Abstract
Inhibition of the angiotensin-converting enzyme (ACE) in the setting of chronic left ventricular (LV) dysfunction has been demonstrated to have 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 AT1angiotensin-II receptor subtype remains unclear. The present project examined the relationship between changes in LV and myocyte function and beta adrenergic receptor transduction in four groups of six dogs each: (1) Rapid Pace: LV failure induced by chronic rapid pacing (4 weeks; 216 ± 2 bpm); (2) Rapid Pace/ACEI: concomitant ACE inhibition (ACEI: fosinopril 30 mg/kg b.i.d.) with chronic pacing; (3) Rapid Pace/AT1 Block: concomitant AT1Ang-II receptor blockade [Irbesartan: SR 47436(BMS-186295) 30 mg/kg b.i.d.] with chronic pacing; and (4) Control: sham controls. With Rapid Pace, the LV end-diastolic volume increased by 62% and the ejection fraction decreased by 53% from control. With Rapid Pace/ACEI, the LV end-diastolic volume was reduced by 24% and the ejection fraction increased by 26% from Rapid Pace only values. Rapid Pace/AT1 Block did not improve LV geometry or function from Rapid Pace values. Myocyte contractile function decreased by 40% with Rapid Pace and increased from this value by 32% with Rapid Pace/ACEI. Rapid Pace/AT1 Block had no effect on myocyte function when compared with Rapid Pace values. With Rapid Pace/ACEI,beta receptor density and cyclic AMP production were normalized and associated with an improvement in myocytebeta adrenergic response compared with Rapid Pace only. Although Rapid Pace/AT1 also normalized betareceptor density, cyclic AMP production was unchanged and myocytebeta adrenergic response was reduced by 15% compared with Rapid Pace only. ACE inhibition with chronic rapid pacing improved LV and myocyte geometry and function, and normalizedbeta receptor density and cyclic AMP production. However, AT1 Ang-II receptor blockade with chronic rapid pacing failed to provide similar protective effects on LV and myocyte geometry and function. These unique findings 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 AT1 Ang-II receptor activation.
Footnotes
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Send reprint requests to: Francis G. Spinale, MD, PhD, Division of Cardiothoracic Surgery, RM 418 CSB, 171 Ashley Avenue, Medical University of South Carolina, Charleston, SC 29425.
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↵1 Supported by National Institutes of Health grant HL-45024 (F.G.S.), a Basic Research Grant from Bristol Myers Research Institute (F.G.S.), American Heart Association Grant-in-Aid (F.G.S.) and an MUSC Post-Doctoral Research Award (R.B.H.). F.G.S. is an Established Investigator of the American Heart Association.
- Abbreviations:
- ACE
- angiotensin-converting enzyme
- Ang-II
- angiotensin II
- AT1 Ang-II
- angiotensin-II subtype-1 receptor
- LV
- left ventricle
- AMP
- adenosine monophosphate
- ANF
- atrial natriuretic factor
- EGTA
- ethylene glycol bis(β-aminoethyl ether)N,N′-tetraacetic acid
- Received April 1, 1997.
- Accepted August 21, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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Angiotensin-Converting Enzyme Inhibition and Angiotensin II Subtype-1 Receptor Blockade during the Progression of Left Ventricular Dysfunction: Differential Effects on Myocyte Contractile Processes
