Vasodilatory and Electrophysiological Actions of 8-iso-Prostaglandin E2 in Porcine Coronary Artery

Abstract

We examined the effects of several E-ring and F-ring isoprostanes on mechanical and electrophysiological activity in porcine coronary artery. Several isoprostanes evoked concentration-dependent contractions, with 8-iso-PGE 2 being the most potent (Ϫlog EC 50 of 6.9 Ϯ 0.1); this excitatory effect has been described in detail elsewhere and was not examined further here. 8-iso-PGE 2 evoked dose-dependent relaxations in tissues preconstricted with the thromboxane A 2 -agonist U46619 (10 Ϫ6 M), with a negative log EC 50 of 6.0 Ϯ 0.1 (n ϭ 5). 8-iso-PGE 1 and 8-iso-PGF 2␤ also evoked relaxations (albeit with lower potency), whereas the other F-ring isoprostanes (8-iso-PGF 1␣ , 8-iso-PGF 1␤ , and 8-iso-PGF 2␣ ) were largely ineffective in this respect. The potency and efficacy of 8-iso-PGE 2 in reversing tone were not dependent upon the concentration of U46619 used to preconstrict the tissues (10 Ϫ8 to 10 Ϫ6 M), indicating a lack of U46619-induced functional antagonism of these responses. 8-iso-PGE 2 was able to completely relax tissues that had been denuded of endothelium (as indicated by loss of responsiveness to bradykinin). 8-iso-PGE 2 -evoked relaxations were markedly reduced by elevating the K ϩ equilibrium potential using 30 mM KCl and abolished by 60 mM KCl; they were also sensitive to charybdotoxin (10 Ϫ7 M) but not to 4-aminopyridine (1 mM). 8-iso-PGE 2 also caused membrane hyperpolarization and augmentation of outward K ϩ current. We conclude that 8-iso-prostaglandin E 2 acts directly on the smooth muscle to increase K ϩ conductance, leading to membrane hyperpolarization and vasodilation.

Evidence that a prostanoid produced by cyclo-oxygenase-2 enhances contractile responses of the porcine isolated coronary artery following exposure to lipopolysaccharide

“…Interestingly, 8-iso-PGF 2a has been reported to be a potent vasoconstrictor in porcine arteries, 31 32 whereas the overall response to 8-iso-PGE 2 is dependent on prevailing vascular tone. 32 As 8-iso PGF 2a activates thromboxane A 2 receptors, this may explain why contractions elicited by U46619 are less affected by indomethacin and NS 398 than those elicited by KCl: there being less potential for the prostanoid to enhance constrictor responses. Although the present study provides strong evidence for the presence of a COX-2 dependent vasoconstrictor prostanoid in PCA exposed to LPS, one of the limitations of this study is a lack of direct demonstration of this prostanoid.…”

Isoprostanes constrict human radial artery by stimulation of thromboxane receptors, Ca2+ release, and RhoA activation

“…13,14 Cytosolic concentrations of [Ca 2ϩ ] i were recorded using a custom-built confocal microscope, and membrane currents were recorded using the standard patch-clamp electrophysiologic technique, both as described previously. [13][14][15][16]…”

Vasoconstrictor responses, and underlying mechanisms, to isoprostanes in human and porcine bronchial arterial smooth muscle

“…We have previously reported the effects of isoprostanes on airway ( Janssen et al , 2000 ; Catalli et al , 2002 ), pulmonary vascular ( Janssen et al , 2001 ; Janssen & Tazzeo, 2002) and coronary vascular ( Zhang et al , 2003 ) smooth muscles. In general, we found the isoprostanes to act on thromboxane A 2 ‐selective prostanoid receptors (TPs), leading to the stimulation of tyrosine kinase and Rho‐kinase activities, and resulting in powerful constriction of the muscle tissues.…”

“…These accumulate to substantial levels in many clinical conditions characterized in part by accumulation of free radicals and reactive oxygen species, including asthma ( Montuschi et al , 1999 ; Wood et al , 2000 ; Kostikas et al , 2002 ), hypertension (Romero and Reckelhoff, 1999; Yamada et al , 1999 ; Cracowski et al , 2001 ) and ischemia – reperfusion injury ( Mathews et al , 1994 ; Reilly et al , 1997 ; Fischer et al , 2000 ). For this reason, they are frequently used as markers of oxidative stress; however, many are now finding that these molecules are not inert, but in fact evoke powerful biological responses in an increasing array of cell types (Janssen, 2001; Janssen et al , 2000 , Janssen et al , 2001 ; Catalli et al , 2002 ; Janssen & Tazzeo, 2002; Zhang et al , 2003 ). In many cases, these biological effects can account in part for the various features and manifestations of those clinical conditions.…”