Inhibition of the formation or action of angiotensin II reverses attenuated K+ currents in type 1 and type 2 diabetes

1. Transient and sustained calcium-independent outward K+ currents (It and I-SS) as well as action potential,,; were recorded in cardiac ventricular m yocytes isolated from two models of diabetes mellitus, 2. Rats injected (Ix.) with streptozotocin (STZ, 100 mg kg(-1)) 6-10 days b efore cell isolation developed insulin-dependent (type 1) diabetes. I-t and I-SS were attenuated and the action potential prolonged. Incubation of myo cytes (6-9 h) with the angiotensin II (ATII) receptor blockers saralasin or valsartan (I muM) significantly augmented these currents. Inclusion of val sartan (I g 1(-1)) in the drinking water for 5-10 days prior to and followi ng STZ injection partially prevented current attenuation. 3. Incubation of myocytes from STZ-treated rats (6-9 h) with 1 am quinapril , an angiotensin-converting enzyme (ACE) inhibitor, significantly augmented I-t and I-SS and shortened the ventricular action potential. I-t augmentat ion was not due to changes in steady-state inactivation or in recovery from inactivation. No acute effects of quinapril were observed. 4. The effects of quinapril and valsartan were abolished by 2 muM cyclohexi mide. 5. Myocytes were isolated from the db/db mouse, a leptin receptor mutant th at develops symptoms of non-insulin-dependent (type 2) diabetes. K+ current s in these cells were also attenuated, and the action potentials prolonged. Incubation of these cells (> 6 h) with valsartan Zn (1 muM) significantly enhanced the transient and sustained outward currents. 6. These results confirm recent suggestions that cardiac myocytes contain a renin-angiotensin system, which is activated in diabetes. It is proposed t hat chronic release of ATII leads to changes in ionic currents and action p otentials, which can be reversed by blocking the formation or action of ATI I This may underlie the proven benefits of ATII receptor blockade or ACE in hibition in diabetes, by. providing protection against cardiac arrhythmias.