Tuesday, 17 December 2013

The Effects of Hormone Prostacyclin(2)

Prostacyclin (or PGI2), also known as known as eicosanoids, a member of the family prostaglandins as a metabolite of arachidonic acid, inhibits platelet aggregation, and dilates blood vessels and is released by healthy endothelial cells and performs its function through a paracrine signaling cascade that involves G protein-coupled receptors on nearby platelets and endothelial cells(a).
9. Prostacyclin-stimulating and/or thromboxane A2-inhibiting action in hypertensive pregnancy complications
Several gynecologic and obstetric disorders are characterized by abnormalities in prostacyclin and/or thromboxane A2. In primary menorrhagia the uterine release of prostacyclin is increased, and consequently menstrual blood loss can be reduced with various prostaglandin synthesis inhibitors. Prostacyclin relaxes the nonpregnant myometrium in vitro and may also do so in vivo, although intravenous infusion of prostacyclin has no effect upon the uterine contractility in nonpregnant or pregnant subjects.  In the study to review the gynecologic and obstetric implications of the smooth muscle-relaxing, antiaggregatory prostacyclin and its endogenous antagonist, thromboxane A2, showed that patients with pelvic endometriosis may have increased levels of prostacyclin and thromboxane A2 metabolites in the peritoneal fluid. The prostacyclin/thromboxane A2 balance shifts to thromboxane A2 dominance in patients with gynecologic cancer. During pregnancy the production of prostacyclin and thromboxane A2 increases in the mother and fetoplacental tissue. Preeclampsia and other chronic placental insufficiency syndromes are accompanied by prostacyclin deficiency in the mother and in fetomaternal tissues and by an overproduction of thromboxane A2, at least in the placenta. These changes may account for the vasoconstriction and platelet hyperactivity, which are pathognomonic for hypertensive pregnancies. By directing the prostacyclin/thromboxane A2 balance to prostacyclin dominance (by dietary manipulation, administration of prostacyclin and/or its analogues, drugs with prostacyclin-stimulating and/or thromboxane A2-inhibiting action), it may be possible to prevent and/or treat hypertensive pregnancy complications in the future(9).

10. Prostacyclin, thromboxane A2, and hypertension
Prostacyclin and thromboxane A2, products of separate branches of the arachidonic acid cascade, can have opposing effects on kidney function and on the vascular musculature. According to the study by the Shandong Medical University, prostacyclin acts as a vasodilator while thromboxane A2 has a vasoconstrictor effect and the balance between these two compounds appears to contribute to the homeostatic regulation of normal blood pressure. In the hypertensive state, this balance is disrupted and, at least in animal models of hypertension, there is excessive production of both. The increase in prostacyclin formation may be a reaction to the elevated blood pressure, possibly due to mechanical stimulation of the vascular smooth muscle cells in the blood vessel wall. However, the increase in thromboxane A2 may be more directly involved in the development and maintenance of hypertension. Not only is thromboxane A2 a vasoconstrictor but it can also stimulate the growth and proliferation of vascular smooth muscle cells which may account for the vascular hypertrophy seen in hypertension(10).

11. Interrelationships between prostacyclin and thromboxane A2
Prostacyclin is a product of arachidonic acid metabolism generated by the vessel wall of all mammalian species studied including man. According to the study by Moncada S, Vane JR. ,prostacyclin is a potent vasodilator and the most potent inhibitor of platelet aggregation. It inhibits platelet aggregationand can also be a circulating hormone constantly released by the pulmonary circulation. In contrast to the vessel wall, in blood platelets arachidonic acid is converted by the enzyme thromboxane synthetase to a potent vasoconstrictor and proaggregating substance, thromboxane A2. Therefore arachidonic acid is metabolized in the vessel wall and the platelets to potent substances with opposing biological activities. The balance between the activities of these substances is important in the homeostatic interaction of the platelets and the vessel wall. The different ways of interfering with this balance and its impact in the development of thrombosis and atherosclerosis(11).

