Cardiovascular activity of endothelium-derived substances and cardiovascular diseases

1、 Cardiovascular activity of endothelium-derived substances and cardiovascular diseasesKeywords: endothelium-derived nitric oxide in cardiovascular active substances (NO) endothelin (ET) angiotensin (Ang ) bradykinin prostacyclin (PGI2) adenosine cardiovascular diseases Cardiovascular activity of end

2、othelium-derived substance is secreted by vascular endothelial cells in the myocardial contractility, heart rate, vascular tone and other influential substances, including nitric oxide (NO), endothelin (ET), angiotensin (Ang ) , bradykinin, prostacyclin (PGI2), adenosine and so on. Since most of the

3、se substances play a role in the local, so in particular, cardiovascular active substances secreted by the heart is more important. Coronary artery endothelial cells and endocardial endothelial cells are able to secrete cardiovascular active substances. Endothelial secretion of known cardiovascular

4、active substances on the cardiovascular system function has an important regulatory role and participate in a variety of cardiovascular diseases, the pathophysiological process. This article on endothelial secretion of cardiovascular active substances and its relationship with various cardiovascular

5、 diseases such as doing a review. A nitric oxide (NO) 1.1 The source of NO from vascular endothelial L-arginine on the N-terminal, in the nitric oxide synthase (NOS) have been synthesized under the action. Now known to have three kinds of nitric oxide synthase isoforms 1. The first subtype is called

6、 constitutive nitric oxide synthase (cNOS), mainly in vascular endothelial cell membrane, it needs to play a role in calcium ions, calmodulin, glutathione (NADPH), etc., as cofactors . The second subtype is called can be inducible (iNOS), mainly in activated macrophages, which play a role without ca

7、lcium and calmodulin involvement. The third major subtype found in the central nervous system. Many physical and chemical factors that can stimulate NO synthesis. Cyclical changes in blood flow to the pressure on vascular endothelial shear stress, is to promote NO synthesis and release of the most i

8、mportant factor. In addition, acetylcholine, bradykinin, histamine, P substance, adenosine triphosphate, noradrenaline and moderate hypoxia Dengjun can increase NO release. N-methyl-L-arginine by NOS competitive inhibition, so that reduction in NO synthesis. A variety of oxygen free radicals can rap

9、idly remove NO. NO half-life is very short, only a few seconds to tens of seconds. Soon after the release of NO from the endothelium in the extracellular fluid in the dispersion, and with vascular smooth muscle receptors to guanylyl cyclase activation, cyclic guanosine monophosphate (cGMP) content i

10、ncreased, and thus play its physiological activity. 1.2 affect the cardiovascular system, cGMP by activating the protease, so that a variety of protein phosphorylation, which led to vasodilator effects. cGMP can promote the outflow of intracellular Ca2 and sarcoplasmic reticulum Ca2 uptake increased

11、, and can reduce the inositol triphosphate generation, so that reduction of Ca2 flow. These are to reduce intracellular Ca2, causing vasodilation. NO can transfer blood vessels, vascular resistance, coronary artery to dilate, the heart before and after the load reduction in coronary perfusion increa

12、se. In recent years, the NO on myocardial contractility more impact studies. NO acting on the papillary muscle of laboratory animals free of myocardial contractility after a slight decline in early myocardial isovolumic relaxation. Other substances such as -blockers, calcium channel blocker mainly a

13、ffected the early systolic function, while NO mainly affects the late systolic function 2. In the whole heart, such as to maintain pre-load, after load and heart rate remain unchanged, NO can advance and accelerate left ventricular relaxation, but the left ventricular dp / dt peak little effect on 3

14、. The role of NO on left ventricular relaxation has nothing to do with the changes in coronary blood flow. The impact of NO on myocardial relaxation mechanism is due to decreased myocardial Ca2 reactivity 4, rather than changes in calcium influx. Clinical studies also show that, after intracoronary

