**15. Crosslink breakers of the end products of advanced glycation**

The abnormal collagen cross links due to the formation of the end products of advanced glycation (AGEs) contribute to increase cardiovascular stiffness, which is a predictor of adverse cardiovascular events in old age, hypertension and diabetes. (Vlassara & Palace, 2002, Susic et al., 2004)

New Therapeutics in Hypertension 19

expression by decreasing its gene activation of NAD(P)H oxidase with increased oxidative stress. (Liao, Seto & Noma., 2007) There is sustained evidence that Rho kinase pathway is substantially involved in the pathogenesis of vasospasm, atherosclerosis, hypertension, pulmonary hypertension, stroke and HF and increased central sympathetic nerve activity.

The Rho kinase inhibitors (Y-27632, fasudil, hydroxyfasudil, KI-2309) induce relaxation of vascular smooth muscle, decrease in BP and inhibition of cardiovascular remodelling and endothelial dysfunction in hypertensive experimental animals. (Rikitake & Liao JK., 2005)

In hypertensive patients they improve endothelial dysfunction, normalize superoxide production, reduce peripheral vascular resistance and inhibit the development of cerebral and coronary vasospasm. (Masumoto et al., 2001) The first Rho kinase inhibitor approved for clinical use was the fasudil in 1995 in Japan and China, which has been used in cerebral vasospasm resulting from subarachnoid haemorrhage surgery. Several adverse effects such as intracranial bleeding, impaired liver function and hypotension have been reported.

As more understanding of the physiological role of each ROCK isoform in the cardiovascular system is needed as well as the development of specific inhibitors of these to

**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

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

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

**17. Antihypertensive drugs with combined mechanisms of action** 

benefits of inhibiting RAAS without causing angioedema. (Ruilope et al., 2010)

(Rikitake & Liao JK., 2005)

(Rikitake & Liao JK., 2005)

and July/7/2008. Aged 18-75 years.

effects and no patients had angioedema.

solve the specificity and safety of ROCK inhibitors.

The first switch of the cross links of AGEs was phenacylthiazolium bromide (PTB), discovered in 1996, which reacts with cross links of AGEs derived from proteins. The PTB is rapidly degraded, so for the search of a more stable one, alagebrium (4.5 dimethylthiazolium or ALT-711) was discovered. (Dhar, Desai & Wu., 2010) Alagebrium breaks cross links of the end products of advanced glycation. In experimental animal models of advanced age, hypertensive or diabetic, the alagebrium reduced aortic stiffness and systolic BP, decreased the speed of pulse wave, improved diastolic ventricular compliance and cardiac output, improved diabetic nephrosclerosis and reduced urinary albumin excretion. Alagebrium also reduced oxidative stress in experimental elder animals by increasing the activity of glutathione peroxidase and superoxide dismutase. (Dhar, Desai & Wu., 2010) In elderly patients, alagebrium improved arterial compliance, reduced systolic BP and was well tolerated.

Today there are numerous studies underway in elderly patients with isolated systolic hypertension, HF and nephropathy; these results will clarify the likely benefit in the aging and cardiovascular diseases.
