ANGIOTENSIN-CONVERTING ENZYME-INHIBITION AND ANGIOTENSIN-II SUBTYPE-1RECEPTOR BLOCKADE DURING THE PROGRESSION OF LEFT-VENTRICULAR DYSFUNCTION - DIFFERENTIAL-EFFECTS ON MYOCYTE CONTRACTILE PROCESSES
Fg. Spinale et al., ANGIOTENSIN-CONVERTING ENZYME-INHIBITION AND ANGIOTENSIN-II SUBTYPE-1RECEPTOR BLOCKADE DURING THE PROGRESSION OF LEFT-VENTRICULAR DYSFUNCTION - DIFFERENTIAL-EFFECTS ON MYOCYTE CONTRACTILE PROCESSES, The Journal of pharmacology and experimental therapeutics, 283(3), 1997, pp. 1082-1094
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.