**9. Urotensin II receptor antagonists**

Human urotensin II (U-II) is a neuropeptide with the most potent vasoconstrictor action known to date. It is even 10 times more potent than endothelin 1. Although known since 1960, it only became a major goal of clinical research recently. It has a wide range of vasoactive properties according to their anatomical location and species studied.

cells, but they have recently been identified in the brain, the liver, the myocardium, and in

Increased ECS activity also contributes to the generation of cardiovascular risk factors in obesity/metabolic syndrome and diabetes such as plasma lipid alterations, abdominal obesity, hepatic steatosis, and insulin and leptin resistance. However, the ECS may also be activated as a compensatory mechanism in various forms of hypertension where it counteracts not only the increase in SP, but also the inappropriately increased cardiac contractility through the activation of CB1 receptors. In addition, the activation of CB2 receptors in endothelial and inflammatory cells by endogenous or exogenous ligands was found to limit the endothelial inflammatory response, the chemotaxis, and the adhesion of inflammatory cells to the activated endothelium with the consequent release of various proinflammatory mediators, which are key processes in the initiation and progression of atherosclerosis and reperfusion

Currently, several types of endogenous cannabinoids have been identified, all of lipid nature and derived from polyunsaturated fatty acids of long chain. Anandamide (Naraquidonoiletanolamina, AEA) and 2-arachidonoylglycerol (2-AG) are the two best known endocannabinoids. AEA may be a partial or full agonist of CB1 receptors with low action over CB2 and 2-AG an agonist both of CB1 and CB2 receptors (Bisogno., 2008, Howlett., 2002).

The possible antihypertensive effect of cannabinoid ligands is based on the lowering of BP seen in the chronic use of cannabis in humans and in response to the acute or chronic

Recently there are results that demonstrate its high hypotensive efficiency in hypertensive animals compared with the normotensive ones and evidence that the tonic activation of the ECS in various experimental models of hypertension could be a possible compensatory mechanism. (Batkai et al., 2004, Wheal et al.,2007) This hipotensive tone could be attributed to a decrease in the mediated activity by the CB1 receptor in myocardial contractility rather than vascular resistance. So preventing the degradation of endogenous AEA by pharmacological inhibition of amidohydrolase fatty acid increases myocardial levels of AEA reducing BP and cardiac contractility in hypertensive rats but not in the normotensive ones. Perhaps the amidohydrolase fatty acid could be a therapeutic target in hypertension, where its inhibition would not only reduce BP but also prevent or stop the development of cardiac

The adverse side effects of these new drugs, their interaction with other ones, their pharmacokinetics, and their efficacy in the medium and long term, their probable use in other diseases are among the many questions that remain to be clarified in this new but

Human urotensin II (U-II) is a neuropeptide with the most potent vasoconstrictor action known to date. It is even 10 times more potent than endothelin 1. Although known since 1960, it only became a major goal of clinical research recently. It has a wide range of

vasoactive properties according to their anatomical location and species studied.

administration of tetrahydrocannabinol in experimental animals. (Bisogno., 2008)

the human coronary endothelial and smooth muscle cells. (Pacher et al., 2008)

injury as well as smooth muscle proliferation. (Pacher et al., 2008)

hypertrophy. (Lépicier et al.,2006)

promising group of antihypertensive drugs.

**9. Urotensin II receptor antagonists** 

The U-II binds to an urotensin II receptor, Gq protein (UT), originally known as orphan GPR14 receptor. This receptor has been identified in central nervous system cells, the bone marrow, the kidneys, the heart, the vascular smooth muscle and the endothelial cells. (Ames et al., 1999) Using immunohistochemistry techniques, U-II has been found in blood vessels of the the heart, the pancreas, the kidney, the placenta, the thyroid, the adrenal glands and in the umbilical cord. UT stimulation induces the release of NO, prostacyclin, prostaglandin E2 and endothelium derived factors that balance the contractile effect on vascular smooth muscle. Vasoconstriction is mediated by receptors in the vascular smooth muscle, whereas the vasodilatation is mediated by the endothelium. However, in HF and essential hypertension, the U-II loses its vasodilator capacity. So the U-II causes vasoconstriction of endothelium independently and vasodilatation of endothelium dependently.

