Medroxyprogesterone acetate inhibits the cardioprotective effect of estrogen in experimental ischemia-reperfusion injury.
OBJECTIVE
Results from recent clinical trials of estrogen and progestogen therapy (EPT) suggest that some progestogens may interfere with the cardiovascular benefits of estrogen (E). The aim of this study was to investigate whether medroxyprogesterone acetate (MPA) modifies the protective effect of E in experimental ischemia-reperfusion (IR) injury in vivo and in vitro in the rat.


METHODS
Ovariectomized female Wistar rats (250-280 g, n = 61) received E, MPA, E and MPA, or placebo subcutaneously. Fourteen days later, hearts were isolated and perfused with Krebs Henseleit for in vitro experiments or left in situ for in vivo experiments. In both cases, the left coronary artery was occluded for 45 minutes, followed by 2 hours of reperfusion.


RESULTS
In vivo E significantly reduced the necrotic zone of reperfused hearts (21.8% +/- 1.7% of area at risk) compared with placebo (42.8% +/- 4.8% area at risk; P < 0.05). This protection was reversed by co-administration of MPA with E (necrotic zone 38.2% +/- 6.1% area at risk). The influence of E on neutrophil infiltration was demonstrated by its ability to reduce myocardial myeloperoxidase activity (0.2 +/- 0.1 U/g tissue) relative to placebo (1.3 +/- 0.5 U/g tissue; P < 0.05). Myocardial myeloperoxidase activity was significantly increased to 1.1 +/- 0.3 U/g tissue in rats receiving E and MPA. However, MPA also reversed the protective effect of E in neutrophil-free buffer-perfused hearts, suggesting that additional mechanisms are involved.


CONCLUSIONS
In this study, we showed that the administration of MPA can inhibit the effects of E that lead to protection of the myocardium from reperfusion injury and that this involves both neutrophil-dependent and neutrophil-independent mechanisms.
Jeanes
Helen L
HL
Centre for Cardiovascular Science, University of Edinburgh, UK. h.l.jeanes@sms.ed.ac.uk
Wanikiat
Payong
P
Sharif
Isam
I
Gray
Gillian A
GA
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002316:Cardiotonic Agents / Q000037:antagonists & inhibitors*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D009336:Necrosis; D009504:Neutrophils / Q000502:physiology; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology; D014599:Uterus / Q000033:anatomy & histology
D002316:Cardiotonic Agents; D004965:Estrogen Antagonists; D004967:Estrogens; D017258:Medroxyprogesterone Acetate; D009195:Peroxidase