**17.1 Dual inhibitors of neutral endopeptidase and angiotensin II receptors blockers**

The Lancet in 2010 published the results of a study by Luis Ruilope and colleagues of LCZ696 a new drug (Novartis), which combines in a single molecule the double blocking action of Ang II and inhibits neprilysin (NEP 24.11) a metallopeptidase membrane that produces degradation of atrial natriuretic peptide, so it would provide the cardiovascular benefits of inhibiting RAAS without causing angioedema. (Ruilope et al., 2010)

This is a double blind multicenter study comparing the effects of LCZ696 with valsartan and another blocker of neprilysin called AHU377. It included 1 328 patients with mild to moderate hypertension, from 134 cities in 18 countries (Argentina, Canada, Denmark, Finland, France, Germany, Hungary, Italy, Latvia, Lithuania, Netherlands, Poland, Russia, Slovakia, Spain, Switzerland, Taiwan, and USA) who were treated between Oct/12/2007 and July/7/2008. Aged 18-75 years.

The patients were randomized to one of 8 groups of treatment: LCZ696 100 mg, 200 mg LCZ696; LCZ696 400 mg, 80 mg of valsartan, 160 mg of valsartan, 320 mg of valsartan, 200 mg AHU377, and placebo. The primary endpoint was the mean difference in diastolic blood pressure (DBP) compared among LCZ696 doses and valsartan doses (100 mg vs 80 mg, 200 mg vs 160 mg and 400 mg vs 320 mg) over a period of 8 weeks. The results showed that the decrease in DBP with the dual inhibitor is more effective when compared with valsartan, especially at 200 and 400 mg vs 160 LCZ696 and 320 mg of the latter. The DBP reduction with LCZ696 was a dependent dose. As data to highlight there were no significant adverse effects and no patients had angioedema.

New Therapeutics in Hypertension 21

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.

Known is the role of Ang II and ET1 in the pathogenesis of essential hypertension. These substances produce vasoconstriction through the activation of its receptors in vascular smooth muscle: the AT1 and ETA, respectively. Ang II promotes the production of

Moreover, evidence suggests the interrelation between the endocrine and paracrine systems of Ang II and endothelin. Ang II increases the expression of RNA messenger in endothelial cells. Ang II stimulates the release of ET1 by endothelial cells involving AT1 receptors, Ca2+ mobilization and activation of kinase C protein. ARBs produce a significant decrease in BP and reduce endothelial dysfunction and cardiovascular mortality in hypertensive, diabetic and HF patients. Thus, the activation of ETA and/or ETB receptors of ET1 causes contraction of vascular smooth muscle cells and increases BP and an antagonist of ETA/ETB receptors like bosetan decreases BP in patients with essential hypertension. Thus the combination in one same drug of properties AT1/ETA receptors antagonists may have a greater effect than either drug alone and with fewer side effects. Today ETA receptor blockers have been modified to acquire AT1 receptor

There are several compounds (MS-248 360, BMS-248360, SB-290 670) that in laboratory animals decreased BP, but these investigations are still in very early stages. (Kowal et al., 2004) But this new class of antihypertensive drug which simultaneously antagonizes the AT1 and ETA receptors promise to be a novel approach in the treatment of hypertension

The development of research at the dawn of the millennium, in nanotechnology, genetic engineering and biotechnology for the understanding of the multiple pathogenic mechanisms of cardiovascular diseases and its consequences and hypertension within them, have caused a real boom in the appearance of new therapeutic options for hypertension. About some of them (those that are the most in advanced stages of preclinical and clinical

Others in earlier stages of experimental research as antagonists of vasopressin receptors (RWJ-676070), NO stimulators and stabilizers: L-arginine, tetrahydrobiopterin (BH4), phosphodiesterase inhibitors PDE-5, N-acetylcysteine, donors of NO (NCX-899,

**17.4 Dual antagonist of angiotensin II and endothelin A receptors** 

endothelin and endothelin in turn increases the synthesis of Ang II.

antagonism.

**18. Conclusions** 

and other cardiovascular diseases.

research) we have tried to give a small and modest updating.

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 prevention and control of target organ damage.
