Key result
Post-ischaemic effluent induced reduction of Ca(++) transient and cell shortening in cardiomyocytes, an effect mediated by protein kinase A-dependent prostaglandin-receptor subtypes EP2 and EP4.
Cardiodepressive effects of post-ischaemic effluent on cardiomyocytes are mediated by protein kinase A-dependent prostaglandin-receptor subtypes EP2 and EP4.
BACKGROUND: After ischaemia and during reperfusion, rat hearts release cardiodepressive substances that are putatively cyclooxygenase-2-dependent. The present study analyses the mechanisms by which these substances mediate their effect downstream of cyclooxygenase-2. MATERIALS AND METHODS: After 10 min of global stop-flow ischaemia, isolated rat hearts were reperfused and post-ischaemic coronary effluent was collected over a period of 30 s. Non-ischaemic effluent collected before ischaemia was used as a control. We investigated the effect of the effluents on cell shortening and Ca(++)-metabolism, by application of fluorescence microscopy of field-stimulated adult rat cardiomyocytes incubated with fura-2. Cells were pre-incubated with inhibitors of protein kinase A and C and with antagonists of protein kinase A-dependent prostaglandin receptors. We examined the expression of prostaglandin receptors in cardiomyocytes by Western blotting. RESULTS: In contrast to non-ischaemic effluent, post-ischaemic effluent induced reduction of Ca(++) transient and cell shortening in the cardiomyocytes. In contrast to protein kinase C inhibitor Myr-PKC [19-27], the protein kinase A inhibitor Rp-cAMPS completely blocked the effect of post-ischaemic effluent. Furthermore, we determined a cyclic adenosine monophosphate increase in cardiomyocytes that were pre-incubated with post-ischaemic effluent. The antagonist of prostaglandin E-receptor EP2 AH6809 and the antagonist of receptor subtype EP4 AH23848 attenuated the effect of post-ischaemic effluent in contrast to other antagonists of prostaglandin D and I receptors, which did not influence the effect. In lysates of adherend cardiomyocytes, expression of prostaglandin D, E and I receptors was detected by Western blotting. CONCLUSIONS: The effect of post-ischaemic effluent is mediated by the protein kinase A-dependent prostaglandin-receptor subtypes EP2 and EP4 downstream of cyclooxygenase-2.
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Birkenmeier et al. (2008) studied Ischaemia/reperfusion. Post-ischaemic coronary effluent vs. Non-ischaemic effluent was evaluated on Cell shortening and Ca(++)-metabolism. Post-ischaemic effluent induced reduction of Ca(++) transient and cell shortening in cardiomyocytes, an effect mediated by protein kinase A-dependent prostaglandin-receptor subtypes EP2 and EP4.
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