Defibrotide reduces infarct size in a rabbit model of experimental myocardial ischaemia and reperfusion

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A non‐invasive technique for the scintigraphic determination of 111indium‐labelled platelet aggregation stimulated with submaximal doses of adenosine diphosphate (ADP, 56 μg kg−1 i.v.), collagen (100 μg kg−1 i.v.), platelet‐activating factor (PAF, 0.1 μg kg−1 i.v.) or thrombin (18 iu kg−1 i.v.) was used to investigate the platelet‐inhibitory effects of endothelin 1 (ET‐1) in anaesthetized rabbits in vivo. ET‐1 (1 nmol kg−1 i.v.) inhibited ADP‐stimulated platelet aggregation in vivo; a maximum inhibition of 78% of the control value was reached at 3 min, with 45% inhibition at 15 min, and a return to control values at 30 min after injection of the peptide. ET‐1 (1 nmol kg−1 i.v.) inhibited in vivo platelet aggregation in response to collagen or PAF by 86% and 52%, respectively, but had no effect on thrombin‐induced platelet aggregation. Indomethacin (5 mg kg−1 i.v.) abolished the ET‐1‐induced inhibition of ADP‐stimulated platelet aggregation and significantly potentiated and prolonged the pressor response brought about by ET‐1. In conclusion, the data demonstrate that ET‐1 potently inhibits platelet aggregation in the anaesthetized rabbit in vivo by releasing a hypotensive and anti‐aggregatory cyclo‐oxygenase product, presumably prostacyclin, into the circulation.

Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Endothelin‐1 inhibits platelet aggregation in vivo: a study with ¹¹¹indium‐labelled platelets

Thiemermann

May

Page

et al. 1990

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“…The method of coronary artery occlusion and reperfusion in the anaesthetized rabbit was performed as previously described (Thiemermann et al, 1989;Hide et al, 1995). Briefly, rabbits were anaesthetized and instrumented as described above for haemodynamic recordings.…”

Section: Myocardial Ischaemia and Reperfusionmentioning

confidence: 99%

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

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Thiemermann

1996

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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.

“…The method of coronary artery occlusion and reperfusion in the anaesthetized rabbit was performed as previously described (Thiemermann et al, 1989;McMurdo et al, 1994). Briefly, rabbits were anaesthetized and instrumented as described above for haemodynamic recordings.…”

Section: Myocardial Ischaemia and Reperfusionmentioning

confidence: 99%

“…Similarly, prostaglandin El (PGEI) exerts beneficial effects on haemodynamic, biochemical, electrocardiographic and functional indices of ischaemia and reperfusion-related injury of the myocardium (Hutton et al, 1973;Takano et al, 1977;Riemersma et al, 1977;Jugdutt et al, 1981;Schr6r et al, 1988a;Simpson et al, 1988). However, an improvement in biochemical indicators of ischaemic tissue injury, such as the loss of cytosolic marker enzymes from the ischaemic myocardium, is not necessarily associated with a reduction in infarct size (Thiemermann et al, 1989).…”

Section: Introductionmentioning

confidence: 99%

Reduction by prostaglandin E₁ or prostaglandin E₀ of myocardial infarct size in the rabbit by activation of ATP‐sensitive potassium channels

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Ney

Piper

et al. 1995

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1 This study examined whether pretreatment of rabbits with infusions of prostaglandin El (PGEI) or prostaglandin Eo (PGEO) (which were terminated prior to the onset of ischaemia) reduce myocardial infarct size arising from coronary artery occlusion (60 min) and reperfusion (120 min). In addition, we investigated whether the observed cardioprotective effects of these two prostaglandins were due to the activation of ATP-sensitive potassium (KATP) channels. 2 In the anaesthetized rabbit, infarct size (expressed as a percentage of the area at risk) after 60 min of coronary artery occlusion followed by 2 h of reperfusion was 59 + 4% (n = 10). PGEI or PGEo treatment (1.0 ,yg kg-' min-'), administered as 1 h pretreatments (0.05 ml min-', i.v.), significantly reduced infarct size to 44 + 6% (n = 6) or 42 + 1 % (n = 6), respectively. PGE, or PGEo pretreatment resulted in a significant reduction in mean arterial blood pressure, which returned to baseline within 15 min of discontinuation of the infusion (i.e. prior to LAL ligation). 3 The reduction in infarct size afforded by PGE, was abolished by pretreatment of rabbits with the KATP channel blockers, glibenclamide (60 + 4%; n =8) or 5-hydroxydecanoate (58 + 6%; n = 6). Similarly, glibenclamide also largely attenuated the reduction in infarct size afforded by PGEo (52 + 3%; n = 8).4 We propose that a 1 h pretreatment of PGEI or PGEO reduces infarct size by activating protein kinase C resulting in the opening of KATP channels.