As indicated by Table 1 prostanoids play roles in numerous physiological settings. In many cases, the nature of these roles and their mechanisms remain to be elucidated. Below are some features of a few well-studied examples chosen to illustrate the local nature of the actions of these molecules, to appreciate their importance to the overall physiological processes in which they participate, and to recognize the basis for the side effects of the drugs that inhibit their production.

Table1. Some Biological Actions of Eicosanoids

A. Prostacyclin and Thromboxane in the Vasculature

The roles of TXA2 and PGI2 in platelet aggregation and vascular tone are shown in Figure 1. Platelets are enucleated cell fragments formed from bone mar row megakaryocytes. They retain many cytoplasmic components including mitochondria, granules containing platelet-specific proteins, coagulation factors, and the enzymes (phospholipase A2, COX-1, and thromboxane synthase) to produce TXA2. When an injury to the vasculature occurs, platelets are activated through the detection of exposed collagen in the wall of the vasculature. A rise in intracellular Ca2+ in the plate lets leads to the activation of phospholipase A2 and cyclooxygenase. The resulting TXA2 is released and acts on the platelets to promote aggregation through interaction with its receptor, TP, and the reduction in intracellular cAMP levels. TXA2 also acts on nearby smooth muscle cells of the vasculature, constricting them to prevent blood loss. A platelet plug is formed at the site of the injury, setting the stage for clot formation.

Fig1. PGI2 and TXA2 in the vasculature. The balance between PGI2 and TXA2 is important in cardiovascular homeostasis. The endothelial cells of the blood vessels produce and release PGI2. Through interaction with its receptors (IP, green triangles) on blood platelets and on the smooth muscle cells of the blood vessel walls, PGI2 decreases platelet aggregation and promotes vasodilation, respectively. Platelets produce and release TXA2 which acts through its receptor, TP (purple ovals), in an autocrine fashion to promote platelet aggregation and through paracrine action to stimulate vasoconstriction.

Under normal conditions, that is when no injury to the vasculature is detected, prostacyclin, PGI2, is produced by COX-2 and PGI synthase and released by the endothelial cells lining the vasculature. PGI2 acts on platelets through its receptor, IP, and increased cyclic AMP production to inhibit aggregation. PGI2 also pro motes vasodilation of the smooth muscle cells. Thus, balance between the actions of TXA2 and PGI2 in the blood vessels is critical in maintaining vascular homeostasis. Since platelets contain COX-1 and endothelial cells contain COX-2, inhibitors selective for the latter enzyme (section III.D) upset the balance between the two prostanoids and can therefore lead to serious cardiovascular side effects.

B. Prostaglandins in the Kidney

Prostaglandins participate in several functions of the kidney. Figure 2 depicts the distribution along the renal tubule of the four receptors for PGE2 and the one for PGF2α. Precise functions for each of the receptors in the different locations have not yet been clearly mapped out, but some have been deduced from experimental observations. For example, inhibition of prostaglandin production by cyclooxygenase inhibitors leads to salt and water retention and the resultant high hypertension. This fact, in the context of studies with mice that have been genetically altered to lack the gene for EP3, FP, or EP1, indicates that each receptor plays a role in NaCl transport sequentially along the tubule, from the thick ascending limb through the distal collecting duct. EP2 is also thought to play a role in salt excretion, but the receptor is present in low levels and its precise location is not yet certain. EP4 has recently been shown to be necessary for the salt- deprivation-induced stimulation of renin secretion, the first step of the renin-angiotensin-aldosterone system.

Fig2. Prostaglandin receptor distribution in the renal tubule. The distribution of receptors for the main prostaglandins produced by and active on the epithelial cells of the renal tubule are shown. See inset at lower left for legend of symbols used.