The complex and contrasting vascular actions of U-II is not only dependent on the condition of the endothelium, but also on the type of vascular bed and species. (Ames et al., 1999, Liu et al.,1999, Matsushita et al.,2001, Maguire et al., 2004, Zhu et al.,2006)

In healthy individuals, the U-II acts as a chronic regulator of vascular tone. In patients with cardiovascular diseases, the balance is lost and elevated plasma levels of U-II in patients with HF, carotid atherosclerosis, kidney failure, diabetes mellitus, liver cirrhosis with portal hypertension and essential hypertension is found.

Endothelial dysfunction causes vasoconstriction or inadequate vasodilatation resulting in a myocardial ischemia and hypertension, associated with an increase in the U-II and UT. In fact, in patients with hypertension U-II is increased 3 or 4 times, and has shown positive correlation between HF and plasma levels of U-II. (Matsushita et al.,2001, Douglas et al.,2002, Richards et al.,2002, Cheung et al.,2004; Suguro et al.,2007)

Today there are several drugs that act on antagonism receptor of U-II: urantide, BIM-23 127, SB-611 812, palosuran. All at different stages of clinical research, so that in the coming years we will have results that allow us to evaluate the effectiveness on BP control and its impact on cardiovascular diseases. (Tsoukas, Kane & Giaid A., 2011)

#### **10. Potassium channel openers**

The openers of potassium channels (KCOs) are a class of drugs with an extreme chemical diversity; they include different structural classes such as benzopirans, cyanoguanidines, thioformamides, and pyrimidines. They base their action on the increase of transmembrane K+ flow, resulting in a hyperpolarization of the cell membrane through the opening of potassium channels and the closing of Ca2+ channels, as a result the cell is less excitable and less prone to stimulation. There are two large families of potassium channels described in smooth muscle: channels regulated by voltage and channels regulated by ATP. (Moreau., et al. 2000) Potassium channels, regulated by intracellular ATP are located in the heart and blood vessels and are important modulators of cardiovascular function. The opening of potassium channels produces an increase in K+ efflux from the cell so that the membrane potential at rest becomes more negative (hyperpolarization) and this leads to inhibition of calcium entry or an indirect antagonism of calcium, causing a drop in intracellular calcium concentration, relaxation of vascular smooth muscle cells and therefore vasodilatation.

New Therapeutics in Hypertension 13

channel openers an attractive antihypertensive class in patients with ischemic heart disease,

The involvement of oxidative stress in hypertension is well known. There is strong evidence that oxidative stress is increased in essential hypertension, renovascular hypertension,

Hypertensive patients have significantly higher levels of hydrogen peroxide (H202) in plasma than the normotensive ones. Besides the normotensive ones which have a family history of hypertension have an increased production of H202 than those who have no family history of hypertension, suggesting that there may be a genetic component in the

expression and actions are regulated by Ang II through AT1 receptor. It has been shown that NAD(P)H oxidase contributes to the pathogenesis of hypertension. (Matsuno et al.,

The NAD(P)H oxidase is found in neutrophils and has five subunits: p67phox, p40phox, p22phox, and gp91phox catalytic subunit (also known as "NOX/DUOX family"), with 7 counterparts known to date, with diverse biological functions in different tissues such as: the colon, the blood vessels, the lungs, the heart, the kidneys, the nervous system, the ear,

Though the interaction of subunits in cardiovascular cells and its regulation and function of each NOX/DUOX is still uncertain, it is clear that NOX/DUOX enzymes are very important in normal biological response and contribute to cardiovascular and renal disease, including

