Angiotensin Antagonists in Models of Heart Failure

Abstract

Occlusion of the left main coronary artery in rats results in a segmental loss of viable myocardium from the anterior lateral aspect of the left ventricular free wall.^1–6 The extent and location of the tissue loss is the major determinant in the subsequent depression of cardiac performance following the acute event.^1–6 If myocardial necrosis is extensive, i.e., encompassing greater than 40% of the ventricular free wall, left ventricular failure rapidly ensues, often with substantial involvement of right side performance and cardiac congestive failure.^1–6 Anatomically, large infarctions precipitate considerable rearrangements in ventricular architecture as evidenced by wall thinning as a result of side-to-side slippage of myocytes and chamber dilatation in both the transverse as well as the longitudinal dimension.^4,7,8 In an attempt to maintain normal pump function, activation of the renin—angiotensin system during conditions of infarction-induced cardiac decompensation engenders increases in circulating levels of angiotensin II (ANG II), a major pressor agent.^9–12 To reduce the work load on this already compromised ventricle and possibly prevent the associated detrimental changes in chamber geometry, prevention of metabolic conversion of ANG I to ANG II by carboxypeptidase inhibitors (i.e., angiotensin-convert-ing enzyme, or ACE, inhibitors) have been employed both clinically¹² and experimentally.^12–16 Although ACE inhibitors like captopril^12–16 have been quite effective in ameliorating the damaging effects of myocardial infarction, undesirable side effects occur from the therapeutic use of these nonspecific kinases.^17–19 With this in mind, compounds have been sought that block specifically the ANG II receptor on cardiac cells. Blockade of this AT₁ receptor has been effectively accomplished by a 2-n-butyl-4-chloro-5-hydroxymethyl-1-[2′-(1H-tetrazol-5yl)biphenyl-4yl) methyl]imidazole potassium salt,³⁴ manufactured by DuPont (losartan or DuP 753).