Physical exercise, ß-adrenergic receptors, and vascular response - PDF

REVIEW ARTICLE Physical exercise, ß-adrenergic receptors, and vascular response Exercício físico, receptores ß-adrenérgicos e resposta vascular Alexandre Sérgio Silva, Angelina Zanesco* Abstract Aerobic

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REVIEW ARTICLE Physical exercise, ß-adrenergic receptors, and vascular response Exercício físico, receptores ß-adrenérgicos e resposta vascular Alexandre Sérgio Silva, Angelina Zanesco* Abstract Aerobic exercise promotes beneficial effects on the prevention and treatment of diseases such as arterial hypertension, atherosclerosis, venous insufficiency, and peripheral arterial disease. β-adrenergic receptors are present in a variety of cells. In the cardiovascular system, β-adrenergic receptors promote positive inotropic and chronotropic response and vasorelaxation. Although the effect of exercise training has been largely studied in the cardiac tissue, studies focused on the vascular tissue are rare and controversial. This review examines the data from studies using animal and human models to determine the effect of physical exercise on the relaxing response mediated by β-adrenergic receptors as well as the cellular mechanisms involved in this response. Studies have shown reduction, increase, or no effect of physical exercise on the relaxing response mediated by β-adrenergic receptors. Thus, the effects of exercise on the vascular β-adrenergic sensitivity should be more deeply investigated. Furthermore, the physiopathology of the vascular system is an open field for the discovery of new compounds and advances in the clinical practice. Keywords: β-adrenergic receptors, blood pressure, vascular smooth muscle, physical exercise. Resumo O exercício aeróbio promove efeitos benéficos na prevenção e tratamento de doenças como hipertensão arterial, aterosclerose, insuficiência venosa e doença arterial periférica. Os receptores β-adrenérgicos estão presentes em várias células. No sistema cardiovascular, promovem inotropismo e cronotropismo positivo cardíaco e relaxamento vascular. Embora os efeitos do exercício tenham sido investigados em receptores cardíacos, estudos focados nos vasos são escassos e controversos. Esta revisão abordará os efeitos do exercício físico sobre os receptores β-adrenérgicos vasculares em modelos animais e humanos e os mecanismos celulares envolvidos na resposta relaxante. Em geral, os estudos mostram resultantes conflitantes, onde observam diminuição, aumento ou nenhum efeito do exercício físico sobre a resposta relaxante. Assim, os efeitos do exercício na sensibilidade β-adrenérgica vascular merecem maior atenção, e os resultados mostram que a área de fisiopatologia vascular é um campo aberto para a descoberta de novos compostos e avanços na prática clínica. Palavras-chave: Receptores β-adrenérgicos, pressão arterial, músculo liso vascular, exercício físico. Introduction The last decades were marked by the increased prevalence of cardiovascular risk factors, such as sedentary lifestyle, obesity, and changes in lipid profile, thereby raising the incidence of chronic degenerative diseases, such as hypertension, type 2 diabetes mellitus, and atherosclerosis. 1 Some vascular diseases greatly compromise blood flow and oxygenation of different tissues, causing poor wound healing, infection, and pain, which may result in amputation mainly of the lower limbs, thus representing an important cause of death. 2 Venous insufficiency and peripheral arterial occlusive disease have a high prevalence in the population, especially among the elderly, affecting about 10-40%, and the etiopathogenesis of both conditions is closely associated with endothelial dysfunction. 2,3 Evidence shows that aerobic physical training promotes beneficial effects on the prevention and treatment of cardiovascular diseases and endocrine/metabolic disorders, such as hypertension, diabetes mellitus, dyslipidemia, and atherosclerosis. 4 One of the mechanisms by which physical exercise promotes these effects is associated with increased blood flow on the vessel wall, resulting in increased production and/or bioavailability of nitric oxide (NO) in vascular smooth muscle. 5,6 *Departamento de Educação Física, Instituto de Biociências, Universidade Estadual Paulista (UNESP), Rio Claro, SP, Brazil. No conflicts of interest declared concerning the publication of this article. Manuscript submitted Jan , accepted for publication Mar J Vasc Bras. 2010;9(2):47-56. 48 J Vasc Bras 2010, Vol. 9, Nº 2 Physical exercise and vascular response, Silva AS & Zanesco A Physical exercise promotes a direct impact on vascular function, with significant beneficial effects on the patient s quality of life. 4 Studies report that patients with peripheral arterial occlusive disease start to feel less pain and increase walking distance without claudication in response to physical exercise, significantly reducing mortality among these patients. 