Angiotensin-(1-7) [Ang-(1-7)] is a vasodilator peptide with cardiac and vascular protective properties. We examined the influence of Ang-(1-7), both endogenous and after chronic treatment with the peptide (576microg/(kgday)), on ischemia/reperfusion (I/R)-induced cardiac dysfunction in streptozotocin-treated spontaneously hypertensive rats (diabetic SHR). In isolated perfused hearts, recovery of left ventricular function from 40min of global ischemia was improved significantly in Ang-(1-7)- or captopril-treated diabetic SHR and worsened in animals treated with A779, an Ang-(1-7) receptor (AT((1-7))) antagonist. The beneficial effect of captopril on cardiac recovery was reduced when co-administered with A779. Cardiac NF-kappaB activity appears to be higher in diabetic SHR and treatment with Ang-(1-7) or captopril decreased NF-kappaB activity in diabetic SHR, an effect partially reversed by co-administration of A779. Real-time PCR-based gene array analysis of cardiac tissue revealed that Ang-(1-7) or captopril treatment may reduce expression of several genes of inflammation involved in the NF-kappaB signalling pathway. The data provide for the first time a role for endogenous Ang-(1-7) as well as confirmation that exogenous treatment with the peptide produces cardioprotection. Whether potential anti-inflammatory and transcriptional factor changes are directly linked to the cardioprotection produced by Ang-(1-7) in diabetic SHR remains to be determined.