Background: 

Ichemia/reperfusion reduces the myocardial pump activity but it induces the expression of hypoxia-regulated genes as well. Intermedin, a peptide hormone structurally related to adrenomedullin, is one of these hypoxia-regulated genes. It activates the adenylyl cyclase and modifies the cardiac function. The corresponding receptor (CRLR) is also target of postischemic changes as its interaction with receptor associated modifier proteins is altered. Thus, it is unclear whether the induction of intermedin in post-ischemic hearts is part of a protective mechanism or contributes to the deleterious effect of ischemia and reperfusion.

Methods: 

Hearts from adult rats were exposed ex vivo to a Langendorff apparatus and exposed to a defined ischemia/reperfusion protocol (45 min ischemia/90 min reperfusion). 30 min after the onset of reperfusion intermedin (0.1 nM or 100 nM) or dbcAMP (100 nM) were added and washed out again 10 min later. Hearts not exposed to ischemia were used as non-ischemic controls.

Results: 

In normoxic hearts intermedin exerted a concentration-dependent effect and reduced contractility and coronary resistance. In normoxic hearts these effects were less pronounced and in addition intermedin caused a positive chronotropic effect. As a result of this the rate-pressure-product was not attenuated in these hearts. Post-ischemic recovery was worsened in post-ischemic hearts exposed to intermedin in a transient way (controls: 52.2%, intermedin low: 48.9%, intermedin high: 44.7%). Intermedin caused a significant up-regulation of the pro-apoptotic gene bax (+60.2%m p=0.016). dbcAMP, used at a concentration too low to induces any changes in functional parameters increased the post-ischemic expression of ornithine decarboxylase (+413%), ANP (+465%), BNP (+405%), bcl-2 (+85%), and bcl-XL (+298%). The expression of none of these genes was modified by intermedin.

Conclusion: 

Intermedin is a hypoxia-regulated gene that contributes to the worsening of post-ischemic myocardial function and that increases the susceptibility to apoptosis. It does not mimic the effects of cAMP-inducing agonists.