WO2013010241A1 - Pharmaceutical composition for the treatment of arterial hypertension, based on the co-administration of anti-hypertensive agents and angiotensin (1-7) or another mas receptor agonist - Google Patents

Abstract

The present invention describes a composition that can increase or prolong the activity of anti-hypertensive pharmaceutical drugs in mammals, in particular humans, by co-administration of the heptapeptide angiotensin (1-7) or another Mas receptor agonist.

Description

 Pharmaceutical composition for the treatment of hypertension based on the co-administration of antihypertensives and angiotensin (1-7) or other Mas receptor agonists.

The present invention describes a composition capable of increasing or prolonging the activity of antihypertensive drugs in mammals, particularly humans, by co-administering the angiotensin (1-7) heptapeptide or other Mas receptor agonist.

Hypertension, popularly called "high blood pressure" or HTN, is a medical condition where blood pressure is chronically high. Hypertension can be classified as essential (primary) or secondary. Essential hypertension indicates that there is no specific medical cause that explains the patient's condition. Secondary hypertension indicates that high blood pressure results from (ie secondary to) another condition, such as kidney disease or certain tumors (especially the adrenal gland). Essential hypertension is often associated with other cardiovascular risk factors, such as aging, overweight, insulin resistance, diabetes, and hyperlipidemia.

Persistent hypertension increases the risk of brain, cardiac and renal events. In industrialized countries, the risk of becoming hypertensive (blood pressure> 140/90 mm Hg) over a lifetime exceeds 90%. Sudden damage to the target organ, such as left ventricular hypertrophy, microalbuminuria, and cognitive dysfunction, occurs early in the course of cardiovascular hypertension. However, catastrophic events such as stroke, acute myocardial infarction, renal failure and dementia usually only occur after long periods of uncontrolled hypertension (Messerli FH et al., Lancet 370 (2007) 591-603).

The renin-angiotensin system (RAS) is one of the main cardiovascular and renal function regulation systems. RAS generates a family of bioactive peptides with varied biological activities. In the classical pathway, the angiotensin (1-10) decapeptide (Ang I) is generated from the precursor angiotensinogen by renin enzyme activity. Ang I is then converted to angiotensin (1-8) (Ang II) by the removal of two carboxy terminal amino acids by the angiotensin converting enzyme (ACE). However, with the identification of enzymes (such as ECA2) and additional peptides, it becomes clear that RAS is much more complex and not yet fully known (Ferreira AJ et al., Hypertension. 2010 Feb; 55 (2): 207- 13).

Bioactive angiotensin peptides include the previously mentioned Ang II, angiotensin (2-8) (Ang III), angiotensin (3-8) (Ang IV), and angiotensin (1-7) (Ang (1-7)). )), with a corresponding diversity of receptors for these peptides. There are two major receptors for Ang II, type 1 (AT1) and type 2 (AT2) receptors. Both are receptors with seven transmembrane propellers, although they have a quite different pharmacology. The AT1 receptor mediates the major pathophysiological activities of Ang II, which include vasoconstriction, endothelial dysfunction, proliferation of cardiac fibroblasts and smooth muscle cells, cardiomyocyte hypertrophy, fibrosis, atherosclerosis, arrhythmogenesis and thrombosis (Ferrario CM. Curr Opin Nephrol Hypertens. 201 1 Jan; 20 (1): 1-6). Heptapeptide Ang (1-7) (Asp-Arg-Val-Tyr-lle-His-Pro) is generated independently of ACE by processing Ang I by endopeptidases or Ang II by prolylpeptidases or carboxypeptidases (ECA2). The effects of Ang (1-7) are opposite to those of Ang II. While AT1 receptor stimulation by Ang II produces cardiac remodeling through a complex mechanism that results in reduced cardiac activity and increased susceptibility to cardiac events, Ang (1-7) appears to be able to reduce cardiac remodeling by decreasing cardiac activity. hypertrophy and fibrosis (Santos RAS, Ferreira AJ, Curr Opin Nephrol Hypertens. 16 (2007) 122-128). In addition to this effect on cardiac remodeling, Ang (1-7) has antiarrhythmogenic effects (Santos RAS et al., Physiol Genomics 17 (2004) 292-299; Ferreira AJ et al., Hypertension 38 (2001) 665-668) and acts as a vasodilator. The effects of Ang (1-7) are not mediated by AT1 and AT2 receptors, but via its own receptor, Mas (Santos RAS et al., Proc. Natl. Acad. Sci USA 100 (2003) 8258-8263). Other synthetic receptor agonists But, such as AVE-0991 and CGEN-856S, were able to mimic the beneficial cardiovascular effects of angiotensin (1-7) (Savergnini SQ et al., Hypertension. 2010; 56 (1): 1 12-20; Santos RA, Ferreira AJ. Cardiovasc Drug Rev. 2006; 24 (3-4) ): 239-46).

