Aims: 

We hypothetized that activation of local renin angiotensin system (RAS) in diabetes may induce impairment of cardiac intracellular calcium(Ca²⁺_i) cycling, a putative etiologic factor for diabetic cardiomyopathy. Beside the classic angiotensin receptor 1 (AR₁) pathway the locally generated angiotensin may act on AR₂ to modulate AR₁ effects, and the role of intracellular AR-s may also emerge. We investigated the contribution of RAS to development of cardiac Ca²⁺_i-handling disorders and participation of alternative angiotensin signaling pathways in this process.

Methods: 

Type 1 diabetic rats obtained either ACE inhibitor enalapril (ENA-25 mg/bwkg/day) or AR₁ antagonist losartan (LOS-20 mg/bwkg/day) orally. After 6 weeks cardiac function was assessed by echocardiography. In isolated Langendorff-perfused hearts left ventricular pressure, coronary flow, and using Indo-1 surface fluorometry Ca²⁺_i-transients were recorded.

Results: 

Neither ENA nor LOS treatment affected blood pressure and blood glucose level. They ameliorated the diminished ejection fraction of diabetic animals. Isolated diabetic hearts developed lower heart rate, and inotropic/lusitropic dysfunction. Analysis of Ca²⁺_i-transients revealed depressed Ca²⁺-release and sequestration. Both ACE inhibitor and AR₁ antagonist treatments normalized contractile performance and Ca²⁺_i-transient disorders, but they had no influence on heart rate.

Conclusion: 

Chronic ACE inhibitor and AR₁ antagonist treatments prevented disturbances of cardiac Ca²⁺_i-handling and pump function. Consequently, activation of RAS in diabetes may play a fundamental role in derangement of myocardial Ca²⁺_i regulatory mechanisms. The actions of angiotensin on cardiac Ca²⁺_i-handling are mediated mainly by AR₁ mechanisms. Major contribution of alternative signaling pathways can be excluded.

Support: 

OTKA grants 61694 and 68502