Inhibitors of arachidonic acid metabolism have variable effects on calcium signaling pathways.
The metabolic pathways of arachidonic acid (AA) have been shown to be important in the regulation of cellular function. Several studies have demonstrated both direct and indirect effects of products of these pathways in the regulation of vascular actions, and in particular on signaling pathways. Because intracellular calcium concentration is a significant mediator of stimulus-coupled signal transduction, we investigated the effects of AA pathway inhibitors on angiotensin II (Ang II)-induced calcium mobilization in cultured rat vascular smooth muscle cells (VSMC). Thus, specific calcium pools were examined for differential effects resulting from inhibitors of the three major pathways of AA metabolism. Inhibition of lipoxygenase (LO) with 2.5 micromol/L of 5,8,11 eicosatriynoic acid (ETI), cyclooxygenase (CO) with 2 micromol/L of ibuprofen (IBU), and cytochrome P-450 (P450) with 1 micromol/L of 7-ethoxyresorufin (7ER) all reduced total Ang II-induced intracellular calcium transients ([Ca2+]i) in fura 2-loaded cultured rat VSMC. However, the sites of action affected were unique for each inhibitor. Pretreatment of VSMC with either ETI or IBU inhibited thapsigargin (TG) (1 micromol/L)-sensitive calcium increments (control; 118.0 +/- 33.1 nmol/L, n = 9, ETI; 34.7 +/- 4.8 nmol/L, n = 9, IBU; 40.3 +/- 8.8 nmol/L, n = 8, P < .05 v control). Both caffeine (CAF) and ryanodine (RY) treatment attenuated Ang II-induced [Ca2+]i; however, pretreatment with ETI, IBU, or 7ER did not alter this effect. In other studies, the LO inhibitor ETI attenuated Ang II-induced Ca2+ influx, whereas inhibitors of CO and P450 pathways had no effect. These data show that 1) E
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Department of Veteran's Affairs Greater Los Angeles Healthcare System, Sepulveda, California 91343, USA.
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D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects*; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D007052:Ibuprofen / Q000494:pharmacology*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D010078:Oxazines / Q000494:pharmacology*; D051381:Rats; D012433:Ryanodine / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D016859:Lipoxygenase Inhibitors; D010078:Oxazines; D012433:Ryanodine; D016718:Arachidonic Acid; D002110:Caffeine; C007649:ethoxyresorufin; D015126:8,11,14-Eicosatrienoic Acid; C010944:mead acid; D002118:Calcium; D007052:Ibuprofen