Due to its central role in regulating renal and cardiovascular function, RAS represents a prominent target for the development of antihypertensive drugs. Inhibitors of this system, such as ACE inhibitors, Ang II receptor blockers (ARBs) and renin inhibitors, are currently first-line treatments for target hypertensive organ damage and progressive kidney disease. ACE inhibitors minimize the vasoconstrictor effects of Ang II by inhibiting the conversion of Ang I to Ang II. ACE inhibitors can be divided into three groups based on their molecular structure: sulfhydryl containing ACE inhibitors (eg Captopril), dicarboxylate containing ACE inhibitors (eg Enalapril, Ramipril, Quinapril, Perindopril, Lisinopril, Benazepril, Trandolapril) and phosphonate-containing ACE inhibitors (e.g. Fosinopril). ACE inhibitors are generally well tolerated, with rare side effects such as angioedema, rash, and dry cough (8-10%). ARBs are AT1 receptor antagonists, that is, they block AT1 receptor activation by Ang II. AT1 receptor blockade directly causes vasodilation, reduced vasopressin secretion, reduced aldosterone production and secretion, among other effects, the combined effect of which being reduced blood pressure. Examples include Candesartan, Eprosartan, Irbesartan, Losartan, Olmesartan, Telmisartan, and Valsartan. Renin inhibitors minimize the effects of Ang II by inhibiting the conversion of angiotensinogen to Ang I. Therefore, the generation of Ang I required for the formation of Ang II by ACE is inhibited, and therefore Ang II, which is the Active peptide responsible for most vasoconstriction effects in this system becomes unavailable. Thus, renin inhibitors decrease plasma renin activity, and in consequently, systemic vascular resistance and systemic blood pressure.

Four classes of compounds are involved in the development of renin inhibitors: renin antibodies directed against the enzyme; the second class of renin inhibitor drug is a synthetic derivative of renin precursor proceeding; the third class of drugs was modeled on the activity of pepstatin, an isolated natural actinomycete culture pentapeptide that universally inhibits aspartylprotease enzymes; and the fourth class of renin inhibitors is formed by angiotensinogen (substrate) analogs.

