**3. Imidazoline agonists**

Many of the antihypertensive drugs that exert their action at the nervous system as methyldopa, clonidine, guanfacine and guanabenz, act by stimulating alpha 2 central receptors located in the pontomedular region and its effect consists in the reduction of the sympathetic outflow with a decrease in the peripheral sympathetic activity, but unfortunately they produce adverse reactions which include sedation, dry mouth and impotence, which high occurrence has determined a progressive decrease in their use.

In 1984, articles on imidazoline receptors located in the central nervous system are beginning to be published, and more recently, drugs capable of acting at this level leading to a peripheral sympathetic inhibition. This mechanism of action similar to the classic agonists differs mainly by a lower incidence of adverse reactions. (Yu & Frishman., 1996)

The existence of imidazoline receptors different from the alpha 2 was established in studies in the brains of cattle which tested the affinity of clonidine with these sites. However, because this drug shares its affinity for both imidazoline receptor as the alpha 2 receptor, new compounds were developed with high selectivity for imidazoline receptors, among which moxonidine and rilmenidine are of the most extensive development. Its action is performed on type I receptors, which include those that exert regulatory actions on BP. (Van Zwieten., 1996) There are also type II imidazoline receptors which are related to the stimulation of insulin release and some metabolic processes in the brain, but not involved in the regulation of BP. Type I receptors when stimulated with direct agonists such as moxonidine and rilmenidine, mediate a fall in BP and heart rate by peripheral sympathetic inhibition. The neural pathway involved has been suggested very similar to that dependent on alpha 2 adrenergic activation. (Chan & Head., 1996) In the case of moxonidine and rilmenidine, its action on type I receptors is predominantly exerted with minimal affinity for alpha 2 receptors.

The central action of the agonist of type I receptors has been demonstrated by studies in which stereotaxic injections have been used in parts of the central nervous system where vasomotor centers are located. The involvement of imidazoline receptors in the antihypertensive action of these compounds has been demonstrated with different techniques including antagonizing its effect through selective antagonists of these receptors. The antihypertensive activity occurs at the expense of reduced central sympathetic activity that leads to a reduction in peripheral vascular resistance and vasodilation. Stimulation of type I receptors by these agonists does not produce significant changes in cardiac output and heart rate, although suppression of episodes of tachycardia and antiarrhythmic activity has been reported. A reduction in plasma levels of catecholamines has also been shown. (Mitrovic et al., 1991)

In animal experimental models a reduction in the left ventricular hypertrophy has been shown, possibly due to sympathetic inhibition. Stimulation of type I receptors located in the kidney is involved to explain the natriuretic effect of these compounds. (Mitrovic et al., 1991) Oral administration of moxonidine determined maximum concentrations after 30 to 60 minutes. The absorption is higher than 90% and no first pass metabolism occurs in the liver. About half of the dose is eliminated without changes in the urine. Plasmatic half-life lasts about two hours but the antihypertensive action is much longer indicating an effect dependent on its accumulation in the central nervous system.

Many of the antihypertensive drugs that exert their action at the nervous system as methyldopa, clonidine, guanfacine and guanabenz, act by stimulating alpha 2 central receptors located in the pontomedular region and its effect consists in the reduction of the sympathetic outflow with a decrease in the peripheral sympathetic activity, but unfortunately they produce adverse reactions which include sedation, dry mouth and impotence, which high occurrence has determined a progressive decrease in their use.

In 1984, articles on imidazoline receptors located in the central nervous system are beginning to be published, and more recently, drugs capable of acting at this level leading to a peripheral sympathetic inhibition. This mechanism of action similar to the classic agonists

The existence of imidazoline receptors different from the alpha 2 was established in studies in the brains of cattle which tested the affinity of clonidine with these sites. However, because this drug shares its affinity for both imidazoline receptor as the alpha 2 receptor, new compounds were developed with high selectivity for imidazoline receptors, among which moxonidine and rilmenidine are of the most extensive development. Its action is performed on type I receptors, which include those that exert regulatory actions on BP. (Van Zwieten., 1996) There are also type II imidazoline receptors which are related to the stimulation of insulin release and some metabolic processes in the brain, but not involved in the regulation of BP. Type I receptors when stimulated with direct agonists such as moxonidine and rilmenidine, mediate a fall in BP and heart rate by peripheral sympathetic inhibition. The neural pathway involved has been suggested very similar to that dependent on alpha 2 adrenergic activation. (Chan & Head., 1996) In the case of moxonidine and rilmenidine, its action on type I receptors is predominantly exerted with minimal affinity for

The central action of the agonist of type I receptors has been demonstrated by studies in which stereotaxic injections have been used in parts of the central nervous system where vasomotor centers are located. The involvement of imidazoline receptors in the antihypertensive action of these compounds has been demonstrated with different techniques including antagonizing its effect through selective antagonists of these receptors. The antihypertensive activity occurs at the expense of reduced central sympathetic activity that leads to a reduction in peripheral vascular resistance and vasodilation. Stimulation of type I receptors by these agonists does not produce significant changes in cardiac output and heart rate, although suppression of episodes of tachycardia and antiarrhythmic activity has been reported. A reduction in plasma levels of catecholamines has also been shown.