The hemodynamics of blood flow through the kidney, and therefore the glomerular filtration rate (GFR), is also subject to control by prostanoids. TXA2 produced in the glomerulus and PGI2 in the vasculature of the arterioles in the glomerulus and other renal blood vessels influence the state of vasoconstriction or vasorelaxation, respectively, as in the vasculature in other parts of the body.

C. Prostaglandins and Pain Perception

 The pain mechanism is essential for survival, since acute pain is a warning mechanism for threatening conditions. The peripheral nociceptors, when excited by potentially harmful stimuli, cause pain by way of their afferent nerve fibers, as shown in Figure 3. Probably every organ in the body contains these receptors. There are two classes of nociceptive afferent nerves: those found among thin myelinated Aδ fibers, associated with sharp focused pain, and those among the non myelinated C fibers and associated with dull, burning and diffuse pain. In response to an injury, chemical sub stances released from the injured tissue excite nociceptors or sensitize them to other stimuli (Figure 3A) resulting in the generation of pain. These substances, referred to as algesic because they produce the sensation of pain, include bradykinin which stimulates the intracellular production of prostaglandins, leading to the firing of the nerve as described in the following. The afferent signals are sent through the spinal cord in ascending fibers to pain centers in the brain.

Fig3. Prostaglandins in pain perception. A. When a tissue injury occurs, cells at the site release several substances including bradykinin, serotonin (5-HT, hydroxytryptamine), and prostaglandins, primarily PGE2, into the acidic environment of the inflammation. All of these act on the terminus of the nociceptor, the afferent neuron, whose cell body lies in the dorsal root ganglion, that will carry the pain signal through the afferent fibers in ascending tracts in the spinal cord to pain perception centers in the brain. At the same time the efferent function of the nociceptor engages, releasing the neurotransmitters substance P and CGRP (calcitonin gene related peptide, see Chapter 9) leading to activation of nearby nonneuronal cells, which contribute other molecules, such as histamine, to the inflammatory milieu. B. Inside the nerve terminal, PGE2 acting through either EP1 or EP4 (depending on the tissue and species under study) activates protein kinase C (PKC) or cyclic AMP-dependent protein kinase (PKA), respectively. Phosphorylation leads to the opening of Ca2+ and Na+ channels, including the vanilloid receptor, VR-1 (a mono- and divalent cation channel), and the closing of K+ channels. Collectively these events lead to membrane depolarization and transmission of the neural signal to the brain.

Prostaglandins produced in the nerve terminals are released to act on their membrane receptors on this or nearby termini, as described in sections III.F and IV. The role of PGE2 will be discussed here, although PGI2 also functions in pain perception pathways through similar mechanisms. Furthermore, although only EP1 and EP4 are discussed here, EP2 and EP3 have also been implicated in pain perception in some tissues. As shown in Figure 3B, PGE2, acting through either protein kinase A (EP4) or protein kinase C (EP1) brings about the phosphorylation of ion channels in the nerve terminus. Inhibition of either COX-1 or COX-2 would lead to analgesia, the effect long known for aspirin and the basis for the intense interest in other cyclooxygenase inhibitors (section III.D).

The efferent function of the nocireceptor is also depicted in Figure 3A. This includes the release of neurotransmitters such as substance P and CGRP (calcitonin gene related peptide) which activate other nearby cells, such as mast cells and neutrophils. These cells secrete substances such as histamine into the inflammatory site. The release of substance P and CGRP also results in vasodilation and in leakage of blood plasma proteins and fluid.

D. Prostaglandins in Reproduction

The processes of reproduction and their hormonal control in the female are covered in Chapters 13 and 14.

It may be useful to make reference to this material while reading the following regarding the role of prostaglandins in some of these processes.