Other antihypertensive drugs include diuretics, beta blockers, and calcium channel blockers. Diuretics, ie drugs that increase the body's rate of urine excretion (diuresis), can be divided into three categories: thiazides, loop diuretics and potassium-sparing diuretics. Thiazides and their analogues include chlorothiazides and hydrochlorothiazides such as Chlorotalidone, Eptizide, Indapamide and Metolazone. They induce, in the first days of treatment, a 10-15% decrease in blood pressure, mainly due to a decrease in extracellular volume and an increase in diuresis and natriuresis. After six months, blood volume and cardiac output return to baseline levels and the decrease in blood pressure is maintained by a decrease in peripheral vascular resistance (Frolich ED, Current Approaches in the Treatment of Hypertension, 405-469, 1994). Side effects include increased peripheral insulin resistance, increased triglyceride levels, increased LDL, hypocalcemia, and hyperuricemia. Examples of loop diuretics include Furosemide, Bumetanide, Torsemide and Ethacrynic Acid, and they are much more potent than thiazides. They act predominantly on the medullary and cortical portions of the Henle loop and exhibit the same side effects as thiazides. Potassium-sparing diuretics, including Amiloride, Trianterena and Spironolactone, are drugs with a weaker diuretic effect and are rarely used alone. Despite being first-line treatment for hypertension, beta-blockers in the UK dropped to the fourth line in June 2006 because they do not perform as well as other drugs, particularly in the elderly. In addition, there is growing evidence that the most commonly used beta-blockers, especially in combination with thiazide-type diuretics, carry an unacceptable risk of causing type 2 diabetes (Elliott J. and Meyer P., The Lancet, Jan. 20, 2007). Beta blockers block the action of endogenous catecholamines (particularly epinephrine (adrenaline) and norepinephrine (norepinephrine)) on β-adrenergic receptors. There are three known types of beta-receptors, called β1, β2 and β3. Βΐ -adrenergic receptors are mainly located in the heart and kidneys. The β2 ^^ ^η ό¾ίοο5 receptors are mainly located in the lungs, gastrointestinal tract, liver, uterus, smooth vascular muscle and skeletal muscle. The β3 receptors are located in fat cells. The stimulation of β1 receptors by epinephrine induces a positive chronotropic and ionotropic effect on the heart and increases the automaticity and cardiac conduction velocity. Stimulation of β1 receptors in the kidneys causes renin release. Stimulation of β2 receptors induces smooth muscle relaxation (resulting in vasodilation and bronchodilation, among other effects), induces tremor in skeletal muscle, and increases gluconeogenesis in the liver and skeletal muscle. Stimulation of β3 receptors induces lipolysis. Beta blockers inhibit normal sympathetic actions mediated by epinephrine. The antihypertensive mechanism appears to involve: decreased cardiac output (due to negative ionotropic and chronotropic effects), reduced renal renin release, and an effect on the central nervous system that reduces sympathetic activity. Examples of non-selective agents include Alprenolol, Carteolol, Levobunolol, Mepindolol, Metipranolol, Nadolol, Oxprenolol, Penbutolol, Pindolol, Propranolol, Sotalol and Timolol. Examples of β1 selective agents include Acebutolol, Atenolol, Betaxolol, Bisoprolol, Esmolol, Metoprolol and Nebivolol. Examples of mixed αΐ / β-adrenergic antagonists are Carvedilol, Celiprolol and Labetalol. An example of β2-5βΙβίί ο agent is Butaxamine. The effects Side effects of beta-blockers include changes in insulin response, increased triglyceride levels, facilitation of hypoglycemia, depression, fatigue, and sexual dysfunction.

Calcium channel blockers (CCBs) act by blocking voltage-dependent L-type calcium channels (VGCCs) in the muscle cells of the heart and blood vessels. In this way, CCBs inhibit the effects of pressure mediators such as Ang II and endothelin-1 (ET-1) on vascular smooth muscle by reducing Ca ²⁺ influx (Ruschitzka FT et al. J Cardiovasc Pharmacol., 31 Suppl 2: S5-16, 1998). In the heart, a decrease in calcium availability with each beat results in a decrease in cardiac contractility. In blood vessels, a decrease in calcium results in less contraction of the smooth vascular muscle and thus vasodilation. Different classes of CCBs include dihydropyridines (eg, Amlodipine, Felodipine, Nicardipine, Nifedipine, Nimodipine, Nisoldipine, Nitrendipine, Lacidipine and Lercanidipine, Isradipine, Lercanidipine), Phenalkylamines (eg, Benzamothiazine and Verepylamine) . Side effects of CCBs may include, but are not limited to: dizziness, headache, redness of the face, lower extremity edema, tachycardia, bradycardia, and constipation. Pepstatin is a natural pentapeptide, isolated from actinomycete cultures, that universally inhibits aspartyl protease enzymes with a high inhibitory potency for pepsin and a low inhibitory activity for renin. Pepstatin contains two statin residues, the central of which determines the renin binding affinity for pepstatin by acting as a mimic of the transition state of peptide binding to renin. Based on rat blood pressure measurements, it is suggested that pepstatin affects endogenous and exogenous renin reaction with plasma substrate. In addition to this effect, pepstatin has a mild nonspecific hypotensive action as demonstrated in a nephrectomized rat (Lazar J et al Naunyn Schmiedebergs Arch Pharmacol. 1972; 275 (1): 1 14-8; Oldham AA et al J Hypertens. 1984 Apr; 2 (2): 157-61). The use of antihypertensive drugs is indicated when patients do not respond to lifestyle changes (eg exercise and low salt diet) for a period of three or six months, and in the presence of target organ damage (hypertrophy). ventricular infarction, myocardial ischemia, stroke or hypertensive retinopathy). All patients with systolic blood pressure above 180 mmHg or diastolic blood pressure above 110 mmHg should undergo pharmacological treatment (Report of the Canadian Hypertension Society. Consensus Conference. 3. Pharmacological treatment of essential hypertension. Xan. Med. Assoe J. 149 (3): 575-584,1993). It has been the object of the present invention to increase the ability of commonly used antihypertensive drugs to lower the blood pressure of mammals, particularly humans. Another object of the present invention was to produce a method that allows administration of lower than standard antihypertensive doses without compromising their efficiency. It was also a goal to extend the effect of antihypertensive drugs without increasing their dose.

