Vascular smooth muscle, endothelial regulation and effects of aspirin in hypertension




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[Frontiers in Bioscience, 3, e23-38, April 27, 98]


VASCULAR SMOOTH MUSCLE, ENDOTHELIAL REGULATION AND EFFECTS OF ASPIRIN IN HYPERTENSION


Munir A. Rahmani

Division of Science and Mathematics, Bethune-Cookman College, Daytona Beach, FL 32114


Received 3/25/98 Accepted 3/30/98


TABLE OF CONTENTS


1. Abstract

2. Introduction

3. Regulation of VSM Contraction and Relaxation

4. Endothelial Mediation

4.1. Endothelins

4.2. Arachidonic Acid Metabolites

4.3. Nitric Oxide

5. Endothelium in Hypertension

6. Aspirin and its Therapeutic Usage

6.1. Role of Cyclooxygenase in Pharmacology of Aspirin

6.1.1. Effects of Cyclooxygenase Inhibition in SHR and WKY rats

6.2. Effects of Aspirin on Vasoreactivity

6.2.1. In Vitro Effects

6.2.1.1. Vasoreactivity of aortic rings with intact endothelium

6.2.1.2. Vasoreactivity of aortic rings denuded of endothelium

6.2.2. In Vivo Effects

6.2.2.1. Intraperitoneal administration of ASA and aortic Contractility in Female SHR Rats

6.2.2.2. Effects of in vivo administration on aortic contractility and blood pressure in male SHR rats

6.2.2.3. Ca2+ Conductance as Measured by Active Tension Generated by Aortic Rings

6.2.2.4. Effects of ASA on Systolic Blood Pressure

7. Significance

8 Acknowledgments

9. References


1. ABSTRACT


Dysfunction of vascular smooth muscle (VSM) is at the center of occlusive disorders of the cardiovascular system such as hypertension, atherosclerosis, coronary artery disease and hypoxia. In addition to circulating biogenic amines and various neurotransmitters originating from the central nervous system and endocrine system, various autocoids of arachidonic acid metabolism in the blood as well as in the endothelium play an important regulatory role in the maintenance of the tone and the contractile function of VSM. A monolayer of endothelial cells lining the heart and large blood vessels is responsible for producing and releasing both endocrine and paracrine substances such as endothelins, nitric oxide, prostaglandins and prostacyclins. Aspirin, (acetylsalicylic acid/ASA) an ancient remedy against fever and pain, is emerging as an effective drug not only against occlusive disorders but also against various cancers and the AIDs virus. During pregnancy induced hypertension (PIH) and in occlusive disorders, aspirin provides relief through inhibition of cyclooxygenase, an enzyme required for the metabolism of arachidonic acid to produce prostaglandins and prostacyclins in platelets and in endothelial cells. Because of its unique molecular constitution, synergistic ability and solubility in the lipidic environment, various mechanisms of aspirin's actions are being currently


investigated. In this review, the effect of aspirin on the regulation of VSM in the presence and absence of endothelium are discussed.


2. INTRODUCTION


Every day, new benefits of aspirin as a wonder drug are being discovered by investiga­tors and clinicians. This review will concern itself with Vascular Smooth Muscle (VSM) regulation via endothelial mediation and will address the direct and indirect effects of aspirin (acetylsalicylic acid) on the contractility of VSM. It is important to understand the mechanism of aspirin action as it is being prescribed increasingly for the management of various oc­clusive disorders of the vascular system and other pathologic conditions. It is the acetylation and consequent inhibition of the enzyme, cyclooxygenase, by aspirin which renders it so effective in the management of disorders of the vascular system. In addition to platelets, cyclooxygenase is found in the endothelial lining of the heart and the blood vessels.


VSM is regulated by a wide variety of factors including neuropep­tides, biogenic amines, prostanoids and endothelium-derived vasoactive substances. The force generated by VSM corresponds to the concentration of intracellular free calcium ion [Ca2+]i which is released from intracellular stores or imported from extra cellular pools of Ca2+, through various channels (1). The myocyte relaxes when Ca2+ returns to sarcoplasmic stores or is extruded to the extracellular space. Impairment of VSM functions is at the center of an array of cardiovascular pathologies such as arteriosclerosis, coronary heart disease, stroke and hypertension (2). Most of these abnormalities are manifested in an impedance of Ca2+ conductance to and from intracellular and extracellular Ca2+ stores (3,4). Similarities exist in VSM and striated mus­cle physiology. However, unlike cardiac and skeletal muscles, many blood vessels remain in a contracted state for long periods of time. There is no refractory period or fatigue in VSM. Also, VSM contraction is mostly tonic in nature. The force maintenance mechanism in VSM termed the “Latch State” is extremely energy efficient (5). Maintenance of the latch state requires Ca2+; however, the levels are considerably lower than those measured during the early phase of activation (6,7,8).