7-9 Although there are drugs that also improve walking ability without claudication, the results are still modest when compared to supervised exercise programs associated with smoking cessation. 10 In post-surgical varicose vein patients, physical exercise appears to be able to restore microvascular endothelial function to levels observed in age-matched healthy controls, even in the first minutes after exercise. 11 In addition to acting on endothelial cells, physical exercise reduces sympathetic activity and increases parasympathetic activity, leading to an improvement in vascular tone. 12 Physical exercise also contributes to morphological changes of the vessels, modulating the growth of vascular smooth muscle cells, the formation of endothelial cells, and apoptosis reduction and promoting angiogenesis. 6 There are reports of improvement in muscle oxidative activity in patients with peripheral arterial occlusive disease via decreased concentration of short-chain acylcarnitine, an intermediate of oxidative metabolism, 13 which contributes to increase the walking distance without claudication in patients with peripheral arterial occlusive disease performing exercise training. Adrenergic receptors are also implicated in vascular activity. Stimulation of α and β receptors in response to exposure to their agonists promotes constriction or relaxation of arteries and production by endothelial cells is partly mediated by activation of β-adrenergic receptors. 14 However, little is known about the role that β-adrenergic receptors play in blood vessels and the influence of physical exercise on these receptors in healthy individuals or patients with different pathological conditions, such as atherosclerosis, hypertension and diabetes mellitus. Therefore, this review approaches the involvement of β-adrenergic receptors in vasorelaxation, the effects of physical exercise on the relaxant response, and the molecular mechanisms involved. The study of β-adrenergic receptors offers an interesting field of study in the area of vascular physiology, which might open new perspectives in the prevention and/or treatment of vascular diseases of different etiologies. Vascular smooth muscle and endothelium Arterial vessels usually have three layers: the intima, which is in contact with blood elements and consists mainly of endothelial cells; the media, composed of smooth muscle cells; and the adventitia, composed of fibrous connective tissue, which is the outer coat of the artery. Smooth muscle cells are often spindle-shaped with larger diameters in the core region. The sarcoplasmic reticulum, less developed compared to reticula of other types of muscle cells, is closely associated with the plasma membrane, which explains its involvement in Ca 2+ signaling mechanisms and muscle contraction. The activation of this biochemical cascade of vascular smooth muscle contraction occurs through binding of contractile agents, such as norepinephrine, phenylephrine and endothelin, to specific membrane receptors present in the muscle cell. These receptors, in turn, activate a protein called G protein that stimulates phospholipase C, present in the cell membrane, which catalyzes the formation of second messengers from membrane phospholipids generating inositol-1,4,5-triphosphate (IP3) and diacylglycerol (DAG). IP3 binds to its receptors located in the sarcoplasmic reticulum, releasing to the cytosol Ca 2+ ions present within this organelle. The DAG molecule activates a protein called protein kinase C (PKC), which, in turn, phosphorylates proteins bound to L-type calcium channels, favoring the influx of extracellular Ca 2+ to the intracellular medium. These two messengers cause an elevation in Ca 2+ concentration, enabling actin-myosin interaction and producing contraction of vascular smooth muscle. 15 The relaxation of vascular smooth muscle is triggered by different agents produced by endothelial cells, including prostacyclin, endothelium-derived hyperpolarizing factor (EDHF), and NO. NO is considered the most potent vasodilator produced by the endothelium, and control of its production is directly related to various diseases, such as hypertension, atherosclerosis, and coronary artery disease. 16 Several mediators and neurotransmitters can promote the release of NO by endothelial cells, such as acetylcholine, bradykinin and norepinephrine, through activation of its specific receptors. More recently, hydrogen peroxide (H 2 O 2 ) and hydrogen sulfide (H 2 S) have been highlighted in vascular research as important mediators in the relaxant response of different vessels. 