15、infusion NO, so that decline in left ventricular peak systolic pressure, left ventricular relaxation occurs early, left ventricular end-diastolic pressure decreased, but the left ventricular dp / dt without significant changes in left ventricular ejection fraction (EF) Each stroke volume decreased s

16、ignificantly 5,6. Animal studies also showed that NO can reduce the myocardial catecholamine responsiveness 2. NO can still slow down the heart rate, has a certain negative chronotropic effect. NO to the heart pre-load decreased, according to Frank-Starlings law also allows reduced myocardial contra

17、ctility. In short, NO has a mild negative inotropic and negative chronotropic effects. NOs primary role is to enable and accelerate the early myocardial relaxation, improve the left ventricular compliance, improve the left ventricular diastolic function. NO on left ventricular diastolic function of

18、the improvement will not only improve the left ventricular diastolic filling, but also by extending the left ventricular diastolic and lower diastolic myocardial tension, increase coronary perfusion. In addition, NO on platelet adhesion and aggregation were significantly inhibited, the mechanism may

19、 be related to the increase in platelet cGMP content, so that Ca2 flow reduced, thus inhibiting protein kinase C, phospholipase C activation, so that platelet adhesion and aggregation on easily. There are cell protective effect of NO, can reduce infarct size during myocardial infarction. NO there is

20、 the role of vascular smooth muscle cell proliferation, for the prevention of atherosclerosis lesions progress, is of great significance. 1.3 NO and cardiovascular diseases of vascular endothelial integrity and endothelial function in cardiovascular function is to protect the normal prerequisite. NO

21、 close relationship with myocardial ischemia. Coronary artery atherosclerotic plaque allows the presence of endothelial dysfunction, NO secretion reduced, and thus increase myocardial oxygen consumption, oxygen reduced, increased myocardial ischemia. At this time intravenous infusion of nitrates nee

22、ded in order to provide exogenous NO. Heart failure to reduce NO synthesis, degradation accelerated, make the heart before and after the load increase in left ventricular diastolic function are affected, so that heart failure is increased even further. Percutaneous transluminal coronary angioplasty

23、(PTCA) restenosis, but also with coronary artery endothelial cells were partially destroyed, NO secretion reduced, NO anti-proliferative effect of vascular smooth muscle weakening. 2 endothelin -1 (ET-1) 2.1 The source of ET is a former ET 53 74 peptide chain fragments. Preproendothelin in vascular

24、endothelial cells, synthesized in the cytoplasm by the role of specific endopeptidase became containing 38 amino acid endothelin precursors, known as big endothelin. The latter under the action of endothelin-converting enzyme changed to contain 21 amino acid endothelin. Of human endothelial known as

25、 three isomers, are known as ET-1, ET-2, ET-3 7. Because ET-1 secretion up to, so its role is most important. The human body there are at least three kinds of ET receptors, respectively, known as ETA, ETB, ETC. ET-1 mainly with ETA binding, causing a strong vasoconstrictive effect. Under normal phys

26、iological circumstances, the vascular endothelial release of ET-1 less. Epinephrine, Ang , vasopressin, thrombin, etc., to promote ET-1 synthesis to increase, and PGI2, NO can reduce the ET-1 synthesis. ET mainly by lung and renal clearance and degradation. 2.2 The impact of cardiovascular system, E

27、T-1 is by far the strongest known vasoconstrictor substances, make small arteries, veins are shrinking, the total peripheral vascular resistance increased, the heart before and after the load had increased. ET-1 has a significant positive inotropic effects, can increase cardiac contractility. Slow o

28、nset of its effect lasted longer. ET-1 positive inotropic mechanisms of action, with the increase in cytoplasmic Ca2 concentration and increasing the sensitivity of myocardial cells are related to Ca2. With NO contrast, ET-1 can significantly delayed myocardial relaxation. 2.3 ET-1 and cardiovascula

29、r diseases involved in a variety of ET-1 the incidence of cardiovascular diseases. The vasoconstrictive effect of ET is a pathological process caused by high blood pressure progress in an important factor. ET-1 are still to promote the role of mitosis will enable the proliferation of vascular smooth