12. Prostacyclin's biosynthesis, actions and clinical potential
Prostacyclin (PGI2) is the product of arachidonic acid metabolism generated by the vessel wall of all mammalian species studies.  According to the study by Moncada S, Vane JR., indicated that prostacyclin inhibits aggregation through stimulation of platelet adenyl cyclase leading to an increase in platelet cyclic AMP. In the vessel wall, the enzyme that synthesizes prostacyclin is concentrated in the endothelial layer. Prostacyclin can also be a circulating hormone released from the pulmonary circulation. Based on these observations we proposed that platelet aggregability in vivo is controlled via a prostacyclin mechanism. The discovery of prostacyclin has given a new insight into arachidonic acid metabolism and has led to a new hypothesis about mechanisms of haemostasis. Reductions in prostacyclin production in several diseases, including atherosclerosis and diabetes, have been described and implicated in the pathophysiology of these diseases. Additionally, since prostacyclin powerfully inhibits platelet aggregation and promotes their disaggregation, this agent could have an important use in the therapy of conditions in which increased platelet aggregation takes place and in which, perhaps, a prostacyclin deficiency exists. Prostacyclin has been used beneficially in humans during extracorporeal circulation procedures such as cardiopulmonary bypass, charcoal haemoperfusion and haemodialysis. Its possible use in other conditions such as peripheral vascular disease or transplant surgery(12).

13. Prostacyclin in vascular tissue
Prostacyclin (PGI2) generated by the vascular wall is a potent vasodilator, and the most potent endogenous inhibitor of platelet aggregation. According to the study by Moncada S, Vane JR., prostacyclin inhibits platelet aggregation by increasing cyclic AMP levels. Prostacyclin is a circulating hormone continually released by the lungs into the arterial circulation. Circulating platelets are, therefore, subjected constantly to prostacyclin stimulation and it is via this mechanism that platelet aggregability in vivo is controlled. Moreover, phosphodiesterase inhibitors such as dipyridamole or theophylline exert their antithrombotic actions by potentiating circulating prostacyclin. The prostacyclin:thromboxane A2 ratio is important in the control of thrombus formation; manipulation of this ratio by small doses of aspirin (which will inhibit mainly platelet cyclooxygenase), a selective inhibitor of thromboxane formation, or the dietary use of a fatty acid like eicosapentaenoic acid (which would be the precursor for a delta17-prostacyclin (PGI3) but is transformed by the platelets into nonaggregating thromboxane A3) might have beneficial effects as antithrombotic therapies. Prostacyclin has interesting potential for clinical application in conditions where enhanced platelet aggregation is involved or to increase biocompatibility of extracorporeal circulation systems(13).

14. Prostacyclin reduces cardiopulmonary bypass-induced pulmonary endothelial dysfunction
Cardiopulmonary bypass triggers a systemic inflammatory response that alters pulmonary endothelial function, which can contribute to pulmonary hypertension.  According to the study by the Montreal Heart Institute, prophylactic use of inhaled prostacyclin has a favorable impact on the pulmonary endothelial dysfunction induced by cardiopulmonary bypass associated with preservation of pulmonary intravascular cyclic adenosine monophosphate content and the pulmonary vascular tone(14).

15. Healthy vascular endothelium
Healthy vascular endothelium is a powerful generator of nitric oxide (NO), prostacyclin (PGI2), prostaglandin E2 (PGE2), and plasminogen activator (t-PA). These endothelial products protect vascular wall against aggression from activated blood platelets and leukocytes. According to the study by Jagiellonian University, In particular they protect against thrombosis, promote thrombolysis, maintain tissue perfusion, and inhibit remodeling of vascular and cardiac walls. Endothelial dysfunction appears on one hand as suppression in the release of the above mediators, and on the other as deleterious discharge of prostaglandin endoperoxides (PGH2, PGG2), superoxide anion O2-, peroxynitrite (ONOO-), and plasminogen activator inhibitor (PAI-1)(15).

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(9) http://www.ncbi.nlm.nih.gov/pubmed/3890549
(10) http://www.ncbi.nlm.nih.gov/pubmed/2078914
(11) http://www.ncbi.nlm.nih.gov/pubmed/6258879
(12) http://www.ncbi.nlm.nih.gov/pubmed/6117893
(13) http://www.ncbi.nlm.nih.gov/pubmed/215463
(14) http://www.ncbi.nlm.nih.gov/pubmed/15224029
(15) http://www.ncbi.nlm.nih.gov/pubmed/12056503

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