The objects of the present invention are achieved by a method of treating high blood pressure in mammals, particularly humans, comprising the co-administration of an antihypertensive agent and angiotensin (1-7).

The antihypertensive is selected from a group comprising beta blockers, calcium channel blockers, angiotensin II receptor blockers, ACE inhibitors, diuretics and renin inhibitors.

Beta-blockers are selected from a group comprising Alprenolol, Carteolol, Levobunolol, Mepindolol, Metipranolol, Nadolol, Oxprenolol, Penbutolol, Pindolol, Propranolol, Sotalol, Timolol, Acebutolol, Atenolol, Betaxolol, Bisoprolebol, Metopranolol , Celiprolol, Labetalol and Butaxamine.

Calcium channel blockers are selected from a group comprising Amlodipine, Felodipine, Nicardipine, Nifedipine, Nimodipine, Nisoldipine, Nitrendipine, Lacidipine, Lercanidipine, Isradipine, Lercanidipine, Verapamil, Gallopamil Θ Diltiazem.

Angiotensin II receptor blockers are selected from a group comprising Candesartan, Eprosartan, Irbesartan, Losartan, Olmesartan, Telmisartan and Valsartan.

ACE inhibitors are selected from a group comprising Captopril, Enalapril, Ramipril, Quinapril, Perindopril, Lisinopril, Benazepril, Trandolapril and Fosinopril.

Diuretics are selected from a group comprising chlorothiazides and hydrochlorothiazides, Furosemide, Ethacrinic acid, Torsemide, Bumetanide, Chlortalidone, Epitizide, Indapamide, Metolazone, Triamterena, Amiloride, Spironolactone.

Renin inhibitors are renin antibodies, synthetic derivatives of renin precursor proceeds, pepstatin and angiotensinogen analogues (substrate).

The antihypertensive agent and angiotensin (1-7) are administered orally, inhalation, intramuscular, intravenous, subcutaneous or topical injection or as a device that can be implanted.

Angiotensin (1-7) is administered in a formulation comprising cyclodextrins, cyclodextrin derivatives, liposomes, biodegradable polymers, biodegradable polymer derivatives or mixtures thereof.

The objects of the present invention are also achieved by a kit comprising a pharmaceutical composition containing, in combination or separately, angiotensin (1-7) and an antihypertensive agent, which may be selected from a group comprising beta blockers, calcium channels, angiotensin II receptor blockers, ACE inhibitors and diuretics. The objects of the present invention are also achieved by the use of an antihypertensive agent and angiotensin (1-7) to lower blood pressure in mammals, preferably humans.

The term "co-administration" refers to the combined administration of an antihypertensive and angiotensin (1-7) in mammals, preferably humans, where both are applied simultaneously or within 10 minutes of each other. Application may be by oral, inhalation, intramuscular, intravenous, subcutaneous, or topical injection, or by an implantable device, where the antihypertensive and angiotensin (1-7) may be administered using the same or different forms of application.

The term "antihypertensive" refers to the class of drugs used in medicine and pharmacology to treat hypertension (high blood pressure). There are many classes of hypertensive people who - by various means - act to lower blood pressure.

The term "mean arterial pressure (MAP)" refers to the notional average of an individual's blood pressure. It is defined as the average blood pressure during a single cardiac cycle.

The term "lowering blood pressure" refers to lowering systolic and / or diastolic blood pressure, resulting in a reduction in mean arterial pressure.