The development of specific inhibitors of these enzymes has attracted attention for its potential therapeutic use in hypertension. Experiments have shown that inhibitors of NAD(P)H decrease the release of O2- and increase the synthesis of NO, thus lowering BP. So far, two specific inhibitors: gp91ds-tat and apocynin have been proven to reduce BP in animals in labs. Other inhibitors such as diphenylene iodonium, aminoethyl benzenesulfono fluoride, S17834, PR39 and VAS2870, have proven to be effective in vitro, its effectiveness,

Many of these drugs not only inhibit the NAD(P)H oxidase but also other enzyme systems and cannot be administered orally, so its clinical use is limited. In addition, reactive oxygen species are so important to the immune and vascular health of human beings as for the disease, so not discriminating against the inhibition of NAD(P)H oxidase derived from

Other drugs such as ACE inhibitors, ARBs and drugs lowering cholesterol like statins have also shown that they attenuate the activation of NAD(P)H oxidase, so this could be a promising avenue in the search for molecules with specific activities over enzymatic systems

the bones, the testicles, the thyroid and lymphoid tissues. (S Wind et al., 2010)

pharmacokinetics and specificity is to be determined in vivo. (S Wind et al., 2010)

reactive oxygen species could produce dangerous side effects.


diabetes mellitus and bronchospastic disease.

**11. Vascular NAD(P)H oxidase inhibitors** 

high production of H202. (Stocker & Keaney, 2004)

2005, Gavazzi et al., 2006)

atherosclerosis and hypertension.

involved in cardiovascular diseases.

preeclampsia and hypertension induced by cyclosporine.

The NAD(P)H oxidase is the largest supplier of superoxide (O2

(Wang, Long & Zhang., 2004) The primary target for KCOs action is through the regulatory subunit of the KATP channel, known as the sulfonylurea receptor or SUR, an ATP-binding cassette protein. (Moreau., et al. 2000)

These drugs came into use in 1980 in Japan with the commercialization of nicorandil, but now availability is wide and includes: celikalim, levcromakalim, birnakalirn, pinacidil, rilmakah, minoxidil, diazoxide and iptakalim among many others. KCOs like minoxidil, diazoxide, nicorandil, pinacidil, cromakalim and levcromakalim act by enhancing the ATPase activity of SUR1 subunit and the resultant channel opening causes hyperpolarization. (Sandhiya & Dkhar 2009)

Some of these drugs have been developed for clinical use and have several advantages such as its sustained and strong action on lowering blood lipids compared with other antihypertensive drugs.

The disadvantage is its lack of selectivity, thus besides smooth muscle cells, both the pancreas and the heart contain high concentrations of K+ channels sensitive to ATP, so that the hypotensive effect is accompanied by other side effects such as hyperglycemia and cardiotoxicity, although changes in the chemical structure have produced good results, that are still not good for widespread use such as antihypertensive drugs. (Butera & Soll, 1994)

 Diazoxide and minoxidil are currently recommended for the management of hypertensive emergencies and severe resistant hypertension, especially in patients with advanced renal disease. Their routine use as antihypertensive agents is limited because of a reflex increase in heart rate due to the stimulation of the sympathetic nervous system in response to arterial vasodilatation causing flushing, headache and/or sodium and water retention. Therefore, KCOs should be administered in conjunction with a diuretic and b-adrenergic blocker to control reflex increase in heart rate. An increase in plasma renin activity (largely due to activation of the sympathetic nervous system) and aldosterone level may also occur. Hyperglycemic effects of diazoxide and possible hypertrichosis with minoxidil also limit their longterm use, particularly in women. (Jahangir & Terzic 2005)

Recently a new KCOs sensitive to ATP has been developed: the iptakalim, which selectively relaxes small arteries with a more powerful action in hypertensive states. The iptakalim increases NO associated with increased intracellular calcium in cultured aortic endothelial cells. In addition, the iptakalim inhibits the synthesis and release of endothelin 1 associated with reduced RNA messenger of ET 1 and of the ECE. It inhibits the over expression of molecular adhesion in aortic endothelial cells subjected to metabolic disturbance induced by low density lipoprotein, homocysteine, or hyperglycemia, so it can reduce vascular and cardiac remodeling and endothelial dysfunction. (Wang et al., 2007)

