**6. Ouabain antagonists**

The sodium pump is the major cellular carrier system that controls sodium homeostasis and membrane potential, both key factors in the regulation of vascular tone and BP. Several experimental evidences suggest that increased endogenous levels of inhibitor prototype of the sodium pump, endogenous ouabain, may participate at least in part, in the pathogenesis of hypertension. (Hamlyn & Manunta., 2011) Chronic administration of ouabain to rats produces hypertension and increases, probably as a compensatory mechanism, negative endothelial modulation of vasoconstrictor responses produced by the endogenous vasodilator NO. (Manunta et al., 2009)

Endogenous ouabain is a fast action circulating hormone, which is present in several species. It is stored and secreted by the hypothalamus, the pituitary and the adrenal glands. In the latter it synthesized in the fasciculata cells zona from progesterone and pregnenolone through various isomers of 3β-hydroxyesters dehydrogenases. The synthesis in the hypothalamus and the pituitary gland has not been clarified yet. It has a half life of 5 to 8 minutes and is eliminated by the liver and kidney. It is humerally secreted by the exercise and the hypoxia through phenylephrine and Ang II by AT2 receptor by means of systems not yet well known. (Manunta et al., 2009)

On the other hand, for more than 200 years the ouabain (G-strophanthin) have been used to treat HF, an arrow poison of the African Ouabaio tree and of Strophanthus gratus plants. (Schoner.,2002). By radioimmunoassay techniques, it has proved that its half-life is of 21 hours in human and renal clearance. It has been found to be the predominant route of excretion and biliary excretion has been estimated at only 2-8%. (Selden, Smith & Findley, 1972)

The blocking action of cardiotonic steroids in sodium pump holds α receptors and has been shown in almost all animals and all types of cells. The sodium pump, the sodium (Na) potassium (K) adenosine triphosphatase, Na+/K+-ATPase, has four isomers α receptors, α-1, α-2, α-3 and α-4. The α-1 is specific for Na+ and is present throughout the cell membrane. α-2 and α-3 receptors are less related to Na+ and are associated with the activity of the exchanger protein Na+/Ca2+, NCX 1.3. Each cell type has a different proportion of these receptors, α-3 receptors are more numerous in nerve, myocardial and arterial smooth muscle cells, α-2 receptors are more abundant in striated muscle and α-1 receptors are more abundant in the kidney. The ouabain receptor acts mainly on α-3 and also in the α-2 recptors but with less affinity. Sperm has only the fourth receivers, the α-4 receptors. (Blaustein et al., 2009; Scheiner-Bobis & Schoner., 2008)

New Therapeutics in Hypertension 9

Ang III more sensitivity and a more prolonged increase in BP was observed in genetically hypertensive rats (GHR) than in normotensive Wistar-Kyoto (WKY) and Sprague-Dawley rats. But if previously treated with bestatin (an inhibitor of AlaAP and ArgAP), which prevents the conversion of Ang III to Ang IV, elevation of BP was enhanced and prolonged. These results indicate, therefore, that dysfunction in the central aminopeptidases activity could lead to Ang II and Ang III act longer and therefore, could carry out a progressive and

Later, Jensen and colleagues showed that in addition to bestatin, a GluAP inhibitor (amastatine), was injected by intracerebroventricular via, which inhibited the formation of Ang III, which is induced BP increase in rats WKYy the GHR so that there should be an effect mediated by the brain RAAS. They also noted that genetically hypertensive rats were more sensitive to the action of inhibitors than the normotensive ones. (Jensen et al., 1989)

RB150 is a prodrug with a specific inhibitory action on aminopeptidase A EC33, when administered intravenously, it inhibits cerebral aminopeptidase A, the Ang III formation and reduces BP over 24 hours in DOCA-salt rats. Thus aminopeptidase A cerebral inhibitors

In conclusion, although the discovery of ACE inhibitors and ARBs were two important milestones in the treatment of hypertension, the study of other RAAS components that act at both peripheral and central levels offer new therapeutic possibilities. The cerebral Ang III is a potent hypertensive factor. However, Ang 2-10 seems to contribute more to reduce hypertension. The results we have so far indicate that they fundamentally prevent the formation of cerebral Ang III, or perhaps also facilitates the formation of Ang 2-10, a line of

Therefore, recent studies on central inhibitors of GluAP, responsible for the formation of Ang III, may provide promising results. It is also increasingly clear that to properly understand the brain's control of the BP, studies should consider the bilaterally of the peripheral and central nervous system. The development of agonists and antagonists specific of the ACE-2, may offer an understanding of the pathophysiological role of ACE 2

The endocannabinoid system (ECS) is a new regulatory system capable of modulating a variety of physiological effects, consisting of endogenous ligands, specific receptors and mechanisms of synthesis and degradation. Endogenous ligands are a new class of lipid regulators among which there are amides and esters of polyunsaturated fatty acid chain. Endocannabinoids are defined as endogenous compounds, produced in different organs and tissues, capable of binding to cannabinoid receptors. The cannabinoids are synthesized "on demand", when they are needed, and released abroad immediately after their production. Its major molecular targets are the cannabinoid receptors (CB) type 1 and type 2 (Brown, 2007). The CB1 receptor is predominantly expressed in the central nervous system, but is also present at much lower, yet functionally relevant levels in various peripheral tissues, including the myocardium, postganglionic autonomic nerve terminals, and vascular endothelial and smooth muscle cells as well as the adipose tissue,liver, and skeletal muscle. The expression of CB2 receptors was thought to be limited to hematopoietic and immune

represent a potential antihypertensive treatment. (Bodineau et al., 2008)

research that could develop possible treatments for hypertension.

**8. Modulators of the endocannabinoid system** 

sustained elevation of BP in RGH rats.

in the modulation of the BP.

A new antihypertensive agent, rostafuroxin (PST2238) a digitalis derivative, has been developed due to the ability to correct abnormalities of the Na-K pump. It is endowed with high potency and efficacy in reducing BP and preventing organ hypertrophy in animal models. (Ferrari et al., 2006) At the molecular level in the kidney, rostafuroxin normalizes the increased activity of the Na-K pump induced by adducin mutants pump and endogenous ouabain. In the vasculature, it normalizes the increasement of myogenic tone caused by endogenous ouabain.

A very high safety factor is the lack of interaction with other mechanisms involved in the regulation of BP, along with evidence of high tolerability and efficacy in hypertensive patients point to the rostafuroxin as the first example of a new class of antihypertensive drug designed to antagonize endogenous ouabain and adducin. Phase II clinical trial was recently completed, Ouabain and Adducin for Specific Intervention on Sodium in Hypertension Trial (OASIS-HT), in which rostafuroxin was used with encouraging results as 23% had a significant decrease in BP. In the future we will have to wait to compare the results of rostafuroxin with other antihypertensive drugs to be validated as ACE inhibitors and ARBs and its influence on the control of BP. (Staessen et al., 2011)
