Ventricular arrhythmias are a significant cause of morbidity and mortality with DCM, and AT1 AT-II receptor activation has been implicated to play a role in arrhythmogenesis. However, the effects of AT1, AT-II receptor activation on changes in LV function and myocyte electrophysiology during the progression of DCM remain unexplored. Accordingly, this study measured weekly changes in LV function (ejection fraction, LVEF; peak systolic wall stress, LVWS) and surface electrocardiography (R-R interval, QRS duration, QTc interval), and myocyte action potentials (resting membrane, RM; upstroke velocity, Vmax; duration at 90% repolarization, APD90) at terminal study in 3 groups of dogs (n=6/group): DCM, chronic pace (216 bpm, 4 weeks); DCM/AT-BLOCK, chronic pace and treatment with a specific non-peptide AT1 AT-II antagonist (SR 47436 (BMS 186295); 30mg/kg BID); and control (CON). All measurements were made with the pacemaker deactivated.LVEF (%)LVWS (g/cm2)R-R (ms).QRS (ms).QTc (ms)Week 2:CON68.7±3.2133±14646±9958.4±1.3291±13DCM40.9±4.1*184±16*519±4060.7±1.9316±9DCM/AT-Block44.1±3.7*138±10+540±566.32±1.2*325±9Week4:CON73.1±2.4127±10629±4557.6±1.4314±9DCM35.2±3.5*223±16*505±41*62.0±1.9313±9DCM/AT-Block35.2±2.7*160±13*, +578±4865.7±1.5*296±6*p<0.05 vs CON+p<0.05 vs DCM

AT-II production and AT1AT-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 AT1AT-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; APD90) 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 AT1AT-II antagonist (BMS-186295; 30 mg/kg BID), and CONTROL.RMP (mV)Vmax (V/s)APD90(ms)MYO%MYOVEL μm/slCONTROL-78±0.8158±9226±74.0±0.157±1DCM-71±0,8*121±5*257±9*2.3±0.1*36±1*OCM/ACEI-74±1*+154±10+236±133.0±0.1*+45±11*+OCM/AT-BLOCK7minus;76±1+165±13+1835±514*+2.6±0.1*41±1*+*p<0.05 vs CONTROL. +p<0,05 vs DCM.

We tested the hypothesis that AT1, AT-II receptor activation with the progression of dilated cardiomyopathy (DCM) causes fundamental changes In myocyte (MYO) sarcolemmal processes. Six dogs were assigned to each of 3 groups: (1) DCM: tachycardia induced DCM (pace 216;4 wks). (2) DCM/AT-BLOCK; chronic pace and concomitant treatment with a specific non-peptide ATl AT-II antagonist (BMS 186295; 30 mg/kg BIDI (3) CONTROL. LV ejection fraction (LVEFO% and end-diastolic volume (LVEDV;cc) were measured by echo/cath. Simultaneous indices of MYO membrane potential (resting;RMP;mV, upstroke velocity;Vmax;V/s, time to 90% repolarization;APD9ms) and contraction (velocity of shortening; MYOVEL;μm/s were measured by videomicroscopy and microelectrodes.LVEFLVEDVRMPVmaxAPD90MYOVELCONTROL73±269±4-78±1158±9226±857±1OCM35±3*101±7*-71±1*121±5*257±9*36±1*DCM/AT-BLOCK35±2*93±6*-76±1+165±13+183±14*+41±1**p<0.05 vs CONTROL+p<0.05 vs DCM