3.29 The role of endothelium in the reactivity of the vascular smooth

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3.29 The role of endothelium in the reactivity of the vascular smooth Powered By Docstoc
					3.29. The role of endothelium in the reactivity of the vascular smooth muscle (R. Sochorov´)
                                                                                          a                          253

                                                                      PGI2 (prostacyclin) – is a metabolite of arachi-
                                                                      donic acid. It stimulates adenylatecyclase and
3.29        The role of endothelium                                   increases the amount of cAMP in cells of vascu-
                                                                      lar smooth muscle.
            in the reactivity of the                                  Endothelium-derived relaxing factor (EDRF) –
            vascular smooth muscle                                    is being synthetized from L-arginine in endothe-
                                                                      lium cells due to the impact of arginine oxidase.
                                                                      Chemically, EDRF is nitrogen oxide (NO) or
                                                                      other labile nitroso compounds (R-NO). EDRF
                                                                      stimulates guanylatecyclase and increases the
   Contractility of vessels is regulated by nervous,
                                                                      amount of cGMP in the vascular smooth mus-
hormonal, but also local humoral regulatory mech-
                                                                      cle. EDRF is released under basal conditions
anisms. The sympatic adrenergic nervous system is
                                                                      and stimulation. The variety of physiological
regarded as the main regulatory mechanism of the
                                                                      stimulations capable of evoking the augmenta-
vascular tonus. Activation of this system which lo-
                                                                      tion of EDRF liberation includes the throm-
cally releases a neurotransmitter (in particular nora-
                                                                      bocytes products (serotonin, ADP), thrombin,
drenaline), leads to contraction of the smooth vascu-
                                                                      hormones, neurotransmitters (acetylcholine),
lar muscle.
                                                                      changes in partial oxygen tension and increased
   Currently, great attention is paid to the study of
                                                                      blood flow. The release of EDRF owing to the
vascular endothelium cells which play an important
                                                                      increased blood flow plays an important role in
role in modulation of the vascular tonus.
                                                                      alteration of the size of arterial lumen. Rapid el-
   Endothelial cells are responsible for a variety of
                                                                      evation of intraluminal pressure stimulates the
physiological functions, as for example uptaking and
                                                                      EDRF release or leads to an increased release
metabolism of noradrenaline or serotonin, conversion
                                                                      of EDCF (endothelium-derived contracting fac-
of angiotensin I to angiotensin II, bradykinin meta-
bolism, prostacyclin (PGI2 ) biosynthesis. They af-
fect the vascular wall permeability, blood coagula-                2. Vasoconstricting factors are produced by en-
tion, and throbocytes activity.                                       dothelial cells (EDCFs). They function as inter-
   Since the discovery of prostacyclin Mondacom,                      mediaries of endothelium-dependent vasocon-
great attention has been paid to vasoactive sub-                      striction. It has been experimentally confirmed
stances produced in the vascular wall. The Furch-                     that the removal of endothelium reduces con-
gott’s discovery of the role of vascular endothelium                  striction caused by antagonists. Endothelium-
in vasodilatation induced by acetylcholin (1980), and                 dependent vasoconstriction can be stimulated
evidence that this response takes place due to par-                   by naturally present substances (noradrenaline,
ticipation of a substance called endothelium–derived                  arachidonic acid (AA), thrombin, prostaglandin
relaxing factor, stirred interest and attention to the                H2 ), by pharmacological substances (nico-
forthright role of endothelium in modulation of vas-                  tine, increased K+ ions), physical stimuli
cular responses.                                                      (stress, pressure) and hypoxia (see fig. 3.55 on
   Endothelium cells produce vasodilatatory and                       page 254).
vasoconstrictive factors.                                             EDCFs which modulate the endothelium-
                                                                      dependent vasoconstriction include three cate-
 1. Vasodilatatory factors include:
        • PGI (prostacyclin)                                           (a) EDCF1 – vasoconstricting matabolites of
        • Endothelium–derived relaxing factor                              arachidonic acid or oxygen radicals (e.g. su-
          (EDRF)                                                           peroxide anion)

        • Endothelium–derived hyperpolarizing fac-                     (b) EDCF2 – which is released due to hypoxia.
          tor (EDHF)                                                       Its chemical structure has not yet been
254                                                                                                   ın, ˇ
                                      Chapter 3. Pathophysiology of the cardiovascular system ( I. Hul´ F. Simko et al.)

                            Figure 3.55: Endothel and some other vasoconstrictors

      (c) EDCF3 – endothelin – substance which in            covered in cells of nonvascular type, as for example
          contrast to the rapid contraction caused by        in kidneys, lungs and other tissues. ET-2 and ET-3
          other EDCFs, causes a long-term slowly             are contained in tissues of the brain, lungs, kidneys,
          developing vasoconstriction                        adrenal glands, and small intestine.