The inventors surprisingly found that co-administration of an antihypertensive drug and the heptapeptide angiotensin (1-7) provides a synergistic effect that enhances the ability of conventional antihypertensive drugs to lower mammalian blood pressure. The inventors have also shown that Ang (1-7) is compatible with all commonly used antihypertensive classes including beta blockers, calcium channel blockers, angiotensin II receptor blockers, ACE inhibitors and renin inhibitors. . Surprisingly, the co-administration of, for example, Atenolol with Ang (1-7) extended the effect of this beta blocker from approximately 2h to 24h without increasing its dose.

Another interesting finding was the extended effect of Pepstatin following Ang administration (1-7).

The method according to the present invention will significantly lower the dose of all commonly used antihypertensive classes without compromising their potential for lowering blood pressure. In contrast, this would lead to a reduction in the risk of common, sometimes severe side effects associated with the use of antihypertensive drugs, such as the risk of causing type 2 diabetes by the use of beta blockers, especially in combination with type diuretics. thiazide.

There are, in the prior art, several documents dealing with drug associations for the treatment of hypertension. For example, WO 2004087132 describes compositions and methods for treating hypertension comprising a combination of three classes of antihypertensive drugs, including calcium channel antagonists, ACE inhibitors and diuretics. However, in no document of this nature has angiotensin (1-7) been associated with antihypertensive agents for the treatment of hypertension.

BRIEF DESCRIPTION OF THE FIGURES

FIGURE 1 - Effects of a single dose of Losartan angiotensin II receptor blocker (ARB) co-administered with angiotensin- (1-7) on mean arterial pressure (MAP) of spontaneously hypertensive rats (lower graph). The upper two graphs represent control experiments, ie separate administration of single doses of angiotensin (1-7) or Losartan.

FIGURE 2 - Effect of a single dose of the ACE inhibitor Enalapril, co-administered with angiotensin (1-7), on mean arterial pressure (MAP) of spontaneously hypertensive rats (lower graph). The two charts higher levels represent control experiments, ie separate administration of single doses of angiotensin (1-7) or Enalapril.

FIGURE 3 - Effect of a single dose of Atenolol beta-blocker, co-administered with angiotensin (1-7), on mean arterial pressure (MA P) of spontaneously hypertensive rats (lower graph). The top two graphs represent control experiments, that is, separate administration of single doses of angiotensin (1-7) or Atenolol.

FIGURE 4 - Effect of a daily dose of Atenolol beta-blocker co-administered with angiotensin (1-7) on mean arterial pressure (MAP) of spontaneously hypertensive rats for one week (lower graphs). The two upper pairs of charts represent control experiments, ie separate administration of daily doses of angiotensin (1-7) or Atenolol for one week. Daytime values are shown in the left graphs, and night values are shown in the right graphs. FIGURE 5 - Effect of a daily dose of Atenolol beta-blocker, co-administered with a low dose of angiotensin (1-7), on the mean arterial pressure (MAP) of spontaneously hypertensive rats for one week (lower graphs). The two upper pairs of charts represent control experiments, ie separate administration of low daily doses of angiotensin (1-7) or daily doses of Atenolol for one week. Daytime values are shown in the left graphs, and night values are shown in the right graphs.

FIGURE 6 - Effect of a daily dose of Atenolol beta-blocker, co-administered with angiotensin (1-7), on the mean arterial pressure (MAP) of spontaneously hypertensive rats for four weeks (lower graphs). The two upper pairs of charts represent control experiments, ie separate administration of daily doses of angiotensin (1-7) or Atenolol for four weeks. Daytime values are shown in the left graphs, and night values are shown in the right graphs. FIGURE 7 - Effect of a daily dose of Atenolol beta-blocker, co-administered with angiotensin (1-7), on diastolic blood pressure (DBH) of spontaneously hypertensive rats for four weeks (lower graphs). The two upper pairs of graphs represent control experiments, ie separate administration of daily doses of angiotensin (1-7) or Atenolol for four weeks. Daytime values are shown in the left graphs, and night values are shown in the right graphs.

FIGURE 8 - Effect of a daily dose of Atenolol beta-blocker, co-administered with angiotensin (1-7), on the heart rate (HR) of spontaneously hypertensive rats for four weeks (lower graphs). The two upper pairs of charts represent control experiments, ie separate administration of daily doses of angiotensin (1-7) or Atenolol for four weeks. Daytime values are shown in the left graphs, and night values are shown in the right graphs.