30、 muscle 8, blood vessel elasticity reduces to accelerate the hypertension-induced target organ damage. Intracoronary ET-1 generation is caused by excessive coronary contraction, coronary blood flow reduction and clinical symptoms of myocardial ischemia in the most important reason. The higher ET con

31、centration in acute myocardial infarction and unstable angina, the worse the prognosis 9. Against the ET-1 to give the drug or ET-1 monoclonal antibody can be reduced myocardial infarct size 10. ET-1 can still be an increase in acute myocardial infarction reperfusion injury 11. Variant angina pector

32、is due to coronary artery spasm caused by the pathological and physiological mechanisms related to excessive secretion of ET-1. ET and close to the pathophysiology of heart failure. Heart failure the effect of increasing ET-1 to eliminate slow. ET-1 can go up high blood pressure, increased cardiac a

33、fterload, increase in the total peripheral vascular resistance and coronary resistance, reducing cardiac output. ET-1 can still reduce the renal blood flow and glomerular filtration rate, increase Shuinazhuliu, increasing plasma renin and aldosterone levels 12. ET-1 is still with primary pulmonary h

34、ypertension, Raynauds syndrome, migraine headache, the incidence of such processes. 3 angiotensin (Ang ) 3.1 The source of the circulatory system are known except for weeks containing renin - angiotensin system (RAS), the heart itself also contains its own RAS. Coronary artery endothelial cells cont

35、ain angiotensin-converting enzyme (ACE), the heart produces Ang containing all the necessary material. ACE by acting on the angiotensin generated within the heart after Ang . 3.2 Cardiovascular effects produced by Ang myocardium has a significant positive inotropic effect, so that increase cardiac c

36、ontractility. Ang also allows the heart to catecholamines in response to increased. Ang can delay ventricular relaxation, cardiac diastolic function are affected. Ang can coronary artery contraction, coronary blood flow was reduced. Ang are still promoting Shuinazhuliu, increasing the role of the he

37、art before and after the load. 3.3 Ang and cardiovascular diseases have increased due to Ang myocardial oxygen consumption and reduce the role of myocardial oxygen supply, the heart produced by Ang can aggravate myocardial ischemia. Ang generate excessive acute myocardial infarction an independent r

38、isk factor. Although Ang positive inotropic effect, but the blood by reducing coronary perfusion to myocardial contractility are affected, their total effect is to increase heart failure. Ang can still stimulate the secretion of various growth factors, is caused by cardiac hypertrophy and restenosis

39、 after PTCA one of the reasons. Long-term use of angiotensin-converting enzyme inhibitor (ACEI) can improve myocardial ischemia, delayed the occurrence and development of heart failure, inhibit left ventricular hypertrophy and left ventricular remodeling after acute myocardial infarction, left ventr

40、icular diastolic function can further be improved to increase the diastolic period compliance 13. 4 bradykinin 4.1 Sources of vascular endothelial generate bradykinin. The role of bradykinin in ACE degrades inactivation. When using ACEI which will take the role of bradykinin the duration of the exte

41、nsion. 4.2 affect the cardiovascular system, bradykinin has a direct vasodilator effect and allow the release of vascular endothelial NO, PGI2, ATP and an increase 14, and anti-cardiac hypertrophy, protecting myocardial cells 15 and anti-arrhythmic effects, etc. 16. Given ACEI and exogenous bradykin

42、in can produce the same effect as the original, suggesting that part of the role of ACEI by delayed inactivation of bradykinin generated 17. 5 prostacyclin (PGI2) Now known to act on the endothelial cell COX-phospholipid arachidonic acid on the key post-produce PGI2, which act on the platelet membra

43、ne phospholipid arachidonic acid on the key post-produce TXA2. On the contrary the role of PGI2 and TXA2. PGI2 with the expansion of blood vessels and inhibit platelet aggregation, while TXA2 has contracted blood vessels and the promotion of platelet aggregation. Produced by vascular endothelial PGI