This review will include a short description of the regulation of contraction and relaxation of VSM and the role of Ca2+ in this event. The discussion will focus on the role of the endothelium on the conductance of Ca2+ in VSM in nor­motensive and hypertensive conditions. Since, cyclooxygenase in the endothelium is responsible for vasoactive metabolites of arachidonic acid, the effects and interaction of aspirin on the regulatory functions of endothelium will be discussed. Finally, a dis­cussion of some of the direct effects of aspirin on VSM in the absence of endothelium will be considered and the possible mechanisms for such effects will be suggested.


3. REGULATION OF VSM CONTRACTION AND RELAXATION


The contraction and relaxation of VSM is regulated by the [Ca2+]i. Free [Ca2+]i makes a complex with calmodulin which activates myosin light-chain kinase (MLCK). The activated MLCK phosphorylates LC20, one of the two light-chain subunits of myosin. Phosphorylation of LC20 is the signal that activates cycling of actin and myosin cross bridges, which in turn initiates contraction in VSM (1,9). The relaxation of smooth muscle comes about with the decomposition of acto-myosin cross bridges. For this to happen, myosin is dephosphorylated by a phosphatase that is not Ca2+ dependent (10). Relaxation of VSM requires re-sequestering of calcium by the sarcoplasmic reticulum (SR). The re-sequestration of calcium is assisted by a Ca2+pump at the plasma membrane (1) and extrusion by a different Ca2+ pump (11,12).


4. ENDOTHELIAL MEDIATION


Large blood vessels and the heart are lined by a monolayer of endothelial cells. Under normal conditions endothelial cells are the only cell type that are in direct contact with the blood (13-16). Since Furchgott and Jawadzski demonstrated in 1980 that acetylcholine-evoked relaxation of blood vessels is dependent upon the presence of intact endothelium, it has become increasingly clear that the endothelium plays a major role in the control of regulation of vascu­lar tone, growth, and adhesion (14,17-33). Endothelial cells synthesize vasoconstrictor and vasodilator substances, inactivate circulating hormones, convert inactive precursors into vasoactive mediators and growth factors. The endothelium also responds to flow and /or shear stress, blood borne agents and cells. Consequently, it exerts influence on VSM tone, and plays a role in angiogenesis, VSM proliferation and differentiation (13,14,16,17,21,22,25,27,28, 31,34-36). Both contracting and relaxing types of vasoactive substances are produced and released by the endothelium in blood vessels and affect VSM. Contracting factors of endothelial origin are: a. Three types of Endothelins which are peptides that contain 21-amino acids and two disulfide bridges (30). b. Metabolites of arachidonic acid (AA), prostacyclins and prostaglandins synthesized through the mediation of cyclooxygenase such as thromboxaneA2 (TXA2), prostaglandin H2 (PGH2), Prostacyclins (PGI2 ,PHE2), and prostaglandin F2 (PGF2) (15,33,37-39). c. Endothelium-derived contracting factor (EDCF1) during hypoxia (32,38,40) and prostaglandin H2 also known as endothelium-derived contracting factor 2 (EDCF2) (41). A major vasorelaxant of endothelial origin is endothelium-derived relaxing factor (EDRF) which has been identified as nitric oxide (NO) (15,42). Other known va­soactive substances are a hyperpolarizing factor of unknown nature named endothelium-derived hyperpolarizing factor (EDHF) (43,44) and angiotensin II (ATII ) (15,33,45). Additionally, mechanical processes like shear stress due to circulating blood in vessels can up-regulate the nitric oxide synthase gene in endothelium and can also induce VSM relaxation during exercise. The latter response is immediate and is not regu­lated at the gene expression level, but has been proposed to involve tyrosine kinase activity (15,46,47).


4.1 Endothelins

Endothelins are a powerful family of vasoconstrictors that contain 21 amino acids (30). Analysis of endothelin (ET) genes has revealed the existence of three distinct ETs, designated ET-1, ET-2 and ET-3. Because of structural similarities with certain neurotoxins, ET-1 is thought to activate directly the voltage-operated Ca2+ channels (26) and phospholipase C (48), thus bringing about contraction. ET-1 is also reported to activate phospholipase A2 (48,49). Three receptors, ETA, ETB and ETC, have also been described for ETs on the VSM cells. Of these, ETA has been identified as the receptor that regulates tone and growth in VSM cells through the action of ET-1 (18,30,48, 50,51). It has been proposed that ET-1 is a mediator of the pressor response to hy­poxia and endothelium plays a modulatory role in these responses (40). In porcine arteries, ET-1 was determined to be capable of attenuating its own vasoconstrictive activity, and PGI2 could attenuate ET-1-induced contraction without altering cAMP levels (52). However, in the rabbit abdominal aorta, ET-1 is reported to stimulate the liberation of vasorelaxant NO (33). In rat aortic rings, ET-1-induced contraction and PGI2 release maintained in part by Protein Kinase C is due to increased influx of extracellular calcium (49). Studies have shown that, during hypoxia, ET-1 release is augmented in humans (53). It is thought that endothelium-derived relaxing factor, nitric oxide, and angiotensin-(1-7) mechanisms may act synergistically to buffer the increase in vascular resistance during renovascular hypertension (54). ET-1 was shown to induce the release of prostaglandin H2, which is also known as EDCF2, from the endothelial cells of rat aorta (41). Increased synthesis of ET-1 is reported during cyclosporin-induced hypertension in rats (55). Isolated rat thoracic aortic rings have been reported to relax in response to ET-3 in­duced NO release from endothelium via ETB receptor. As a result of NO release, soluble guanylate is activated which subsequently produces cyclic GMP. The enzyme contributing to NO formation is suspected to be of the calcium-calmodulin-dependent, constitutive type (56). ET-1 in humans is shown to have a transient vasodilatory effect followed by a pronounced constrictive effect when applied luminally. The vasodilator effect also involves the en­dothelial cyclooxygenase pathway, suggesting that there is a complex interplay of endothelial mechanisms for vasoconstriction as well as vasodilation (35,57).