FIGURE 9 - Effect of a single dose of renin inhibitor Pepstatin, co-administered with angiotensin (1-7), on mean arterial pressure (MAP) of hypertensive transgenic mice overexpressing the renin gene [TG (mREN2) 27] (graph bottom). The upper graph represents control experiments, that is, separate administration of single doses of angiotensin (1-7) after delivery (left) and separate administration of single dose pepstatin (Right).

FIGURE 10 - Effects of calcium channel blocker Verapamil alone or co-administered with Ang (1-7) on the vasoconstrictor response of

25 Ang II. Graph A shows the Ang II vasoconstrictor response in conscious Wistar rats treated with Ang (1-7) or excipient. Graph B shows Ang II vasoconstrictor response in animals treated with Verapamil alone or combined with Ang (1-7). Results are presented as mean ± S.E.M. Two-way ANOVA was used.

30 post-test Bonferroni multiple comparisons to compare dose-response curves. The hypertensive effect of Ang II was expressed as modification MAP (mmHg). All statistical analyzes were considered significant when p <0.05. ^*** P <0.001.

DETAILED DESCRIPTION OF TECHNOLOGY

 The present invention will be described on the basis of the following examples in order to illustrate, without limitation, the scope of the invention.

Example 1;

 Drug preparation

Angiotensin (1-7) (Asp-Arg-Val-Tyr-lle-His-Pro, C ^ HeaN ^ On, Bachem) and antihypertensives Atenolol (C ₁₆ H _{22 2} 0 ₃ , Biosynthetic), Losartan ( C ₂₂ H ₂₂ CIKN ₆₀ ), and Enalapril (C ₂₂ H ₂₂ CIKN ₆₀ ) were weighed, diluted and administered within 10 minutes or less. Angiotensin (1-7) was administered in a formulation comprising hydroxypropyl-β-cyclodextrin (HPCD) (C ₄₂ H ₇ o03 ₅ - n (CH ₃ CHOHCH ₂ ), Cerestar).

 Experimental procedure

 Animals used:

 Species: Mice (Rattus norvegicus) Lineage: Spontaneously Hypertensive Mice (SHR)

 Provider Source: CEBIO - Center for Bioterism, Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais.

 Sex and age: Males 12 to 13 weeks (at the time of surgery)

Acclimatization: the animals were acclimatized at least two weeks before the experiments.

Rats were anesthetized with tribromoethanol (0.25 g / kg weight), a 4-6 cm incision was made in the abdomen and a catheter was implanted in the abdominal aorta. After surgery, antibiotics (0.1 ml) were administered intramuscularly, the animals rested for 7-10 days and were then tested for regular circadian cycle for 2-3 days. Drugs were administered orally, in single or daily doses, by gavage in a volume of 0.1 ml / 100 g of animal weight.

 SBP (sitolic blood pressure), DBP (diastolic blood pressure), MBP (mean arterial pressure) and HR (heart rate) data were collected for 10 seconds at 10-minute intervals for the indicated period. The values are given as arithmetic means of the values observed during the 10 second readings. In some analyzes, SBP, DBP, MBP and HR were collected at 12-hour intervals, corresponding to the day and night periods. The values presented for one week and four weeks correspond to the mean subtracted from the values obtained in the corresponding control experiments.

 Example 2

 Co-administration of anqiotensin II receptor blocker (ARB) Losartan and Anq- (1-7) decreases blood pressure

The graphs in FIGURE 1 show the variation in mean arterial pressure (MAP) in spontaneously hypertensive rats following single oral administration of Ang- (1-7) / hydroxypropyl cyclodextrin (HPCD) (149 pg / kg, N = 4) ( top panel), Losartan (1 mg / kg; N = 5) (center panel), or Ang- (1-7) / HPCD + Losartan (N = 5) (bottom panel). The effect of this administration was followed by telemetry for 12h. τ p <0.05 relative to Ang- (1-7) / HPCD; ^* p <0.05 compared to antihypertensive (two-way ANOVA, followed by Bonferroni post-test). Co-administration of Losartan and Ang- (1-7) resulted in a decrease in MAP compared to control experiments.

