Differential effects of olmesartan and ramipril on inflammatory response after myocardial infarction in rats

Abstract

This study compares the effect of two different strategies to inhibit the renin-angiotensin system in the setting of acute myocardial infarction (MI). Male Wistar rats were treated with placebo, the angiotensin-converting enzyme (ACE) inhibitor ramipril (1 mg/kg/day), or the AT1 receptor antagonist, olmesartan (1 mg/kg/day), both initiated 1 week before induction of MI and continued for 6 weeks after MI. The inflammatory reaction in the heart was investigated 7 days post-MI by determination of macrophage infiltration and the expression of tumor necrosis factor (TNF-alpha), interleukin (IL)-1beta and IL-6 at mRNA and protein levels. Six weeks post-MI, cardiac function was measured following chronic implantation of catheters in the LV and femoral artery, and cardiac morphology and coronary structure were investigated in picrosirius-red stained hearts. In placebo-treated rats, macrophage infiltration was accompanied by upregulation of IL-1beta and IL-6 mRNA in the peri-infarct zone. TNF-alpha and IL-1beta mRNA and protein were also upregulated in the non-infarcted myocardium. Whereas both treatment regimes significantly reduced IL-6 upregulation, olmesartan additionally reduced macrophage infiltration and IL-1beta expression. Six weeks post-MI, placebo-treated MI animals developed an impaired cardiac function with structural remodeling of the myocardium and coronaries. While olmesartan and ramipril both improved cardiac function and reduced infarct size and myocardial/coronary remodeling, olmesartan was more effective not only in increasing vascular perimeter, inner vascular diameter and septal thickness but also in lowering media thickness of coronary arteries, inner left ventricular diameter, left ventricular circumference and left ventricular end-diastolic pressure than ramipril. Thus, following MI the AT1 receptor blocker, olmesartan, attenuated cardiac inflammatory reactions and protected myocardial/coronary structure and function of the failing heart proving to be of similar, in some cases superior effectiveness in this respect than the ACE inhibitor, ramipril.

Effect of early versus late AT1 receptor blockade with losartan on postmyocardial infarction ventricular remodeling in rabbits

“…Another important issue to be considered, and closely related to the previous topic, is the effect of RAS blockade on inflammatory infiltrate and the healing process after MI (21,32). In our previous study (12), we found that early long-term therapy with Los in rabbits with MI unfavorably modified ventricular remodeling.…”

Additive Effect of TAK-491, a New Angiotensin Receptor Blocker, and Pioglitazone, in Reducing Myocardial Infarct Size

“…Intravenous valsartan limits IS in rats and dogs [16]. Oral olmesartan (another ARB), started 1 week before infarction and continued for 6 weeks was more effective than the ACE-I ramipril in attenuating remodeling and inflammation in the rat [17]. However, this study did not separate the effects of pretreatment on IR injury from the favorable post-infarction therapeutic effects on remodeling.…”

Angiotensin II receptor antagonism reverts the selective cardiac BNP upregulation and secretion observed in myocarditis

“…Although the differences in experimental models are very significant, it may be worth exploring the possibility that the ability of olmesartan to revert to control levels in both anatomical parameters and BNP gene expression in EAM is due to the additional known action of olmesartan on cytokines. In rats with acute myocardial infarction, olmesartan administration improved cardiac function and reduced the infarct size better than ramipril, and it, but not ramipril, decreased macrophage infiltration and decreased IL-1␤ mRNA levels (22). In human peripheral blood mononuclear cells, ramipril did not suppress the genetic expression of IL-1␤ or TNF-␣ as did other ACE inhibitors (23).…”