In animal experimental models a reduction in the left ventricular hypertrophy has been shown, possibly due to sympathetic inhibition. Stimulation of type I receptors located in the kidney is involved to explain the natriuretic effect of these compounds. (Mitrovic et al., 1991) Oral administration of moxonidine determined maximum concentrations after 30 to 60 minutes. The absorption is higher than 90% and no first pass metabolism occurs in the liver. About half of the dose is eliminated without changes in the urine. Plasmatic half-life lasts about two hours but the antihypertensive action is much longer indicating an effect

dependent on its accumulation in the central nervous system.

differs mainly by a lower incidence of adverse reactions. (Yu & Frishman., 1996)

**3. Imidazoline agonists** 

alpha 2 receptors.

(Mitrovic et al., 1991)

However, repeated doses are not accompanied by plasma accumulation. A glomerular filtration rate <30 ml/min should be considered a contraindication for use. The antihypertensive efficacy of moxonidine has been shown in controlled trials in which its effect has been compared with other classes of antihypertensive drugs that have included atenolol, hydrochlorothiazide, captopril and nifedipine. In all cases the effectiveness of BP control was statistically comparable. The antihypertensive effect is due to a vasodilator effect with reduced peripheral resistance without changes in heart rate and cardiac output. The administration of moxonidine produced a significant reduction in plasma catecholamine levels and long-term use determines reducing left ventricular hypertrophy without changing serum glucose and lipids levels.

The main advantage of moxonidine in relation to classical central agonists is given by a lower incidence of adverse reactions, even though there have been no studies comparing the two classes of drugs. Neither prospective studies have been conducted to demonstrate their protective effect on stroke, myocardial infarction, HF and kidney failure. The pharmacological characteristics of rilmenidine are very similar to those of moxonidine. Thus, experiments were made with a high number of patients in which its vasodilator effect as a result of reduced plasma concentrations of norepinephrine has been demonstrated. Another effect is the reduction of sympathetic baroreflex responses of heart and kidney, while vagal dependent cardiac baroreflex sensitivity is increased. As with moxonidine, left ventricular hypertrophy has proven reduction and be neutral on lipids and glucose levels. (Pillion et al., 1994)

#### **4. Vasopeptidase inhibitors**

In the early twenty first century vasopeptidase inhibitors were discovered as a new class of drugs for cardiovascular diseases by simultaneously inhibiting the angiotensin converting enzyme (ACE), thereby inhibiting the production of Ang such as Ang II, Ang 1-7 and Ang 2- 8, completely blocking the substrates for the activation of AT1 and AT2 receptors and neutral endopeptidase (NEP), NEP metabolizes NP into inactived molecules, blocking this enzyme determines the increased blood concentrations of NP, such as brain NP, C and D, which decreases peripheral resistance and preload. It increases venous capacitance and promotes natriuretic action. There is a reduction in sympathetic tone, inhibition of catecholamine release and activation of vagal afferent endings, suppressing the tachycardia reflex and vasoconstriction, also promoting structural changes in the myocardial remodelling with a potent hypotensive effect. (Corti et al., 2001)

These drugs inhibit various metallopeptidases such as NEP, which catalyzes the breakdown of vasodilators and antiproliferative peptides (NP, kinins), ACE and endothelin 1. Several drugs of this group are known: omapatrilat fasidotril, mixampril, sampatrilat, CGS30440, MDL100, 240, Z13752A, among others. (Sagnella, 2002)

The most representative drug of this group is omapatrilat, a dual inhibitor of ACE and NEP. This inhibition results in an increase in vasodilator mediators (PN, adrenomedullin, kinins, prostacyclin-PGI 2, NO) and a reduction of vasoconstrictors (Ang II, sympathetic tone). Omapatrilat causes a reduction in systolic and diastolic BP higher than other antihypertensives (amlodipine, lisinopril), regardless of age, sex and race of the patient. It is well absorbed orally and reaches peak plasma concentrations of 0.5-2 h. It presents a half life

New Therapeutics in Hypertension 7

to the limits of these studies, the role of these drugs is yet to be determined, because they have found significant adverse effects such as teratogenicity, hypertransaminemia and so its

The future of these drugs is uncertain. The results of human trials with these drugs have not reached the results from animal models. To date, these compounds have only been approved for use in patients with pulmonary arterial hypertension. Although they may reduce BP, there are antihypertensive drugs, safer and better tolerated available. However, the biological understanding of endothelin is rapidly evolving and its role in endothelial dysfunction of cardiovascular diseases is still a promising via in the pathogenesis and

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

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

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

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.,

biliary excretion has been estimated at only 2-8%. (Selden, Smith & Findley, 1972)

use has been limited by the FDA. (Krum et al., 1998)

treatment of hypertension.

**6. Ouabain antagonists** 

vasodilator NO. (Manunta et al., 2009)

not yet well known. (Manunta et al., 2009)

2009; Scheiner-Bobis & Schoner., 2008)

of 14-19 h, allowing the administration of the drugs once a day. It is biotransformed into several inactive metabolites which are eliminated by the kidneys.

The OCTAVE study (Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril) conducted in 25 267 hypertensive patients, confirmed the appearance of pictures of angioedema in omapatrilat treated patients, showing that the incidence of angioedema was 3 times higher than in patients treated with an ACE inhibitor, while in the OVERTURE (Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events) performed in 5770 patients with HF, functional class II-IV, ejection fraction ≤ 30% was 0.8% in patients treated with omapatrilat and 0.5% in those treated with enalapril. This dangerous side effect has stopped marketing the product. The simultaneous inhibition of ACE and NEP, both involved in the degradation of bradykinin, could lead to an accumulation of bradykinin and be responsible, at least in part, of the angioneurotic edema. (Sagnella, 2002)
