Relative effects of α1-adrenoceptor blockade, converting enzyme inhibitor therapy, and angiotensin II subtype 1 receptor blockade on ventricular remodeling in the dog

K. M. McDonald, M. Garr, P. F. Carlyle, G. S. Francis, K. Hauer, D. W. Hunter, T. Parish, A. Stillman, J. N. Cohn

Research output: Contribution to journalArticle

91 Scopus citations

Abstract

Background: Progressive ventricular remodeling after myocardial damage is associated with a poor prognosis. Optimal prevention of the histopathological processes involved in remodeling requires a more complete understanding of the mechanisms involved in initiating and maintaining these structural changes. Since the sympathetic nervous system and the renin-angiotensin system may be involved in the remodeling process, the structural effects of pharmacological inhibitors have been evaluated in a canine model of localized myocardial injury resulting from transmyocardial DC shock. Methods and Results: The study is comprised of two protocols run in series. In protocol 1, zofenopril (Z), a converting enzyme inhibitor (CEI), prevented the increase in left ventricular mass (LVM) and end-diastolic volume (LVV) observed in the control group (C) at 16 weeks (Z: LVM, 69.8±3.4 to 65.4±2.6 g, P=NS; LVV, 45.4±2.7 to 51.6±2.7 mL, P=NS; C: LVM, 68.4±3.2 to 91.4±2.9 g, P=.0001; LVV, 56.6±3.0 to 71.9±2.4 mL, P=.0003). Terazosin, an α1- adrenoceptor antagonist, failed to prevent remodeling at 16 weeks despite continued receptor blockade. In protocol 2, the antiremodeling effect of full-dose CEI therapy with ramipril was confirmed. Low-dose ramipril that exerted no hemodynamic effect failed to prevent remodeling (LVM, 89.7±4.6 to 105.7±3.4 g, P=.01; LVV, 61.8±3.8 to 76.8±3.3 mL, P=.002). An angiotensin it subtype 1 receptor blocker also failed to prevent the increase in LVM or LVV (LVM, 89.0±4.6 to 109.7±5.3 g, P=.0001; LVV, 66.0±1.9 to 78.4±3.6 mL, P=.007). Conclusions: High-dose CEI therapy can prevent progressive structural changes resulting from localized myocardial damage induced by DC shock. The failure of α1-adrenoceptor blockade and angiotensin II subtype 1 blockade to attenuate remodeling argues against an important direct role for norepinephrine acting through α1-receptors or angiotensin II acting through the type I receptor in the remodeling process in this model.

Original languageEnglish (US)
Pages (from-to)3034-3046
Number of pages13
JournalCirculation
Volume90
Issue number6
DOIs
StatePublished - Dec 1994

Keywords

  • angiotensin
  • myocardium
  • pharmacology
  • receptors, adrenergic, alpha
  • ventricles

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