Hemodynamic Effects of Isoprostanes (8-Iso-Prostaglandin F2α and E2) in Isolated Guinea Pig Hearts

Abstract

Isoprostanes are a family of prostaglandin-related compounds formed from arachidonic acid in a cyclooxygenase-independent manner as products of free radical-initiated lipid peroxidation. To elucidate the biological activity of the F2-and E2-isoprostanes, 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha) and 8-iso-prostaglandin E2 (8-iso-PGE2), we measured hemodynamic effects in isolated perfused guinea pig hearts after cumulative administration (3 x 10(-9)-10(-5) M) of these compounds into the coronary system. Coronary flow (CF), left ventricular pressure (LVP), maximal rate of pressure development (dP/dt(max)), and heart rate were determined continuously. Furthermore, net release of lactate into the coronary venous effluent and myocardial pyruvate consumption were measured. Comparative studies were performed with the known potent vasoconstrictor endothelin-1 (6 x 10(-12)-2 x 10(-9) M). Both 8-iso-PGF2alpha and 8-iso-PGE2 induced concentration-dependent decreases in CF, which declined maximally to approximately 50% of the baseline level. The potencies of the two compounds were almost identical. Alterations in CF were associated in both groups with parallel reductions of LVP and dP/dt(max); heart rate was not influenced. Furthermore, the diminished CF caused enhanced lactate release and a reduced pyruvate consumption. All isoprostane-induced hemodynamic changes were prevented by coapplication of the thromboxane A2-receptor antagonist SQ 29548 (1 microM). Endothelin-1 caused CF reductions associated with loss of myocardial contractility, just like the isoprostanes. We conclude that in isolated guinea pig hearts, 8-iso-PGF2alpha and 8-iso-PGE2 are potent vasoconstrictors. The action appears to be mediated by SQ 29548-responsive thromboxane receptors. The accompanying loss of contractility is a secondary phenomenon, elicited by infringed oxygen supply.

The cyclooxygenase-2 product prostaglandin E2 modulates cardiac contractile function in adult rat ventricular cardiomyocytes

“…This cardiac potentiating property of PGE 2 is consistent with those elicited by PGE 2 or its precursor arachidonic acid reported at the whole animal or multicellular myocardial levels [6,9,11]. The PGE 2 -elicited positive cardiac contractile response is expected to counter-balance the vasoconstrictive action of PGE 2 on main arteries such as aorta to facilitate cardiac energy expenditure and ventricular performance [3,12]. The enhanced cardiac contractility in isolated ventricular myocytes is also consistent with the PGE 2 -elicited protection against myocardial dysfunction due to free radical generation [13].…”

Propofol cardioprotection for on-pump aortocoronary bypass surgery in patients with type 2 diabetes mellitus (PRO-TECT II): a phase 2 randomized-controlled trial

“…12 While the effects of ROS are largely compartmentalized within cells, they trigger generation of stable diffusible lipid peroxidation products like 15-F 2t -isoprostane, a coronary artery vasoconstrictor implicated in the development of postoperative ventricular dysfunction. 19,26 We attribute our findings to patient characteristics, surgical conditions, and study interventions that differ from prior studies. We studied higher risk patients undergoing normothermic CPB and blood cardioplegic arrest.…”

“…It exacerbates myocardial IRI, producing left ventricular dysfunction directly via receptor-induced coronary artery vasoconstriction. 19 Furthermore, we previously found that propofol upregulates anti-apoptotic B-cell lymphoma 2 (Bcl-2) gene and protein expression in cardiomyoblasts, allowing them to withstand subsequent oxidative challenge. 20 B-cell lymphoma 2 sequesters pro-apoptotic BAX, a protein that promotes mitochondrial pore opening.…”

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

“…In particular, 8-iso-PGE 2 , 8-iso-PGE 1 , and 8-iso-PGF 2␣ were the most potent, with negative log EC 50 (half-maximally effective concentrations) of 6.9 Ϯ 0.1, 6.6 Ϯ 0.1, and 6.3 Ϯ 0.1, respectively. These excitatory effects of isoprostanes have been examined in detail in numerous vascular beds (Janssen, 2001) including the coronary artery (Mobert et al, 1997;Kromer and Tippins, 1999) and have been shown to involve TP receptors: we did not characterize these effects any further in this study.…”

“…There have been many reports of the excitatory actions of isoprostanes and the receptor-effector coupling pathways underlying them in vascular, airway and gastrointestinal smooth muscles (Janssen, 2001;Mobert et al, 1997;Kromer and Tippins, 1999;Janssen et al, 2000Janssen et al, , 2001. However, their inhibitory effects on smooth muscle have been largely unexplored: only two groups have described their relaxant effects in pulmonary vasculature (Jourdan et al, 1997;Janssen et al, 2001) and airway smooth muscle (Janssen et al, 2000), and none have examined the signaling pathways involved.…”