Relaxation of porcine coronary artery to bradykinin. Role of arachidonic acid.

Abstract

Bradykinin-induced relaxation of precontracted, porcine coronary artery (PCA) rings is mediated by distinctly different endothelium-derived relaxing factors depending on the contractile agent used. Thus when contracted with KC1, bradykinin-induced relaxation of PCA rings is mediated solely by nitric oxide (NO), whereas when contracted with the thromboxane mimetic U46619, a small component of the relaxation is attributable to NO and a large component is attributable to a non-NO mechanism that is independent of cyclooxygenase activity. We hypothesized that the non-NO component was mediated by arachidonic acid (AA) or by a non-cyclooxygenase product of AA metabolism. Bradykinininduced relaxations of PCA rings precontracted with U46619 in the presence of indomethacin (10 /imol/L) were moderately attenuated by the NO synthase inhibitor W-nitro-L-arginine methyl ester (L-NAME, 100 fxmolfL), whereas when precontracted with KC1, L-NAME abolished the relaxations. AA produced endothelium-dependent relaxations of rings precon-T he concept of the vascular endothelium as a fundamental participant in circulatory control is rapidly evolving.1 -2 In addition to several vasoconstricting agents, 3 -5 at least two vasorelaxing substances of vascular endothelial origin have been identified: prostaglandin I 2 (PGI 2 ), 6 a product of cyclooxygenase-mediated arachidonic acid metabolism, and nitric oxide (NO), 78 or a closely related compound, 9 which is produced by the action of NO synthase on L-arginine. More recently, endothelium-dependent relaxations of several vascular tissues have been reported to occur through a mechanism(s) distinct from one involving either cyclooxygenase or NO synthase.1013 Thus relaxation of isolated porcine coronary arterial (PCA) rings to bradykinin, for example, persisted despite inhibition of both cyclooxygenase and NO synthase. 1315 It was proposed that this relaxation was mediated by an endothelium-derived hyperpolarizing factor. 16Bradykinin activates phospholipase A 2 , 1718 purportedly through receptor-mediated increases in intracellular calcium. 19 The activation of phospholipase A 2 results in hydrolysis of tissue phospholipids, in turn releasing fatty acids, including arachidonic acid. traded with U46619 that were unaffected by L-NAME, whereas AA did not relax rings precontracted with KC1. In rings precontracted with U46619, in the presence of L-NAME and indomethacin the phospholipase inhibitors quinacrine (50 fimolfL) and 4-bromophenacyl bromide (10 jtmol/L) attenuated bradykinin-but not AA-induced relaxations. Key Words • endothelium-derived relaxing factor • coronary artery • arachidonic acid • bradykinin acid may in turn be reacylated 21 or metabolized further through three known pathways, ie, the cyclooxygenase pathway* to prostaglandins and thromboxanes, the lipoxygenase pathway 22 to leukotrienes and oxygenated fatty acids, and the cytochrome P-450 monooxygenase pathway 23 to epoxides and oxygenated fatty acids. Several of the non-cyclooxygenase-mediated products of arachidonic...

Inhibitors of the cytochrome P450‐mono‐oxygenase and endothelium‐dependent hyperpolarizations in the guinea‐pig isolated carotid artery

“…Furthermore, in some vascular beds, cytochrome P450 inhibitors inhibit endothelium-dependent vasorelaxation resistant to cyclo-oxygenase and nitric oxide synthase blockade, although in these studies, the membrane potential was not measured Bauersachs et al, 1994;Fulton et al, 1995). In the present study, different cytochrome P450 inhibitors (SKF525a, metyrapone, clotrimazole, 17-ODYA and methoxsalen) did not inhibit the hyperpolarization produced by acetylcholine, although the concentrations studied were equivalent to or even higher than that used by other authors to block endothelium-dependent relaxations Bauersachs et al, 1994;Oyakan et al, 1994;Weintraub et al, 1994;Fulton et al, 1995). These results were confirmed by the absence of inhibitory effect of ETYA, a non specific inhibitor of lipoxygenases/cyclo-oxygenases/cytochrome P450 monooxygenases and quinacrine and an inhibitor of phospholipase A2.…”

Importance of endothelium-derived hyperpolarizing factor in human arteries.

“…However, it should be noted that these experiments were done in bovine arteries. Weintraub et al reported that the nature of acetylcholine-induced EDHF in porcine coronary arteries may not be a metabolite of cyclooxygenase or cytochrome P450 monooxygenase (27). Corriu et al reached the same conclusion with the guinea pig carotid artery (28).…”

Pulsed ultrasound enhances the delivery of nitric oxide from bubble liposomes to ex vivo porcine carotid tissue

“…3,4,[15][16][17][18][19] Optical techniques, such as fluorescence 16,20,21 or luminescence, 18,22,23 take advantage of the native optical properties of the therapeutic or conjugation of tracer molecules. Electrophysiological approaches, such as voltage-clamp techniques, 19,24,25 directly assess the changes in membrane potential provoked during UMDD, but often require isolated cells cultured in vitro, where cellular processes can vary from in vivo conditions.…”

“…Isolated tissue bath perfusion systems have been used extensively to characterize contractility changes induced by a therapeutic 20,[29][30][31][32][33] in a variety of muscular tissue beds, including gastric, 1,2,12-14 peripheral vascular, 3,4,[15][16][17][18][19] and cardiovascular 16,20,21 beds. In these systems, dosedependent changes in active muscular tension can be characterized in response to vasorelaxing agents such as bradykinin, 18,22,23 sodium nitroprusside, 19,24,25 nitroglycerin, [26][27][28] and NO.…”

“…In these systems, dosedependent changes in active muscular tension can be characterized in response to vasorelaxing agents such as bradykinin, 18,22,23 sodium nitroprusside, 19,24,25 nitroglycerin, [26][27][28] and NO. 20,[29][30][31][32][33] Adaptation of the isolated tissue bath model to drug delivery studies could provide relevant, real-time quantitative data on the drug release and delivery profiles triggered by ultrasound. We hypothesize that these isolated tissue bath systems can be used to characterize NO-mediated changes in carotid vascular tone upon ultrasound exposure.…”