ANGIOTENSIN-CONVERTING ENZYME-INHIBITION AND ANGIOTENSIN-II SUBTYPE-1RECEPTOR BLOCKADE DURING THE PROGRESSION OF LEFT-VENTRICULAR DYSFUNCTION - DIFFERENTIAL-EFFECTS ON MYOCYTE CONTRACTILE PROCESSES

Inhibition of the angiotensin-converting enzyme (ACE) in the setting o f chronic left ventricular (LV) dysfunction has been demonstrated to h ave beneficial effects on survival and symptoms, However, whether ACE inhibition has direct effects on myocyte contractile processes and if these effects are mediated primarily through the AT(1) angiotensin-II receptor subtype remains unclear, The present project examined the rel ationship between changes in LV and myocyte function and beta adrenerg ic receptor transduction in four groups of six dogs each: (1) Rapid Pa ce: LV failure induced by chronic rapid: pacing (4 weeks; 216 +/- 2 bp m); (2) Rapid Pace/ACEI: concomitant ACE inhibition (ACEI: fosinopril 30 mg/kg b.i.d.) with chronic pacing; (3) Rapid Pace/AT(1) Block: conc omitant AT(1) Ang-II receptor blockade [Irbesarian: SR 41436(BMS-18629 5) 30 mg/kg b.i.d.] with chronic pacing; and (4) Control: sham control s. With Rapid Pace, the LV end-diastolic volume increased by 62% and t he ejection fraction decreased by 53% from control, With Rapid Pace/AC EI, the LV end-diastolic volume was reduced by 24% and the ejection fr action increased by 26% from Rapid Pace only values, Rapid Pace/AT(1) Block did not improve LV geometry or function from Rapid Pace values. Myocyte contractile function decreased by 40% with Rapid Pace and incr eased from this value by 32% with Rapid Pace/ACEI, Rapid Pace/AT(1) Bl ock had no effect on myocyte function when compared with Rapid Pace va lues, With Rapid Pace/ACEI, beta receptor density and cyclic AMP produ ction were normalized and associated with an improvement in myocyte be ta adrenergic response compared with Rapid Pace only. Although Rapid P ace/AT(1) also normalized beta receptor density, cyclic AMP production was unchanged and myocyte beta adrenergic response was reduced by 15% compared with Rapid Pace only. ACE inhibition with chronic rapid paci ng improved LV and myocyte geometry and function, and normalized beta receptor density and cyclic AMP production. However, AT(1) Ang-ll rece ptor blockade with chronic rapid pacing failed to provide similar prot ective effects on LV and myocyte geometry and function. These unique f indings suggest that the effects of ACE inhibition on LV geometry and myocyte contractile processes in the setting of developing LV failure are not primarily caused by modulation of AT(1) Ang-ll receptor activa tion.