serotonin; ER/SR = endoplasmic/sarcoplasmic reticulum. Other abbreviations expanded in text or legend of Figure 1 .

As described above, when compared to other vessels, ₁-adrenoreceptors present in the pulmonary arteries are unique in that they have greatly enhanced affinity to NE and, therefore, produce greater contractile responses. By increasing the levels of NE and upregulating ₁-adrenoreceptors, prolonged hypoxia may produce a greatly enhanced ₁-adrenergic activity in the pulmonary arteries. Under physiologic conditions, ₁-adrenergic receptors regulate pulmonary vascular tone and maintain an adequate / match. However, under conditions of high receptor expression and/or in the presence of high agonist concentrations, these receptors might couple to signaling mechanisms that they would not activate under normal expression levels.⁵ The same signals that produce functional changes (such as vasoconstriction) can promote structural changes in the vessel wall.

Hypoxia not only upregulates ₁-adrenoreceptors in the lung, it enhances the production of other growth factors such as ET-1,⁵³ VEGF,⁵⁴ and PDGF⁵⁵ by activating the hypoxia-sensitive transcription factor HIF-1. ET-1 is a potent pulmonary vasoconstrictor, and VEGF and PDGF are growth-promoting factors. The intracellular signaling pathways used by these factors are the same as the pathways used by ₁-adrenoreceptors (the increase in Ca²⁺i and the activation of PKC [Fig 2 ]). Synergy in signal transduction mechanisms between these growth factors and the ₁-adrenergic pathway would be an important means of augmenting hypoxia-initiated vascular growth, and it could yield dramatically increased pulmonary artery smooth muscle contraction and proliferation.

The Appetite Suppressant Model for PH
Ever since they were introduced, appetite suppressant drugs have been strongly associated with the development of PH, and they have been responsible for several small epidemics.⁵⁶ A recent multicenter, prospective case-control study⁵⁷ from 35 centers in Europe reported that the use of appetite suppressants was associated with a sixfold greater risk for the development of PH. This risk increased to 23-fold when these drugs were used for > 3 months. Severe PH and death have been reported⁵⁸ with the use of appetite suppressant drugs, even for as few as 23 days.

₁-Adrenoreceptors are present in high density in the paraventricular nucleus of the hypothalamus, the area associated with the regulation of food intake.⁵⁹ Recent studies^{60 ,61} have shown that appetite suppressant agents, such as phenylpropanolamine, cirazoline, amidephrine, SK & F-89478, and, more recently, sibutramine, suppress food intake by stimulating the ₁-adrenoreceptors in the paraventricular hypothalamic nucleus. In experimental animals, paraventricular injection of ₁-agonists have been shown to suppress food intake, and injections of ₁-antagonists enhance feeding behavior.⁶⁰ Most of the currently available appetite suppressant drugs, therefore, act mainly by releasing NE, by blocking its reuptake, or by directly stimulating the ₁-adrenoreceptors in the hypothalamus.⁶²

Dexfenfluramine, a new appetite-suppressant drug, has also been associated with the development of PH. Its anorectic, pulmonary vasoconstrictive, and smooth muscle proliferative effects are currently thought to be mediated by the release of serotonin in the brain and pulmonary circulation. However, the effective inhibition of serotonin synthesis does not prevent the anorectic effect of dexfenfluramine.⁶³ Moreover, a dose of the metabolite D-norfenfluramine, which does not cause a detectable rise in extracellular serotonin, produces almost total anorexia.⁶⁴ Pure serotonin reuptake inhibitors such as fluoxetine that increase plasma serotonin levels do not produce PH,⁶⁵ although primary PH is not seen in carcinoid syndrome, a condition in which high levels of circulating serotonin are found. These observations raise the possibility that the mechanism of dexfenfluramine-induced appetite suppression and PH is not caused by elevated levels of serotonin alone, and may in fact be a secondary associated event. Recently, it has been demonstrated⁶⁶ that dexfenfluramine possesses ₁-adrenergic-stimulating properties in liver cells. It produces an increase in [Ca²⁺]i levels that can be blocked by prazosin, a specific ₁-adrenoreceptor antagonist. It has previously been reported⁶⁷ that calcium is required for a dexfenfluramine-induced release of serotonin in the hippocampus, suggesting that serotonin release by dexfenfluramine may be mediated by its ₁-adrenergic effect. Moreover, the central stimulation of ₁-adrenoreceptors is known to increase the neuronal discharge of serotonin.⁶⁸ Recent experiments involving patch-clamp techniques on single cells using aminorex, fenfluramine, and dexfenfluramine suggest that the underlying mechanism of action of these drugs for producing PH appears to be the inhibition of the K⁺ current in pulmonary vascular smooth muscle cells,^{69 ,70} a downstream effect also mediated by the stimulation of ₁-adrenoreceptors and hypoxia.^{10 ,71}

₁-Adrenergic receptors present in the brain that regulate appetite and those on pulmonary artery smooth muscle cells may be of similar subtypes and possess similar agonist affinities. It is therefore likely that the chronic use of appetite-suppressant drugs would produce prolonged stimulation of the ₁-adrenergic receptors not only in the brain, but also in the pulmonary artery vasculature to produce vasoconstrictor and smooth muscle proliferative responses.

