**4.1 ARB and oxidative stress**

312 Myocarditis

Hypertrophy of cardiac myocytes is an adaptive response in the damaged heart. Initially, hypertrophy acts as a compensatory mechanism to preserve cardiac function, but when sustained, it becomes a major risk factor for congestive heart failure and sudden cardiac death. Until recently, most in vitro and in vivo studies of the roles of AT1 and AT2 indicated that AT1 mediates the growth promoting, fibrotic, and hypertrophic effects of Ang II on cardiovascular tissues and that AT2 exerts counterbalancing suppressant effects (Gao & Zucker, 2011). Evidence has been provided that the circulating and local RAS promote the development of myocardial fibrosis in hypertensive heart disease and chronic heart failure where both Ang II and aldosterone stimulate collagen synthesis in a dose-dependent manner while Ang II additionally suppresses the activity of matrix metalloproteinase 1, the key enzyme of interstitial collagen degradation, that synergistically leads to progressive collagen accumulation within the myocardial interstitium (Lijnen & Petrov, 2003). Therefore, the physiological role of RAS on the development of myocardial fibrosis could be

In addition to its role in the regulation of arterial pressure, Ang II is known to mediate effects on cell growth and apoptosis and to have pro-oxidative and proinflammatory effects. Apoptosis can be induced in cardiomyocytes by a variety of factors and pathways, a number of findings suggest that the effectors of the RAS can be critically involved in cardiomyocyte

Peroxisome proliferator activated receptors (PPARs), members of the superfamily of ligand regulated transcription factors, are expressed in the cardiovascular system and control diverse vascular functions by mediating appropriate changes to gene expression. PPARα and PPARγ modulate the RAS by transcriptional control of renin, angiotensinogen, ACE

ARBs preferentially block AT1 and leave AT2 unopposed. Long-term administration of ARBs results in a several-fold increase in plasma Ang and thus a possible overstimulation of AT2. It is generally accepted that the effects of stimulation of AT2 on the cardiovascular system are beneficial and that no harm would result from increased activation of these receptors; indeed, activation of AT2 is believed to contribute to the benefits of blocking AT1

Various ARBs were screened for their role in the treatment of acute myocarditis and are found to have significant activity against acute myocarditis. ARBs prevent progression of systolic heart failure, thereby reducing cardiac morbidity and mortality (Lindholm et al., 2002; Cohn & Tognoni, 2001). They also reduce myocardial damage during myocarditis. The major cardiovascular actions of Ang II have been reported to be mediated by the AT1, and AT1 antagonists are therapeutically effective for the treatment of patients with heart failure by reducing cytokines and oxidative stress through their anti-inflammatory effects. Thus, the blockade of AT1 is an important way to interrupt the RAS (Sukumaran et al., 2010). Recently, an AT1 antagonist has been shown to ameliorate EAM by the suppression of myocardial damage and inflammatory events in the myocardium in addition to hemodynamic modifications, and it has been reported to inhibit nitric oxide (NO) production in macrophages and IL 1 production. ARB treatment decreased myocardial fibrosis and its marker molecules (i.e. RNA expression of TGF-1 and collagen-III), and improved the survival rate and cardiac function in rats with DCM after myocarditis in a

apoptosis (Fabris et al., 2011; Guleria et al., 2011; Yamada et al., 1996).

and AT1 (Takeyama et al., 2000; Lansang et al., 2006).

**4. Angiotensin receptor blockers (ARBs)** 

established.

(Levy, 2004).

EAM rats also suffer from various stresses including reactive oxygen species (ROS) mediated oxidative stress. There are several evidences for the adverse cardiac effects triggered by redox cycling of ROS, generated in part by an NADPH oxidase dependent pathway. Reports also add the role of Ang II in triggering the oxidative stress in which increase in the levels of NADPH oxidase subunits like gp91phox, NOX4, p22phox, p40phox, p47phox, p67phox, rac1 and 3-Nitrotyrosine in rat EAM. ARBs can block the myocardial oxidative stress in EAM evidenced by the decreased levels of these markers (Sukumaran et al., 2011b; Seko, 2006; Singh et al., 2008).