17,18 Thus, the discovery of these molecules in vascular function opens a relevant field on the therapeutic potential of thromboembolic disease. β-adrenergic receptors Adrenergic receptors were initially divided into two broad categories, α and β. Subsequently, they were subdivided into subtypes α 1, α 2, β 1, β 2, and β 3 by using subtype-selective antagonists and sequencing of amino acids that participate in Physical exercise and vascular response, Silva AS & Zanesco A J Vasc Bras 2010, Vol. 9, Nº 2 49 their protein structures. α-adrenergic receptors are further subdivided into α 1A, α 1B, α 1D, α 2A, α 2B, and α 2C β-adrenergic receptors are present in different cells, acting on a variety of functions, including modulation of hormone release, metabolic control, and cardiovascular regulation. Stimulation of β-adrenergic receptors, in the islets of Langerhans, increases glucose in humans, thus β 2 - adrenergic agonists are used in the treatment of hypoglycemia. 22,23 In adipocytes, β 3 receptors have been shown to act on leptin release. 24 Moreover, the balance between lipogenesis and lipolysis is associated with stimulation of α- and β-adrenergic receptors, respectively. 25 Particularly in the cardiovascular system, β-adrenergic receptors promote positive cardiac chronotropic and inotropic response (increasing heart rate and contractile force, respectively) and vasodilation. These actions are triggered by the binding of catecholamines (epinephrine and norepinephrine, released from autonomic fibers) to different β-adrenergic receptor subtypes present in cardiac muscle cells and blood vessels. Currently, at least three β-adrenergic receptor subtypes are recognized: β 1, β 2, and β 3. β 1 and β 2 receptors were the first to be classified based on the use of subtype-selective agonists and antagonists. 26 β 3 -adrenergic receptors were first described in adipocytes, 27 and their presence was subsequently demonstrated in cardiac tissue, mediating chronotropism, 28 and also in blood vessels, promoting vasodilation. 14 The classification of β-adrenergic receptors was possible through the synthesis of selective agonists, such as BRL and CL ,30 The existence of a fourth β-adrenergic receptor, called β 4, which would mediate muscle glucose uptake and cardiac chronotropism and inotropism in humans and rats, was proposed by various authors However, other studies report that β 1 receptors may present an altered conformational state, in which they lose affinity for their specific ligands and start to have affinity for other agonists that activate β 3 and also β 4 receptors, such as the agonist CGP Thus, the existence of β 4 -adrenergic receptor remains unclear. The affinity and efficacy of β-adrenergic drugs may also vary depending on the conformational state of receptors and their mechanisms for coupling to proteins and second messengers present within the cells that constitute the tissue. 39,40 The density of β-adrenergic receptors also varies greatly among different cells and tissues and according to the species studied Vascular β-adrenergic receptors Early studies investigating vascular beds have shown the existence of two β-adrenergic receptor subtypes, β 1 and β 2, in different arteries and veins. It was observed that the vasodilator response was mediated predominantly by β 2 - adrenergic receptors compared with β 1 -receptor subtypes, with an order of potency of epinephrine norepinephrine phenylephrine, although this classification of potency does not apply to all vascular beds. 5 Some studies show that β 1 -adrenergic receptors also promote vasodilation, 48,49 whereas other studies show that β 3 -receptor subtypes participate in the vasodilator response of arteries of various species, such as human coronary arteries, 14,50 rat aorta, 51 and canine pulmonary arteries In rat aorta, it was demonstrated that some relaxant responses appear to be mediated by a population of atypical receptors (presumably β 4 ), through the use of conventional agonists/antagonists that stimulate β 1 -, β 2 -, and β 3 -receptor subtypes On the other hand, other studies failed to confirm the participation of β 3 -adrenergic receptors and of this atypical receptor (β 4 ) in this preparation. 58,59 In rat mesenteric arteries, β 4 -adrenergic receptor also seems to be present, 60 but these data were not confirmed in a subsequent study in these arteries. 48 Studies involving femoral and brachial arteries are scarce compared to more central and larger arteries, such as the aorta and mesenteric artery. In one of these few studies, the presence of β 1 - and β 2 -adrenergic receptors was observed through the use of selective agonists/antagonists in porcine femoral artery. 61 On the other hand, in rabbit femoral arteries, only β 2 -receptor subtypes were shown to mediate the vasodilator response. 62 Mechanism of action of β-adrenergic receptors The multiple intracellular signaling pathways in response to the activation of β-adrenergic receptors in blood vessels modify according to the β-adrenoceptor subtype that is mediating relaxant responses and to the vascular bed studied. 61 Although the activation of cyclic adenosine monophosphate (camp) is the classic pathway for the vasodilator response to β-adrenergic stimulation, dependent and independent mechanisms of formation of this second messenger contribute to the relaxant response induced by the activation of these receptors. 