**17.3 NO releasing drugs with dual action: NO releasing sartans + NO releasing statins**

Both hypertension and hypercholesterolemia are risk factors of cardiovascular diseases. Both produce endothelial dysfunction and promote the development of atherosclerosis. Increased Ang II levels are correlated with endothelial dysfunction and the expression of ACE activity is increased in hypercholesterolemia and atherosclerosis. Moreover, the oxidative stress is involved in many pathophysiological conditions in the cardiovascular system including hypercholesterolemia, hypertension, diabetes and HF.

The Ang II and the activation of AT1 receptors stimulate NAD(P)H oxidase, generating reactive oxygen species in vascular cells and thus endothelial dysfunction. It has been shown that NO is involved in modulating numerous vital functions and its role is known as the regulator of cardiovascular homeostasis, inflammatory response and cell proliferation of vascular smooth muscle.

The beneficial effects of inhibitors of hydroxy methylglutaryl CoA reductase 3 (statins) have been well tested in the treatment of hypercholesterolemia, a condition which is strongly associated with the development of atherosclerosis. In addition, statins significantly reduce cardiovascular mortality in patients with cardiovascular disease risk and which have direct effects on atherosclerotic plaque stability, NO metabolism, inflammation, endothelial function, oxidative stress and thrombosis. (Shepherd et al., 1995)

Moreover ARBs or sartans have demonstrated its safety and efficacy in controlling hypertension, they have reduced endothelial dysfunction and decreased cardiovascular morbility and mortality in diabetic patients, in hypertensive ones with HF and coronary artery disease. (Brenner et al.,2001, Cohn & Tognoni.,2001, Lewis et al.,2001, Dahlof et al.,2002, Pfeffer et al.,2003) Currently, there are drugs being developed that combine the antihypertensive action of ARBs with the releasing of NO in a single molecule, with the aim of improving the safety profile and effectiveness of their native drugs. Hybrids which combine the action of ARBs with a NO releasing statin, (also called statins sartans-NO), antagonize the effects of Ang II in experimental animals with similar power than losartan or captopril. (Nickenig, 2004) The nitric ester derivatives of pravastatin (NCX 6550) and

Although, there were very promising results there is still much to clarify respecting its usefulness in the medium and long term, not only in the control of hypertension, but on the

Endothelin produced by endothelin converting enzyme (ECE) is a potent vasoconstrictor and profibrotic agent, while natriuretic peptides are degraded by NEP which have diuretic, vasodilator and antifibrotic properties, so that in a combination same drug of these actions could have a beneficial effect on cardiovascular remodelling, control of BP and cardiovascular mortality. Recently, several drugs have been synthesized: CGS 26303, CGS 34226, SLV88, SLV306 and SLV388, with which promising effects in experimental animals on cardiovascular hemodynamic independently of the BP have been shown. (Dhaun & Webb., 2011) That is why pre-clinical and clinical studies will be the future stage in these

**17.3 NO releasing drugs with dual action: NO releasing sartans + NO releasing statins**  Both hypertension and hypercholesterolemia are risk factors of cardiovascular diseases. Both produce endothelial dysfunction and promote the development of atherosclerosis. Increased Ang II levels are correlated with endothelial dysfunction and the expression of ACE activity is increased in hypercholesterolemia and atherosclerosis. Moreover, the oxidative stress is involved in many pathophysiological conditions in the cardiovascular

The Ang II and the activation of AT1 receptors stimulate NAD(P)H oxidase, generating reactive oxygen species in vascular cells and thus endothelial dysfunction. It has been shown that NO is involved in modulating numerous vital functions and its role is known as the regulator of cardiovascular homeostasis, inflammatory response and cell proliferation of

The beneficial effects of inhibitors of hydroxy methylglutaryl CoA reductase 3 (statins) have been well tested in the treatment of hypercholesterolemia, a condition which is strongly associated with the development of atherosclerosis. In addition, statins significantly reduce cardiovascular mortality in patients with cardiovascular disease risk and which have direct effects on atherosclerotic plaque stability, NO metabolism, inflammation, endothelial

Moreover ARBs or sartans have demonstrated its safety and efficacy in controlling hypertension, they have reduced endothelial dysfunction and decreased cardiovascular morbility and mortality in diabetic patients, in hypertensive ones with HF and coronary artery disease. (Brenner et al.,2001, Cohn & Tognoni.,2001, Lewis et al.,2001, Dahlof et al.,2002, Pfeffer et al.,2003) Currently, there are drugs being developed that combine the antihypertensive action of ARBs with the releasing of NO in a single molecule, with the aim of improving the safety profile and effectiveness of their native drugs. Hybrids which combine the action of ARBs with a NO releasing statin, (also called statins sartans-NO), antagonize the effects of Ang II in experimental animals with similar power than losartan or captopril. (Nickenig, 2004) The nitric ester derivatives of pravastatin (NCX 6550) and

system including hypercholesterolemia, hypertension, diabetes and HF.

function, oxidative stress and thrombosis. (Shepherd et al., 1995)

**17.2 Dual inhibitors of endothelin converting enzyme and neutral endopeptidase** 

prevention and control of target organ damage.

novel drugs.

vascular smooth muscle.

fluvastatin (NCX 6553) have demonstrated antiinflammatory and antiproliferative action, so it has potential application in diseases with endothelial dysfunction and vascular inflammation. There are additional properties that make NO releasing statins more effective than the native ones. It has been shown that NCX 6550 inhibits platelet aggregation in vitro and reduces mortality in thromboembolism in experimental animals. (Dever et al., 2007)

Thus, the combination of the beneficial effect of ARBs and statins in a single drug may not only be favorable for the prevention of cardiovascular disease but also contribute to adherence of treatment in patients that need this therapeutics for a long period of time.
