Arachidonic acid in membranes

Although the acute vasodilator effects, as shown in in vitro studies (see above), may participate in the antihypertensive effects, the reduced blood pressure persisted even 42-48 h after the last administration of quercetin, when the plasma quercetin concentration and its metabolites fell bellow 25% of the peak post-administration levels [43]. Furthermore, the antihypertensive effects of quercetin did not appear to be related to its antioxidant properties since quercetin did not lower the urinary isoprostane F20 excretion, a prostaglandin-like compound produced in a non enzymatic reaction of arachidonic acid in membrane lipids and superoxide, which is currently used as a reliable marker of oxidative stress. The mechanisms involved in the antihypertensive effects and protection from organ damage... 

With respect to vasodilation, niacin-elicited vasodilation requires the activation of GPR109A in skin Langerhans cells [34,35], which then triggers the release of arachidonic acid from membrane phospholipids and its subsequent metabolism to PGD2. The production of PGD2 then activates DPI receptors in dermal blood vessels to cause vasodilation [36]. 

The family of heterotrimeric G proteins is involved in transmembrane signaling in the nervous system, with certain exceptions. The exceptions are instances of synaptic transmission mediated via receptors that contain intrinsic enzymatic activity, such as tyrosine kinase or guanylyl cyclase, or via receptors that form ion channels (see Ch. 10). Heterotrimeric G proteins were first identified, named and characterized by Alfred Gilman, Martin Rodbell and others close to 20 years ago. They consist of three distinct subunits, a, (3 and y. These proteins couple the activation of diverse types of plasmalemma receptor to a variety of intracellular processes. In fact, most types of neurotransmitter and peptide hormone receptor, as well as many cytokine and chemokine receptors, fall into a superfamily of structurally related molecules, termed G-protein-coupled receptors. These receptors are named for the role of G proteins in mediating the varied biological effects of the receptors (see Ch. 10). Consequently, numerous effector proteins are influenced by these heterotrimeric G proteins ion channels adenylyl cyclase phosphodiesterase (PDE) phosphoinositide-specific phospholipase C (PI-PLC), which catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) and phospholipase A2 (PLA2), which catalyzes the hydrolysis of membrane phospholipids to yield arachidonic acid. In addition, these G proteins have been implicated in... 

T FIGURE 10-18 Arachidonic acid and some eicosanoid derivatives. (a) In response to hormonal signals, phospholipase A2 cleaves arachidonic acid-containing membrane phospholipids to release arachidonic acid (arachidonate at pH 7), the precursor to various eicosanoids. (b) These compounds include prostaglandins such as PCE, in which C-8 and C-12 of arachidonate are joined to form the characteristic five-membered ring. In thromboxane A2/ the C-8 and... 

PI is synthesized from free inositol and CDP-diacylglycerol as shown in Figure 17.5. PI is an unusual phospholipid in that it olten contains stearic acid on carbon 1 and arachidonic acid on carbon 2 of the glycerol. PI, therefore, serves as a reservoir of arachidonic j acid in membranes and, thus, provides the substrate fa-prostaglandin synthesis when required (see p. 211 for a discussion of these compounds). 

The levels of cardiovascular factors could also be influenced by the ability of vitamin E to affect activation of arachidonic acid from membrane phospholipids by phospholipase A2. Vitamin E, either given in the diet or by incubation with platelets themselves, was found to inhibit phospholipase A2 in a dose-dependent manner. a-Tocopheryl acetate had little or no effect on the activity of this enzyme, but tocol, without methyl groups in the chroman ring, was more potent than either (+)- or ( )-a-tocopherol, suggesting that the methyl groups were not important for the inhibition but the hydroxy group in the ring was critical for activity [131]. 

Phospholipase A2, not C, is involved in the release of arachidonic acid from membrane phospholipids. 

Prostaglandins are synthesized as shown in Fig. 13-17 from arachidonic acid in a metabolic pathway that begins with plasma membrane phospholipids. The double-bond arrangement in the carbon chain of arachidonic acid, C2o 4A5,8,ll,14, makes the fatty acid very susceptible to oxidation... 

A major platelet response during activation is liberation of arachidonic acid fix>m jdio holipids and its subsequent oxygenation to TxA2. Patients have been described with impaired liberation of arachidonic acid from membrane phospholipids during platelet stimulation (32,54,46). In the patients described by Rao et al (32) platelet TxA2... 

PG synthesis involves four steps (Figme 2). The first two steps are common to all cells involved in prostaglandin synthesis while the final two steps are cell-specific (14-16). Release of the substrate, arachidonic acid, from membrane phospholipid stores by phospholipase is the initial event in prostaglandin synthesis, and this is followed by formation of the common PG intermediate, PGHj catalyzed by PGH synthase. At this point, rearrangement of PGH to form either stabk (PGD / Ej/ F, ) or unstable (platelet thromboxane - TxA, endothelial prostacyclin - PGy products takes place. The final step, also cell-specific, involves breakdown of the active compounds to irractive metabolites. 

Hydrolysis of 1P3 from membrane lipids yields l-acyl-2-arachidonyl-glycerol, which remains in the piasma membrane. The arachidonate esterified at the 2-po-sition may be hydrolyzed by phospholipase Aj, to yield free arachidonate. The pathway leading to the release of IP3 and arachidonate is show o in Figure 9.98, The events depicted occur in a burst. They occur mainly within a time frame of a minute or so of stimuiation of the cell, Stimulation of the cell can induce an increase in the concentration of free arachidonic acid in the cell. This arachidonate car be used by cyclooxygenase, Cyclooxygenase is a membrane-bound enzyme of the endoplasmic reticulum. The active site faces the cytoplasm. The enzyme Is bifunchonal. It catalyzes the attachment of oxygen moiecuies to arachidonic acid,... 

Because the function of individual phospholipid molecular species is unclear at this time, the precise implication of our findings is not known. However, phospholipids are an important part ofthe lipid bilayer of the cell membrane. Different phospholipid molecular species would be expected to have different metabolic and physical properties. Our recent observation seems to support this assumption. When we examined the fatty acid composition of the testes of monkeys with different ages, we found that there was an increase in DHA and a decrease in arachidonic acid in the monkey testes during puberty (Reisbick et al., 1990). Interestingly, these changes were mainly due to the increase of a... 

Two groups have studied the incorporation of labeled arachidonic acid into membrane phospholipids, a reaction that depends on the sequential effects of FACE and ACLAT. Excess amounts of LyPL substrate are available in schizophrenic platelets, but in spite of that, the rate of incorporation of AA into phospholipids is impaired (Yao, 1999 Demisch, Heinz, Gerbaldo, Kirsten, 1992). 

As previously discussed (see p. 338), many important eicosanoids are derived from arachidonic acid. Almost all cellular arachidonic acid is stored in cell membranes as esters at C-2 of glycerol in phosphoglycerides. Release of arachidonic acid from membrane, considered to be the rate-limiting step in eicosanoid synthesis (Figure 12D), results from binding an appropriate chemical... 

Phospholipase A Enzyme in the cell membrane that generates arachidonic acid from membrane lipid constituents... 

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