**16. Rho kinase inhibitors**

The intracellular signalling pathway of RhoA/Rho kinase (ROCK) is a mechanism discovered in the mid 90's of the twentieth century by japanese researchers, with a significant participation in the pathological remodeling of cardiovascular diseases. Two isoforms have been identified: the Rock 1 and ROCK 2. (Liao, Seto & Noma., 2007)

The vascular smooth muscle contraction is controlled by the concentration of free cytosolic Ca2+ and Ca2+ sensitivity of contractile proteins. The sensitization of Ca2+ in contractile proteins is determined by means of the RhoA/Rho kinase, which regulates the degree of phosphorylation of myosin light chains (MLC) by the phosphatase phosphorylation of the CLM, keeping the force of generation.

The contraction and relaxation of blood vessels is significantly regulated through phosphorylation and dephosphorylation reactions of the CLM in the regulatory subunit of protein phosphatase 1 target of myosin (myosin phosphatase target protein 1 or MYPT-1). It has been shown that the small GTPase Rho and its effector Rho A kinase modulate the phosphorylation of MYPT-1, so that when intracellular signalling pathway RhoA/Rho kinase is activated MYPT-1 increases. (Liao, Seto & Noma., 2007)

The route of the RhoA/Rho kinase is involved in pathological cardiovascular remodelling and in the regulation of BP and it is activated by agonists of receptors coupled to G membrane protein, such as Ang II, endothelin or noradrenaline, and produces contraction of the smooth muscle cells and hypertension. Rho kinase activation by Ang II is also involved in the oxidative stress and increased production of proinflammatory and profibrotic mediators. ROCK thus promotes oxidative stress and remodeling. (Liao, Seto & Noma., 2007)

Furthermore, RhoA-ROCK pathway is involved in cellular processes involved in the pathogenesis of various cardiovascular and renal diseases, as it participates in the effects of vasoactive and promoting of molecules of cardiovascular and renal remodeling, such as Ang II, 5 hydroxytryptamine, thrombin, platelet derived growth factor, endothelin, norepinephrine, thromboxane A2 and U II. The activation of ROCK, a target of Rho A also produces a chain of cellular events such as the regulation of endothelial NO synthase

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

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

The intracellular signalling pathway of RhoA/Rho kinase (ROCK) is a mechanism discovered in the mid 90's of the twentieth century by japanese researchers, with a significant participation in the pathological remodeling of cardiovascular diseases. Two

The vascular smooth muscle contraction is controlled by the concentration of free cytosolic Ca2+ and Ca2+ sensitivity of contractile proteins. The sensitization of Ca2+ in contractile proteins is determined by means of the RhoA/Rho kinase, which regulates the degree of phosphorylation of myosin light chains (MLC) by the phosphatase phosphorylation of the

The contraction and relaxation of blood vessels is significantly regulated through phosphorylation and dephosphorylation reactions of the CLM in the regulatory subunit of protein phosphatase 1 target of myosin (myosin phosphatase target protein 1 or MYPT-1). It has been shown that the small GTPase Rho and its effector Rho A kinase modulate the phosphorylation of MYPT-1, so that when intracellular signalling pathway RhoA/Rho

The route of the RhoA/Rho kinase is involved in pathological cardiovascular remodelling and in the regulation of BP and it is activated by agonists of receptors coupled to G membrane protein, such as Ang II, endothelin or noradrenaline, and produces contraction of the smooth muscle cells and hypertension. Rho kinase activation by Ang II is also involved in the oxidative stress and increased production of proinflammatory and profibrotic mediators.

Furthermore, RhoA-ROCK pathway is involved in cellular processes involved in the pathogenesis of various cardiovascular and renal diseases, as it participates in the effects of vasoactive and promoting of molecules of cardiovascular and renal remodeling, such as Ang II, 5 hydroxytryptamine, thrombin, platelet derived growth factor, endothelin, norepinephrine, thromboxane A2 and U II. The activation of ROCK, a target of Rho A also produces a chain of cellular events such as the regulation of endothelial NO synthase

ROCK thus promotes oxidative stress and remodeling. (Liao, Seto & Noma., 2007)

isoforms have been identified: the Rock 1 and ROCK 2. (Liao, Seto & Noma., 2007)

arterial compliance, reduced systolic BP and was well tolerated.

kinase is activated MYPT-1 increases. (Liao, Seto & Noma., 2007)

and cardiovascular diseases.

**16. Rho kinase inhibitors** 

CLM, keeping the force of generation.

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. (Rikitake & Liao JK., 2005)

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. (Rikitake & Liao JK., 2005)

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 solve the specificity and safety of ROCK inhibitors.