63,64 For details, see Figure 1. Signaling pathway: camp-protein kinase A Adrenoceptors belong to a superfamily of membrane receptors closely related and coupled to G proteins. All these proteins share a common peptide structure, in which the amino-terminal portion (N), extracellularly, is connected to the carboxyl-terminal chain (C) 50 J Vasc Bras 2010, Vol. 9, Nº 2 Physical exercise and vascular response, Silva AS & Zanesco A intracellularly by seven transmembrane domains. The relative size of N- and C-terminal chains and of the third intracellular loop varies considerably from receptor to receptor. 65,66 The third intracellular loop of β-adrenoceptors is the site for coupling of these receptors to G protein. G proteins are heterotrimers, consisting of one hydrophilic α-subunit and two hydrophobic subunits, β and γ. In the absence of agonists, when G protein is inactive, a molecule of guanosine diphosphate (GDP) is bound to the α-subunit, forming a complex associated with β- and γ-subunits. In the presence of agonists, the activated receptor interacts with G protein and induces the conversion of GDP into guanosine triphosphate (GTP) in the α-subunit. After binding to GTP, the α-subunit dissociates from βγ-subunits and becomes active. The α-subunit remains free until GTP hydrolysis and formation of GDP occurs, leading to its reassociation with βγ-subunits. The α-subunit of Gs protein, when activated, leads to stimulation of adenylyl cyclase, which leads to the formation of camp second messenger from ATP breakdown. camp activates protein kinase A that will promote reduction in intracellular Ca 2+ concentration in vascular smooth muscle cells, with consequent vasodilation. 66,67 For details, see Figure 1. Signaling pathway by activation of calciumdependent potassium channels Maintenance of relaxant activity of the aorta in response to isoprenaline, even in the presence of SQ 22,536 (an adenylyl cyclase inhibitor), supports the existence of camp-independent mechanism in certain vessels. 51 In addition, relaxation is abolished in the presence of iberiotoxin, a K + channel blocker, suggesting the involvement of large-conductance Ca 2+ -activated K + channels (MaxiK). These data are consistent with a previous study that demonstrated the importance of K + channels in the relaxant response of the basilar artery of the guinea pig. 68 Additionally, relaxation was shown to be dependent on MaxiK channels only for responses mediated by β 1 - and β 2 -adrenergic receptors, whereas, for β 3 receptors, K v channels do not appear to be involved. 51 The mechanism by which activation of β-adrenergic receptors promotes relaxation is carried out through the activation and opening of K + channels, allowing their extracellular release, which, in turn, causes reduction in membrane potential, leading to cell hyperpolarization. This results in the closure of voltage-dependent Ca 2+ channels. Ca 2+ channel closure by membrane hyperpolarization causes a reduction in the Ca 2+ -calmodulin complex and in the phosphorylation of the myosin light chain, leading to relaxation. 10 For details, see Figure 1. Signaling pathway: nitric oxide-cgmp Classic pathway of G-protein activation of β-adrenergic receptors, activation of adenylyl cyclase, and formation of camp, which, in turn, activates protein kinase A (panel B). Two other pathways include activation of a variety of proteins that activate enos and result in NO formation (panel A) and opening of potassium channels, promoting membrane hyperpolarization, which, in turn, promotes the closure of voltage-dependent calcium channels (panel C). Both the classic pathway, camp formation, and voltage-dependent calcium channel activating pathway occur in vascular smooth muscle, whereas NO formation occurs in the endothelium. BAR = β-adrenergic receptors; enos = endothelial nitric oxide synthase; NO = nitric oxide; α, β, and γ = G protein subunits; KC = potassium channels; CC = voltagedependent calcium channels. Figure 1 Mechanisms by which β-adrenergic receptors promote vasorelaxation. Another signaling pathway of β-adrenergic receptormediated, camp-independent relaxation is the endothelial pathway. Vasodilator response by stimulation of β-adrenergic receptors has been shown to be partially 69,70 or completely 14 inhibited by endothelium removal or in the presence of NO synthase inhibitors, such as L-NAME. Furthermore, inhibition of soluble guanylate cyclase in vessels without endothelium eliminates the vasodilator response, whereas addition of sodium nitroprusside restores vasorelaxation. Thus, these studies show that NO produced by endothelial cells is involved in β-adrenoceptor-induced relaxation. The mechanisms by which β-adrenergic receptors promote NO release seem to involve several signaling pathways, such as mitogen-activated protein kinase (MEK), p42/p44 mitogen-activated protein kinase (MAPK) or ERK1/2, and phosphatidylinositol 3-kinase (PI3K), both in humans and laboratory animals The activation of these enzymes by β-adrenergic receptors leads to activation of endothelial NO synthase
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