RELATIVE EFFECTS OF ALPHA(1)-ADRENOCEPTOR BLOCKADE, CONVERTING-ENZYME-INHIBITOR THERAPY, AND ANGIOTENSIN-II SUBTYPE-1 RECEPTOR BLOCKADE ON VENTRICULAR REMODELING IN THE DOG

Background Progressive ventricular remodeling after myocardial damage is associated with a poor prognosis. Optimal prevention of the histopa thological processes involved in remodeling requires a more complete u nderstanding 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, t he structural effects of pharmacological inhibitors have been evaluate d in a canine model of localized myocardial injury resulting from tran smyocardial DC shock. Methods and Results The study is comprised of tw o protocols run in series. In protocol 1, zofenopril (Z), a converting enzyme inhibitor (CEI), prevented the increase in left ventricular ma ss (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=.00 01; LVV, 56.6+/-3.0 to 71.9+/-2.4 mL, P=.0003). Terazosin, an alpha(1) -adrenoceptor antagonist, failed to prevent remodeling at 16 weeks des pite continued receptor blockade. In protocol 2, the antiremodeling ef fect of full-dose CEI therapy with ramipril was confirmed. Low-dose ra mipril 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 II subtype 1 receptor blocker also fail ed 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 resul ting from localized myocardial damage induced by DC shock. The failure of alpha(1)-adrenoceptor blockade and angiotensin II subtype 1 blocka de to attenuate remodeling argues against an important direct role for norepinephrine acting through alpha(1)-receptors or angiotensin II ac ting through the type 1 receptor in the remodeling process in this mod el.