Therefore, the protective profile of iptakalim may not only be due to the controlling of BP but may also relate to its effects in the endothelium system. Iptakalim has a selective antihypertensive efficacy with steady and long-lasting characteristics and produces less side and toxicity effects under the effective doses. It has the virtue for hypertension treatment by reversing hypertensive cardiovascular remodeling and protecting the target organs. (Wang, Long & Zhang.,2005)

However, cardioprotective and antiischemic properties of KCOs, beneficial effects on glycation and plasma lipids and bronchial smooth muscle relaxation still makes potassium

(Wang, Long & Zhang., 2004) The primary target for KCOs action is through the regulatory subunit of the KATP channel, known as the sulfonylurea receptor or SUR, an ATP-binding

These drugs came into use in 1980 in Japan with the commercialization of nicorandil, but now availability is wide and includes: celikalim, levcromakalim, birnakalirn, pinacidil, rilmakah, minoxidil, diazoxide and iptakalim among many others. KCOs like minoxidil, diazoxide, nicorandil, pinacidil, cromakalim and levcromakalim act by enhancing the ATPase activity of SUR1 subunit and the resultant channel opening causes

Some of these drugs have been developed for clinical use and have several advantages such as its sustained and strong action on lowering blood lipids compared with other

The disadvantage is its lack of selectivity, thus besides smooth muscle cells, both the pancreas and the heart contain high concentrations of K+ channels sensitive to ATP, so that the hypotensive effect is accompanied by other side effects such as hyperglycemia and cardiotoxicity, although changes in the chemical structure have produced good results, that are still not good for widespread use such as antihypertensive drugs. (Butera & Soll, 1994) Diazoxide and minoxidil are currently recommended for the management of hypertensive emergencies and severe resistant hypertension, especially in patients with advanced renal disease. Their routine use as antihypertensive agents is limited because of a reflex increase in heart rate due to the stimulation of the sympathetic nervous system in response to arterial vasodilatation causing flushing, headache and/or sodium and water retention. Therefore, KCOs should be administered in conjunction with a diuretic and b-adrenergic blocker to control reflex increase in heart rate. An increase in plasma renin activity (largely due to activation of the sympathetic nervous system) and aldosterone level may also occur. Hyperglycemic effects of diazoxide and possible hypertrichosis with minoxidil also limit

Recently a new KCOs sensitive to ATP has been developed: the iptakalim, which selectively relaxes small arteries with a more powerful action in hypertensive states. The iptakalim increases NO associated with increased intracellular calcium in cultured aortic endothelial cells. In addition, the iptakalim inhibits the synthesis and release of endothelin 1 associated with reduced RNA messenger of ET 1 and of the ECE. It inhibits the over expression of molecular adhesion in aortic endothelial cells subjected to metabolic disturbance induced by low density lipoprotein, homocysteine, or hyperglycemia, so it can reduce vascular and

Therefore, the protective profile of iptakalim may not only be due to the controlling of BP but may also relate to its effects in the endothelium system. Iptakalim has a selective antihypertensive efficacy with steady and long-lasting characteristics and produces less side and toxicity effects under the effective doses. It has the virtue for hypertension treatment by reversing hypertensive cardiovascular remodeling and protecting the target organs. (Wang,

However, cardioprotective and antiischemic properties of KCOs, beneficial effects on glycation and plasma lipids and bronchial smooth muscle relaxation still makes potassium

their longterm use, particularly in women. (Jahangir & Terzic 2005)

cardiac remodeling and endothelial dysfunction. (Wang et al., 2007)

cassette protein. (Moreau., et al. 2000)

hyperpolarization. (Sandhiya & Dkhar 2009)

antihypertensive drugs.

Long & Zhang.,2005)

channel openers an attractive antihypertensive class in patients with ischemic heart disease, diabetes mellitus and bronchospastic disease.
