727-4 Differential Effects of Chronic Angiotensin Converting Enzyme (ACE) Inhibition and Angiotensin II (AT-II) Receptor (AT 1 AT-II) Blockade on Myocyte Excitation and Contraction in Dilated Cardiomyopathy

AT-II production and AT 1 AT-II receptor activation have been suggested to contribute to the progression of dilated cardiomyopathy (DCM). However. the direct effects of chronic ACE inhibition (ACEI) or specific AT 1 AT-II receptor blockade (AT-BLOCK) on myocyte (MYO) electrophysiology and contractility with the progression of DCM are unknown. Accordingly, simultaneous indices of isolated MYO membrane potential (resting; RMP, max upstroke velocity; Vmax, time to 90% repolarization; APD 90 ) and contraction (percent; MYO% and velocity of shortening; MYOVEL) were obtained from 4 groups of dogs (n = 6/group): DCM; chronic pacing (216bpm; 4 weeks). DCM/ACEI; chronic pace and concomitant ACEI (fosinopril; 30 mg/kg BID). DCM/AT-BLOCK; chronic pace and treatment with a specific non-peptide AT 1 AT-II antagonist (BMS-186295; 30 mg/kg BID), and CONTROL. RMP (mV) Vmax (V/s) APD 90 (ms) MYO% MYOVEL μm/sl CONTROL -78 ± 0.8 158 ± 9 226 ± 7 4.0 ± 0.1 57 ± 1 DCM -71 ± 0,8 * 121 ± 5 * 257 ± 9 * 2.3 ± 0.1 * 36 ± 1 * OCM/ACEI -74 ± 1 *+ 154 ± 10 + 236 ± 13 3.0 ± 0.1 *+ 45 ± 1 1 *+ OCM/AT-BLOCK 7minus;76 ± 1 + 165 ± 13 + 1835 ±5 14 *+ 2.6 ± 0.1 * 41 ± 1 *+ * p l 0.05 vs CONTROL. + p l 0,05 vs DCM. MYO membrane potential at the end of MYO contraction increased with DCM and DCM/ACEI (4.9 ± 1.9*.4.4 ± 2.4*mV) compared to CONTROL (0.8 ± 0.3 mV) but was normalized with DCM/AT-BLOCK (1.4 ± 0.9 mV). Thus, ACEI during the progression of DCM improved MYO function whereas AT-BLOCK had selective effects on MYO electrophysiology. Summary These findings suggest that ACEI and AT-BLOCK have unique and different mechanisms of action with cardiomyopathic disease.