Cocaine and PH
It has been speculated that ₁-adrenergic receptors present in the brain regulate mood.⁹ Many of the currently available antidepressants (such as amphetamines and euphorogenic drugs), apart from acting on dopamine and serotonin receptors, also act by inhibiting the reuptake of NE or by directly stimulating the ₁-adrenergic receptors in the brain.⁷² The use of cocaine has been associated with the development of PH and various contractile vascular responses.⁷³ The mechanism of action of cocaine is primarily dependent on ₁-adrenoreceptor stimulation,⁷⁴ suggesting that PH associated with cocaine could be due to stimulation of the ₁-adrenergic receptors in pulmonary arteries.

PH Associated With Pressure and Volume Overload
The pulmonary circulation is a low-resistance circuit comprising only one fifth of the resistance noted in the systemic circulation. Increases in pulmonary artery pressure and volume secondary to various pulmonary vascular occlusive and cardiac disease states are commonly associated with the development of PH. The mechanical stimulation of the vessel wall, including stretch induced by increases in pressure, were described in 1902 by Bayliss⁷⁵ as an initiating factor for vascular contractile responses. Rapid stretch applied to the pulmonary arteries of guinea pigs and cats has been demonstrated to produce vascular smooth muscle contractions.^{76 ,77} A recent study by Nakayama et al⁷⁸ has demonstrated that even slow stretch produces contractile vascular responses in rabbit isolated pulmonary artery. Recent in vitro studies in vascular smooth muscle cells suggest that mechanical load (pressure changes) modulates the expression of ₁-adrenergic receptors,⁷⁹ and that stretch increases the expression of ₁-adrenergic receptors in vascular smooth muscles.⁸⁰

The regulation of the expression of ₁-adrenoreceptors by mechanical factors such as pressure and volume changes have mainly been studied in cardiac myocytes. Mechanical factors have been implicated as a stimulus for the induction of hypertrophy and/or hyperplasia in the cardiovascular system under physiologic and pathologic conditions.⁸¹ The stretch of cardiac myocytes in vitro or cardiac hypertrophy secondary to pressure and volume overload is associated with the induction of several genes, such as ET-1, skeletal and smooth muscle -actins, and the atrial natriuretic factor,^{82 ,83} all of which have been shown to be upregulated by ₁-adrenergic stimulation.⁸⁴ Cardiac hypertrophy has been demonstrated with the use of ₁-agonists,⁸⁵ and transgenic mice that express constitutively active ₁-adrenergic receptors in the myocardium have been shown to develop cardiac hypertrophy in which the muscle phenotype corresponds to the in vivo response seen with pressure overload and other cardiac diseases.⁸⁶ These observations suggest that stretch or pressure overload in the heart muscle is associated with the upregulation of ₁-adrenergic receptors that, with chronic stimulation, produce a hypertrophic response.

In response to chronic increases in pressure or volume, the pulmonary arteries may mount an adaptive response by activating a hypertrophic state that is similar to that noted in cardiac myocytes. It is therefore hypothesized that stretch of the pulmonary vascular smooth muscles secondary to pressure or volume overload would produce the upregulation of ₁-adrenergic receptors that, on persistent stimulation, would induce various contractile protein genes to promote smooth muscle contraction and proliferation leading to PH.

Clinical Evidence for the Usefulness of ₁-Antagonists
₁-Blockers were among the first drugs used in the treatment of PH.¹ Several studies^{4 ,38 ,40 ,87 ,88} have demonstrated that these agents either abolish or attenuate hypoxia-induced pulmonary vasoconstriction. Other studies^{89 ,90 ,91} have demonstrated no effect; however, most of these studies have analyzed pressure or resistance changes that may be misleading when flow also changes. ₁-Blockers have been shown to be more superior than calcium channel blockers (nifedipine) and hydralazine in attenuating hypoxia-induced increases in pulmonary vascular resistance that are noted in dwellers at high altitudes; in combination with oxygen therapy, ₁-blockers almost completely reverse hypoxia-induced PH.⁹² Several studies^{93 ,94 ,95 ,96 ,97} have reported beneficial effects with the long-term use of prazosin, a selective ₁-blocker, in the control of PH. Recently, it has been reported⁹⁸ that doxazosin and prazosin inhibit the proliferation and migration of human vascular smooth muscle cells. Experimental studies in rats have demonstrated that the long-term use of bunazosin, a selective ₁-blocker, reduces PH as well as right ventricular hypertrophy that is induced by monocrotaline toxicity.⁹⁹

