Sulprostone‐induced reduction of myocardial infarct size in the rabbit by activation of ATP‐sensitive potassium channels

Abstract

1 This study examined whether (i) a 1 h pretreatment with or (ii) a continuous infusion of sulprostone reduces myocardial infarct size arising from coronary artery occlusion (60 min) and reperfusion (120 min) in the anaesthetized rabbit. In addition, we investigated whether the observed cardioprotective effect of this selective agonist of prostanoid EP,/EP3 receptors were due to the activation of ATPsensitive potassium (KATP) channels.2 In anaesthetized rabbits pretreated with vehicle (5% ethanol in 0.9% saline; 0.05 ml min-', i.v.) infarct size (expressed as a percentage of the area at risk) after 60 min of coronary artery occlusion followed by 120 min of reperfusion was 59 + 4% (n = 10). Pretreatment of rabbits with sulprostone (1.0 ug kg-' min-' for 1 h, discontinued immediately prior to coronary artery occlusion) did not reduce infarct size (60 + 4%; n = 4). In contrast, a continuous infusion of sulprostone (1.0 ig kg-' min-') starting 10 min prior to the onset of LAL occlusion and continued throughout the experiment, significantly reduced infarct size (41 + 5%, n = 6) when compared to the respective vehicle-treated controls (57 + 4%, n = 10; P <0.05). Sulprostone (pretreatment or continuous infusion) had no effect on any of the haemodynamic parameters measured. 3 The reduction in infarct size afforded by continuous infusion of sulprostone was abolished by pretreatment of rabbits with the KATP channel blocker 5-hydroxydecanoate (5-HD 5 pg kg-'; 63+4%; n =6). When administered alone, 5-HD had no effect on infarct size when compared to control (52+6, n=10). 4 We propose that a continuous infusion of the selective EP,/EP3 prostanoid receptor agonist, sulprostone, reduces infarct size in the anaesthetized rabbit by a mechanism that involves the opening of KATP channels.

Effects of the prostanoid EP3‐receptor agonists M&B 28767 and GR 63799X on infarct size caused by regional myocardial ischaemia in the anaesthetized rat

“…The observed (moderate) reduction in infarct size amounted to 35% and, hence, was similar to the reductions in infarct size caused by either PGE 1 (non-selective EP 3 -receptor agonist) or sulprostone (selective EP 1 /EP 3 -receptor agonist) in the anaesthetized rabbit (*40%, see Hide et al, 1995;Hide & Thiemermann, 1996). A reduction in infarct size of this magnitude may well be biologically important, as the reduction in left ventricular function (Field et al, 1972) as well as the incidence of arrhythmias (Roberts et al, 1975) occurring as a consequence of myocardial ischaemia are directly proportional to the size of the infarcted myocardium.…”

“…As in previous studies (Hide et al, 1995;Hide & Thiemermann, 1996), we have determined the degree of necrosis caused by regional ischaemia and reperfusion of the heart by staining of viable tissue within the area at risk (non-perfused myocardium) with the tetrazolium dye NBT. In the presence of intact dehydrogenase enzyme systems (viable myocardium), NBT forms a dark blue formazan, whilst areas of necrosis lack dehydrogenase activity and therefore do not stain (Nachlas & Shnitka, 1963).…”

“…This hypothesis is supported by the following ®ndings: (1) The cardioprotective eects of PGE 1 (non-selective agonist for all EP-receptors) and sulprostone (selective agonist of EP 1 and EP 3 -receptors) are abolished by inhibition of K ATP -channels with glibenclamide or 5-hydroxydecanoate (Hide et al, 1995;Hide & Thiemermann, 1996). (2) Sulprostone causes cardioprotection without having any haemodynamic (EP 2 -mediated) eects (Hide & Thiemermann, 1996). (3) Activation of EP 1 and EP 3 -receptors may result in activation of protein kinase C (PKC) (Coleman et al, 1990;.…”

“…In 1995/96, we have discovered that the cardioprotective eects of E-type prostaglandins are (at least in part) due to activation of EP 1 or EP 3 -receptors which, in turn, leads to the opening of ATP-sensitive potassium (K ATP ) channels (Hide et al, 1995;Hide & Thiemermann, 1996). This hypothesis is supported by the following ®ndings: (1) The cardioprotective eects of PGE 1 (non-selective agonist for all EP-receptors) and sulprostone (selective agonist of EP 1 and EP 3 -receptors) are abolished by inhibition of K ATP -channels with glibenclamide or 5-hydroxydecanoate (Hide et al, 1995;Hide & Thiemermann, 1996).…”

Rostral Ventrolateral Medulla EP3 Receptor Mediates the Sympathoexcitatory and Pressor Effects of Prostaglandin E2 in Conscious Rats

“…Further, we investigated the effect of prior EP1 (8-Chloro-dibenzo(Z) [b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-acetylhydrazide; SC-19220; 2 nmol), EP2 (TG4-155; 2 nmol), or EP4 (L-161982; 2 nmol) receptor blockade on the cardiovascular responses elicited by intra-RVLM sulprostone, which also activates the EP1 receptor (Hide and Thiemermann, 1996), to determine their potential contribution to the sulprostone-evoked BP effects. It was important to determine, for the first time, the dose of L-798106 that optimally blocks the RVLM EP3 receptor in a pilot study (n 5 3).…”