Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Antagonists in Experimental Myocarditis

Abstract

Myocarditis is a disease whose pathogenesis is not completely understood and whose prevalence is likely underestimated. Individuals afflicted with this condition may be treated with agents that relieve symptoms arising from inflammation and concurrent cellular damage. One class of drugs commonly used in the treatment of myocarditis includes the angiotensin converting enzyme inhibitors, such as captopril, enalapril and lisinopril, and the angiotensin Pi receptor antagonists, such as L-158,809 and losartan. The effects of these drugs on cardiomyopathy have been studied using a variety of animal models of heart failure and hypertension. However, less research has been done in the area of animal models of frank myocarditis. Here we review the use of angiotensin converting enzyme inhibitors and angiotensin Pi receptor antagonists in animal models of myocarditis. We extend the implications of that published work by correlation with results from studies of other disease models and in vitro experiments that highlight the immunomodulatory potential of these compounds. The literature strongly suggests that aggressive therapy employing angiotensin converting enzyme inhibition and/or blockade of angiotensin Pi receptors is beneficial. Treatment is useful not only for reducing complications associated with myocarditis, but also for downregulating the potential autoimmune component of disease without increasing the levels of the infectious agent that may initiate the myocarditis.

Captopril Ameliorates Myocarditis in Acute Experimental Chagas Disease

“…By interfering with the angiotensin II and bradykinin pathways, captopril reduces systemic arterial pressure, peripheral vascular resistance, and cardiac filling pressure, and increases cardiac output. Captopril is also an antiinflammatory agent, acting through the immunomodulatory actions of angiotensin II and the downstream effects of bradykinin (reviewed in Godsel et al 3 ). Together, the effects of captopril result in reduced inflammation and fibrosis, improvement of cardiac function, and enhanced survival in heart failure patients.…”

Comparison of angiotensin converting enzyme inhibition and angiotensin II receptor blockade for the prevention of experimental autoimmune myocarditis

“…Although Ang II receptor blockade clearly reduces myocarditis, the effects of captopril and losartan on all immunologic parameters are not superimposable. Ang II is involved in the chemotaxis and adhesion of monocytes and macrophages [10]. Therefore, Ang II may upregulate chemotactic factors important for attracting immune cells to the affected tissue and may induce expression of molecules that enable cells to adhere to endothelium.…”

“…Therefore, Ang II may upregulate chemotactic factors important for attracting immune cells to the affected tissue and may induce expression of molecules that enable cells to adhere to endothelium. Ang II has also been shown to modulate the release of cytokines, including IL-6, IL-1β, IL-5, and TNF-α [10]. By blocking the Ang II receptors with losartan, chemotaxis and cytokine release would theoretically be decreased or inhibited and thus cause a decrease in myocarditis.…”

“…In particular, it inhibits the formation of Ang II from Ang I and prevents the degradation of bradykinin [9,10]. By interfering with the renin-angiotensin system and bradykinin pathways, captopril reduces sytemic arterial pressure, peripheral vascular resistance and cardiac filling pressure, and increases cardiac output.…”

“…Captopril is also an antiinflammatory agent, acting through the immunomodulatory actions of Ang II and the downstream effects of bradykinin. Among the many ACE inhibitors and Ang II receptor antagonists, captopril has been shown to modulate chemotaxis, motility, adhesion, differentiation, activation and cytokine and chemokine production of immune cells [10]. Together, the effects of captopril result in reduced inflammation and fibrosis, improvement of cardiac function and enhanced survival in heart failure patients.…”