Why then are ₁-blockers not popular in clinical practice? The role of ₁-adrenoreceptors in the development of PH has not been widely understood. Most of the ₁-blockers that have been used to date have been prescribed for their known vasodilator properties. These drugs are administered mainly by IV route, they have a very short half life, and they produce various systemic side effects.¹ Different ₁-blockers have been shown to produce differential responsiveness in different arteries.⁹ Currently, three different subtypes of ₁-adrenoreceptors have been identified (₁-A, ₁-B, and ₁-D), and each subtype is a product of a separate gene, each has a unique tissue distribution and drug specificity, and each activates the same or similar signal-transduction mechanisms.⁵ The subtypes that are present in human pulmonary vessels have not been studied in detail, and it would seem likely that additional subtypes may exist having properties that are not yet clear.

Ca²⁺ channel blockers, and drugs that increase cyclic adenosine monophosphate levels (ß₂-agonists, prostacyclin, and adenosine) are the drugs most commonly used in the treatment of PH, although their underlying mechanisms of action are not clear. An increase in cyclic adenosine monophosphate activates protein kinase A, which inhibits Ca²⁺ entry into the cell, augments [Ca²⁺]i-extrusion mechanisms, and inhibits PKC and phosphoinositol metabolism,¹⁰⁰ effects that are largely mediated by ₁-adrenergic stimulation. The vasodilator and antiproliferative effects of these drugs may therefore be related to their antagonist effects on the intracellular signals generated by ₁-adrenergic stimulation.

	What Could Be the Explanation for the Female Gender Predominance in PH?

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Primary PH is predominant among young women in their reproductive years, and its risk of development has been shown to increase with the earlier use of contraceptive pills,¹⁰¹ suggesting that the female sex hormones may in some way be responsible. Experimental data indicate that sex hormones can alter the sensitivity of blood vessels to -adrenergic agonists. Colucci et al¹⁰² have demonstrated that estrogen increases vascular catecholamine sensitivity and ₁-adrenergic receptor affinity in female rats, and that this increase can be induced in male rats when treated with estrogen, thereby suggesting a specific effect of estrogen on vascular ₁-adrenoreceptors. In female rats, estrogens have also been shown to increase the numbers of ₁-adrenoreceptors in the aorta¹⁰³ and hypothalamus,¹⁰⁴ and in the rabbit myometrium.¹⁰⁵ It is therefore plausible that estrogen-induced increases in the numbers and affinity of vascular ₁-adrenoreceptors in women provide a potential explanation for their predominance in PH.

Some people appear to be more susceptible to the development of PH than others, and a clear genetic basis for this has been suggested,¹⁰⁶ although the gene responsible has not been identified. It is likely that this genetic defect could lie in a defective oxygen cell sensor, in abnormal HIF-1 activity, in abnormal ₁-adrenoreceptor number expression or affinity, or in the abnormal release of catecholamines to defective intracellular signaling mechanisms.

In summary, it is hypothesized that ₁-adrenoreceptors present in the pulmonary vasculature play an important role, not only in regulating normal physiologic responses, but also in the pathogenesis of PH. ₁-Adrenoreceptors in the pulmonary arteries have greatly increased affinity and responsiveness with their agonists when compared to other vessels. The downstream signaling events in ₁-adrenergic stimulation are an increase in [Ca²⁺]i levels and the activation of PKC, which mediate vascular contractile and proliferative responses. The excessive stimulation of ₁-adrenergic receptors produces smooth muscle contraction, proliferation, and growth. Conditions that produce an increase in ₁-adrenoreceptor gene synthesis, density, and activity (such as hypoxia or pressure changes), or increase the local levels of its agonists (NE, appetite suppressants, and cocaine) greatly enhance pulmonary artery smooth muscle contractile and proliferative responses. An insight into the role of ₁-adrenoreceptors in the pathogenesis of PH may not only help to avoid using ₁-agonists for appetite suppression and other disease states, but it may also help to devise newer drugs that could specifically block the ₁-adrenergic subtypes present in the pulmonary vasculature. A further understanding into the factors regulating ₁-adrenoreceptor expression, activation, and its intracellular signaling pathways could also help researchers to further understand its role in the pathogenesis of this crippling disease and, hopefully, to find a cure.

	Footnotes

 
Correspondence to: Sundeep S. Salvi, MD, University Medicine, Level D Centre Block, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK; e-mail: sss@soton.ac.uk

Abbreviations: [Ca²⁺]i = intracellular Ca²⁺; ET-1 = endothelin-1; GLUT = glucose transporter; HIF-1 = hypoxia-inducible factor 1; IP₃ = inositol 1,4,5-triphosphate; mRNA = messenger RNA; NE = norepinephrine; PDGF = platelet-derived growth factor; PH = pulmonary hypertension; PKC = protein kinase C; VEGF = vascular endothelial growth factor; / = ventilation/perfusion ratio

Received for publication December 11, 1998. Accepted for publication February 3, 1999.

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