44、2 is to ensure patency of the important factors. Local endothelial cell damage PGI2 production was reduced to enable the vasoconstriction, platelet aggregation, once again shows that the integrity of vascular endothelial cells is to maintain patency of the necessary conditions. Endocardial endotheli

45、al cells during hypoxia compared with coronary artery endothelial cells to produce more PGI2 18, has a certain compensatory effect. TXA2/PGI2 ratio of increase is aggravated or caused by myocardial ischemia-induced myocardial infarction in one of the reasons, but aspirin makes TXA2/PGI2 decline in t

46、he prevention of myocardial infarction beneficial. 6 Adenosine Endothelial cells through degradation of ADP, ATP produces adenosine. Of adenosine on ventricular muscle, atrial muscle have negative inotropic effect. Of adenosine on ventricular negative inotropic effect of mechanism is by inhibiting a

47、denylate cyclase to make cAMP production was reduced 2. Adenosine can still reduce the myocardial catecholamine responsiveness. Of adenosine on atrial mechanism of negative inotropic effects by activating ATP-dependent potassium channels. Vasodilative effect of adenosine with a clear and is caused b

48、y coronary blood flow auto-regulation of the important factors. When the local ATP production was reduced, ATP degradation to adenosine increased, coronary artery to dilate, and local blood flow. Regular clinical application of adenosine caused by coronary steal phenomenon of drug provocation test f

49、low. Recent studies have shown that adenosine in myocardial ischemic preconditioning play an important role 2. Adenosine still inhibited sinus rhythm and suppress the role of atrioventricular node. Rapid intravenous injection of ATP to terminate supraventricular tachycardia that is the use of adenos

50、ine on atrioventricular node in vivo. In summary, endothelial cells (especially coronary artery endothelial cells and endocardial cells) can secrete a variety of cardiovascular active substances. Abnormal secretion of these substances, by changing the cardiac contractility, heart rate, myocardial be

51、fore and after the load, coronary perfusion of these five factors have an impact on cardiac hemodynamics in a variety of cardiovascular diseases (such as myocardial ischemia, hypertension, heart failure , left ventricular hypertrophy, left ventricular remodeling, PTCA restenosis) and play an importa

52、nt role in the pathogenesis. These cardiovascular active substances exists between the complex interaction and mutual influence. Given by exogenous nitrates, ACEI, aspirin, adenosine triphosphate and other changes in the cardiovascular effects of active substances has been in a variety of cardiovasc

53、ular diseases have played an important role. In this area continue to conduct studies to identify more certainly can contribute to cardiovascular therapy. Reposted elsewhere in the paper for free download References 1 Dinerman JL, Lowenstein CJ, Snyder SH.Molecular mechanism of nitric oxide regulati

54、on.Circ Res, 1993,73 (2): 217 2 Shah AM, Grocott-Mason RM, Pepper CB, et al.The cardiac endothelium: cardioactive mediators.Prog Cardiovasc Dis, 1996,39 (3): 263 3 Grocott-Mason R, Fort S, Lewis MJ. Myocardial relaxant effect of exogenous nitric oxide in the isolated ejecting heart.Am J Physiol, 199

55、4,266 (5): H1699 4 Shah AM, Spurgeon H, Sollott SJ, et al.8-bromo cyclic GMP reduces the myofilament response to calcium in intact cardiac myocytes.Circ res, 1994,74 (5): 970 5 Paulus WJ, Vantrimpont PJ, Shah AM.Acute effects of nitric oxide on left ventricular relaxation and diastolic distensibilit

56、y in man.Circulation, 1994,89 (5): 2070 6 Paulus WJ, Vantrimpont PJ, Shan AM.Paracrine coronary endothelial control of left ventricular function in humans.Circulation, 1995,92 (8): 2119 7 Haynes WG, Webb DJ.The endothelin family of peptides: local hormones with divers roles in health and disease? Clin Sci, 1993,84 (5): 485 8