   Endothelin – is a peptide comprising 21 amino-            3.29.1      Effects of endothelin
acids. It has a strong vasoconstricting effect. A sig-
nificant resemblance between endothelin and sarafa-           Endothelin had been formerly identified as a strong
toxin which is a compound of snake venom has been            vasoconstricting substance, later a wider spectrum
revealed. Sarafatoxins, similarly as endothelin, have        of its effects was discovered.
a strong coronaconstricting, hence cardiotoxic lethal
                                                               1. Vasoconstricting effects of endothelin - in de-
                                                                  pendence on dosage endothelin evokes contrac-
   Three different endothelin genes, and consequently
                                                                  tions of arteries and veins, already in doses of
three different endothelins were confirmed in man.
                                                                  10−11 − 10−8 , regardless of anatomical localisa-
Endothelin 1 (ET-1 in pigs, human endothelin),
                                                                  tion of blood vessels. In general, the veins are
endothelin 2 (ET-2 differs from ET-1 by two
                                                                  more sensitive to endothelin than arteries. The
aminoacids) and endothelin 3 (ET-3 differs from ET-
                                                                  onset of the coronary vessels response to the ET
1 by six aminoacids).
                                                                  constricting effect is slow and of prolonged du-
   Endothelin 1 is formed from a precursor protein,               ration (several hours).
the so-called big endothelin by the effect of endothe-
linconvertase. ET-1 is the only endothelin contained           2. Pressoric and depressoric ET effects – intra-
in vascular endothelium cells, additionally it was dis-           venous administration of endothelin causes a
3.29. The role of endothelium in the reactivity of the vascular smooth muscle (R. Sochorov´)
                                                                                          a                        255

     short-term (0,5–2 min.) depressoric response                parenchyma organs (heart, kidneys, lungs, small in-
     which is followed by elevation of arterial pres-            testine, suprarenal glands, brain). Endothelin effect
     sure dependently on the dosage. The mecha-                  is based on the increased influx of Ca2+ via calcium
     nism of the initial depressoric response can be             canals in target cells.
     explained by the fact that endothelins, mainly                 It can also mobilize Ca2+ from intracellular depot
     ET-1 and ET-3, induce a release of prostacyclin             sites by induction of the phosphatidylinositol system.
     or EDRF from the vascular endothelium. The                     The evidence of endothelin effects, other than
     pressure elevation in the vascular network lasts            vasoconstrictive, as well as of endothelin receptors
     for 2–3 hours. This extremely prolonged effect               existence in various nonvascular tissues, draws at-
     represents one of the most important vascular               tention to the fact that endothelin affects regula-
     effects of endothelin.                                       tory functions of various cardiovascular and non-
                                                                 cardiovascular tissues. Endothelin participates in
 3. Contraction of nonvascular smooth muscles –                  regulation of the systemic arterial pressure and lo-
    endothelin causes contraction of the small in-               cal blood distribution, formation and composition
    testine, tracheal and bronchial smooth muscles.              of urine, release of circulating hormones (e.g. re-
    The endothelin effect is comparable with that of              onin, ANP, adrenaline) from kidneys, atrium and
    histamin and exceeds that of leucotrien D4 .                 suprarenal glands, tonus of bronchial smooth mus-
                                                                 cles, small intestine motility, various CNS functions
 4. Endothelin has a positive inotropic                and       including autonomous regulation and higher func-
    chronotropic effect on myocardium.                            tions.
                                                                    There are two different models of endothelin for-
 5. Endothelin stimulates secretion of atrial natri-
                                                                 mation in relation to the cardiovascular system reg-
    uretic peptide (ANP) in myocardium
 6. Renal effects – endothelium participates in regu-               1. Endothelin participates in maintainance of the
    lation of renal functions by inhibiting the release               systemic and local circulation under physiologi-
    of renin in kidneys. It decreases renal blood flow                 cal conditions. It functions similarly as a num-
    accompanied by reduction of glomerular filtra-                     ber of vasoactive substances, e.g. catecholamins,
    tion, urine volume and excretion of Na+ and K+                    angiotensin II, vasopressin and ANP. Plasmatic
    by the kidneys.                                                   concentration of endothelin in man is in average
                                                                      cca. 1 pmol·l−1, which is a too small amount
 7. Endothelin decreases aggregation of thrombo-
                                                                      for it to be classified as a circulating hormone.
    cytes, assumedly by cAMP decreasing.
                                                                      It is quickly eliminated from circulation by the
 8. Proliferation of smooth muscle cells                              lungs. Endothelin has a local impact. Inhibi-
                                                                      tion of renin-angiotensin system by means of en-
   In addition, endothelin has trophic effects on the                  dothelin, as well as stimulation of ANP secretion
smooth muscle cells of vessels, the effect being of                    (strong vasorelaxing factor) represent examples
importance in regard to its role in both pathogenesis                 of negative feed back between endothelin and
of atherosclerosis and vascular hypertension, and in                  other hormonal systems.
elevated blood flow.
                                                                   2. A greater amount of endothelin is produced in
                                                                      damaged tissues due to their lesion or protec-
3.29.2      The mechanism of endothelin                               tive reactions (e.g. healing of wounds, inflamma-
            effect                                                     tion), its formation being induced by thrombin.
Endothelin can be released due to the effect of va-                 Abrogation of regulatory mechanism which partic-
sopressin, adrenaline and thrombin. It is active via             ipate in endothelin formation, leads to various patho-
endothelin receptors of several subtypes, whilst the             logical states, e.g. coronary and cerebral vasospasms,
affinity of ET-1, ET-2 and ET-3 to these receptors                 bronchospasms, atherosclerosis and hypertension.
is variable. The binding loci for endothelin are situ-             Endothelin is to a greater extent produced within
ated in the media of variously calibrated vessels and            the site of endothelial impairment and has contrac-
256                                                                                                  ın, ˇ
                                     Chapter 3. Pathophysiology of the cardiovascular system ( I. Hul´ F. Simko et al.)

tile and proliferative effects on cells of the vascular      in people with essential hypertension, vasospastic
smooth muscle representing the pathogenic factors           angina pectoris, and in acute myocardium infarction
of atherosclerosis and vasospasm pathogenesis.              (IM).
   Undoubtful is the role of endothelin especially in          From the clinical point of view, the changes in plas-
the pathogenesis of cardiocascular diseases. An in-         matic ET concentration could be regarded as indices
crease of plasmatic ET 1 concentration was observed         of IM course.

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