4.2. Arachidonic Acid Metabolites

Arachidonic acid (AA) metabolites synthesized through the mediation of cyclooxygenase are prostacyclins (PGI2), prostaglandins PGH2, PGE2, and PGF2 (33,38,58,170). Another AA metabolite synthesized by cyclooxygenase is thromboxaneA2 (TXA2). However, the site of TXA2 synthesis is the platelets. Endothelium-dependent contraction can also be mediated by activation of cyclooxygenase and PGH2 and TXA2 receptors (38,41,59,60). The endothelial pathway has been implicated in ET-1 induced vasodilation in humans, suggesting a complex interplay between the vasoactive agents of endothelial origin (57). It has been reported that E-series prostaglandins produce relaxation and at the same time, increase [Ca2+]i levels in isolated rat aortic muscle, leading to activation of Ca2+-dependent K+ channels. Very low effective concentrations of PGEs (50-100 nM) support the idea of receptor-activated mechanism in the VSM (61). For the most part, the vascular endothelium functions in a paracrine fashion. However, the endocardial endothelium has been found to produce copious amount of PGI2 during hypoxia. The spillover from hypoxia-induced endocardial secretion of PGI2 has been found to affect the vessel muscles downstream from the heart. Thus, endocardial endothelium acts in an endocrine manner in addition to its paracrine effect on myocardium (62). In the endothelium, arachidonic acid metabolism mediated by the enzyme cyclooxygenase is known to be inhibited by acetylsalicylic acid and indomethacin (63-68).


4.3. Nitric Oxide (NO)

Exposure to increased NO desensitizes VSM to vasoconstrictors (69,70) and attenuates the relative rate of protein syn­thesis in the endothelium and VSM (71). NO is an inhibitor of platelet aggregation and is produced in the endothelium as well as in the plasma membrane of VSM cells via the mediation of the enzyme, NO-synthase (NOS) (30). In the endothelium, NO is synthesized when hormones and autocoids like acetylcholine, bradykinin and substance P act on specific receptors or when the endothelium experiences increased flow and shear stress (15,46,47,72). The release of NO by calcium ionophore is independent of receptor activation (33,34). In rat aortic rings, NO is also reported to be produced in response to ET-3 stimulation (73). It is now well established that NO accounts for all oxygenated nitrogen species such as, dinotrosyl-Fe2+ or S-nitrosothiol, synthesized enzymatically from L-arginine (20,34,72, 74-76). NO-Synthase the NO producing enzyme is a reduced NADPH-dependent dioxygenase. Three isozymes of inducible and constitutive types exist as isoform I, II and III (72,77). The inducible isoform II is Ca2+-independent and found mostly in cytokine-activated cells such as macrophages, smooth muscle cells and endothelial cells. The constitutive isoform I and isoform III of NO-synthase are found mainly in neuronal and endothelial cells respectively and are Ca2+/calmodulin dependent (77,78). The constitutive type has a basal level of production in endothelial cells. However, higher levels of the constitutive type can be produced in the endothelium through receptor dependent as well as independent stimulation (72). Human genes for these three isozymes have been localized on chromosome number 12 region 12q24.1 to 12q24.3 for isoform I (79), chromosome number 17 region 17p11-17q11 for isoform II (80) and chromosome number 7 region 7q35-7q36 for the isoform III (81). Endothelial dysfunction associated with aging and hypertension results in reduced production of NO in heart and large blood vessels (30,45,52,77,82). Recently, it was demonstrated that NO from the endothelium, through the mediation of cGMP, inhibits ET-1 activated Ca2+-permeable non-selective cation channels in rat aortic VSM (52,83) and activates both ATP- and Ca2+-dependent K+ current in small mesenteric arteries of rat (84). Thus, it is clear that NO of endothelial origin is an important agent for the regulation of vascular reactivity.

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