 1. Ovulation Much of the information gathered about the role of prostaglandin synthesis and action during ovulation has come from the examination of mice genetically altered to be deficient in either COX-1 or COX-2. The cascade of cellular events that follows the midcycle surge of LH and leads to release of the ovum shares several characteristics with the process of inflammation. Thus it is not surprising that induced COX-2 in granulosa, rather than the constituitively expressed COX-1 in the thecal cells, is the critical enzyme for the prostaglandin pathway in ovulation. In mice lacking the COX-2 gene, in which ovulation does not take place, follicle rupture and release of the ovum can be achieved most effectively by the administration of PGE2. In nonhuman primates it has been shown that PGE2 is specifically involved in the regulation of plasminogen activator-mediated proteolysis required for follicule rupture.

 2. Luteolysis In nonprimate mammals, such as rodents and domesticated species, the regression of the corpus luteum (luteolysis) at the end of a nonfertilization reproductive cycle, is brought about by PGF2α produced by the uterus. In primates including humans, the corpus luteum can undergo regression in the absence of the uterus although PGF2α is synthesized by the human corpus luteum and FP receptors are found there. While this and other evidence suggests that locally produced PGF2α may participate in primate luteolysis, further studies are required to have a definitive answer on this point.

3. Cervical Ripening A critical step in the birth of the newborn is the softening (or ripening) of the uterine cervix, which has functioned to retain the fetus throughout pregnancy, so that the fetus can be expelled when gestation is concluded. Several prostaglandins are produced in the cervix and the tissue contains both EP and FP receptors. It is likely that the mechanism of prostaglandin action in the cervix includes the induction of enzymes responsible for remodeling of collagen and proteoglycans that occurs during cervical softening. The local administration of PGE2 is a common way to stimulate the process, particularly when labor is being induced, and brings about the same changes as those seen in non-therapeutically assisted softening.

4. Parturition/Preterm Labor

The biological effect of the first prostaglandins studied was their powerful ability to contract uterine smooth muscle. PGE2 is a potent abortifactant and is used in the early termination of pregnancy. It has been known for three decades that aspirin and indomethacin, both cyclooxygenase inhibitors that, at low doses, are specific for COX-1, delay parturition (birth) in humans and other animals. At higher doses these NSAIDs both inhibit COX-2 as well. The cyclooxyge nases occur in the placenta and fetal membranes and during normal labor, prostaglandin production by COX-1 is regulated by other hormones involved in parturition. Preterm labor, on the other hand, which shares physiologic features with inflammatory processes, is mediated largely by COX-2. Clinically, preterm labor can be curtailed with systemic or vaginally delivered local doses of indomethacin, attesting to the importance of prostaglandins in parturition. However, a side effect of this approach, in addition to possible renal and cardiac damage in the fetus, is the effect of indomethacin on the remodeling of the ductus arteriosus, or DA.

During fetal development the DA carries deoxygenated blood away from the fetal pulmonary circulation to the umbilical-placental circulation to be reoxygenated in the maternal blood pools. Immediately upon birth, this shunting vessel must close so that the fetal circulation is adapted to air-breathing. Fetal PGE2 is necessary for the maintenence of the open DA prior to birth, as indicated by the closure of the duct by pharmacological dose of COX inhibitors, such as indomethacin. In fact, the use of such inhibitors is a common treatment to close the DA in infants born prematurely. However, if given to stop premature labor, indomethacin can bring about the closure of the DA prior to the birth of the infant, compromising its circulatory health.

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مواضيع ذات صلة

Cyclooxygenase Inhibitors

Prostaglandin H Synthase/ Cyclooxygenase

Phospholipase A2

Overview of Eicosanoid Synthesis

Structure and Nomenclature of Eicosanoids

Water is an Excellent Nucleophile

Interaction with Water Influences the Structure of Biomolecules

Fibrin Clots Are Dissolved by Plasmin

The Activity of Antithrombin, an Inhibitor of Thrombin, Is Increased by Heparin

Conversion of Fibrinogen to Fibrin Is Catalyzed by Thrombin

Factor Xa Leads to Activation of Prothrombin to Thrombin

Most Transmembrane Proteins Have Membrane Spanning α Helices