Synergistic Effects of Atorvastatin and Sildenafil in Cardioprotection—Role of NO

Abstract

HMG-CoA (3-hydroxy-3-methylflutaryl coenzyme A) reductase inhibitors, or statins, were originally designed to reduce serum cholesterol levels and the development of cardiovascular disease. Statins prevent the formation of cholesterol as well as other products in the biosynthetic pathway, which include isoprenoid intermediates such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate [1]. Over the years, it has become clear that use of statins extend well beyond their lipid lowering actions, and the unexpected pleiotropic effects have a major role in protecting the myocardium against ischemic injury. A number of studies have shown that statins improve cardiac function, reduce infarct size and infiltration of polymorphonuclear neutrophils following ischemia/reperfusion injury [2,3]. The myocardial protective effect of statins is mediated by increasing eNOS protein expression due to stabilizing eNOS mRNA [4,5]. However, others suggested that statins may increase the activity of eNOS not by altering its absolute concentration, but by increasing eNOS phosphorylation at serine-1177 through the phosphatidyl-inositol-3-kinase and protein kinase Akt signaling cascade [6]. Atorvastatin added at the onset of reperfusion, increased eNOS phosphorylation at serine-1177 in isolated mice hearts subjected to ischemia [7]. Furthermore, these protective effects of statins are dependent on eNOS because mice deficient in eNOS were completely resistant to the cardioprotective actions of statin treatment [3]. We recently showed that atorvastatin induced both acute and delayed myocardial preconditioning effect in-vivo resulting in marked reduction in infarct size. The preconditioning in the delayed phase was mediated by iNOS and involves opening of mitochondrial KATP channels [8]. Because delayed preconditioning can be maintained by intermittent stimuli, our results suggest that atorvastatin may be able to produce a chronically preconditioned state which might render the myocardium more resistant to prolonged episodes of ischemia. Recent work suggests that statins activate protein kinase G (PKG) to elicit further activations of MAPK pathways, induce hemeoxygenase-1 gene expression, which provides a novel anti-inflammatory mechanism in the therapeutic validity [9]. Statins have also been shown to attenuate the myocardial dysfunction associated with heart failure and significant increases in the survival rate following the induction of myocardial infarction [10,11]. Furthermore, statins reduced cardiac myocyte hypertrophy, interstitial fibrosis, as well as preserved left ventricular ejection performance [10‐12]. Interestingly, the ability of statins to exert its beneficial effects in models of heart failure also appears to be eNOS dependent [11]. Clinical studies suggest that statins reduce mortality in patients with severe heart failure [13]. The statin treated patients experienced a reduction in mortality that was demonstrated as early as 30 days post intervention and statins remained a predictor for survival at six months [14].