 Example 3

 Co-administration of ACE inhibitor Enalapril and Ang- (1-7) decreases blood pressure

The graphs in FIGURE 2 show the variation in mean arterial pressure (MAP) in spontaneously hypertensive rats following single oral administration of Ang- (1-7) / HPCD (147 pg / kg, N = 4) (upper panel), Enalapril ( 2 mg / kg; N = 3) (center panel), or Ang- (1-7) / HPCD + Enalapril (N = 4) (lower panel). The effect of this administration was followed by telemetry for 12h. τ p < 0.05 relative to Ang- (1-7) / HPCD; ^* p <0.05 compared to antihypertensive (two-way ANOVA, followed by Bonferroni post-test). Co-administration of Enalapril and Ang- (1-7) resulted in a decrease in MAP compared to control experiments.

 Example 4

 Co-administration of beta-blocker Atenolol and Ang-Q -7) lowers blood pressure

The graphs in FIGURE 3 show the variation in mean arterial pressure (MAP) in spontaneously hypertensive rats following single oral administration of Ang- (1-7) / HPCD (147 g / kg, N = 8) (upper panel), Atenolol ( 3 mg / kg; N = 5) (center panel), or Ang- (1-7) / HPCD + Atenolol (N = 5) (lower panel). The effect of this administration was followed by telemetry for 12h. τ p <0.05 relative to Ang- (1-7) / HPCD; ^* p <0.05 compared to antihypertensive (two-way ANOVA, followed by Bonferroni post-test). Co-administration of Atenolol and Ang- (1-7) resulted in a decrease in MAP compared to control experiments.

 The graphs in FIGURE 4 show the variation in mean arterial pressure (MAP) in spontaneously hypertensive rats during one week of daily oral administration of Ang- (1-7) / HPCD (147 pg / kg, N = 8), Atenolol (3). mg / kg; N = 5), or Ang- (1-7) / HPCD + Atenolol (N = 6). Daytime values are shown in the left graphs, and night effects are shown in the right graphs, τ p <0.05 relative to Ang- (1-7) / HPCD (Two-factor ANOVA, followed by Bonferroni post-test) . Co-administration of Atenolol and Ang- (1-7) resulted in a decrease in MAP compared to control experiments.

The graphs in FIGURE 6 show the variation in mean arterial pressure (MAP) in spontaneously hypertensive rats during four weeks of daily oral administration of Ang- (1-7) / HPCD (30 pg / kg, N = 3), Atenolol (3). mg / kg; N = 5), or Ang- (1-7) / HPCD + Atenolol (N = 6). Daytime values are shown in the left graphs, and night effects are shown in the right graphs, τ p <0.05 relative to Ang- (1-7) / HPCD (Two-factor ANOVA, followed by Bonferroni post-test) . The Administration of Atenolol and Ang- (1-7) resulted in a decrease in MAP compared to control experiments.

 Coadministration of beta-blocker Atenolol and Anq- (1-7) decreases diastolic blood pressure

 The graphs in FIGURE 7 show the variation in diastolic blood pressure (DBH) in spontaneously hypertensive rats during four weeks of daily oral administration of Ang- (1-7) / HPCD (30 pg / kg, N = 3), Atenolol ( 3 mg / kg; N = 5), or Ang- (1-7) / HPCD + Atenolol (N = 5). Daytime values are shown in the graphs on the left, and nighttime effects are shown.

I O shown in the graphs on the right, τ p <0.05 relative to Ang- (1 -7) / HPCD (two-way ANOVA, followed by Bonferroni post-test). Co-administration of Atenolol and Ang- (1-7) resulted in a decrease in PAD compared with control experiments.

 Co-administration of beta-blocker Atenolol and Anq- (1-7) decreases the

15 heart rate

 The graphs in FIGURE 8 show the change in heart rate (HR) in spontaneously hypertensive rats during four weeks of daily oral administration of Ang- (1-7) / HPCD (30 pg / kg, N = 3), Atenolol (3 mg / kg; N = 5), or Ang- (1-7) / HPCD + Atenolol (N = 5). The average of the weekly experimental values 0 is shown in relation to the weekly values of the controls. Daytime values are shown in the left graphs, and night effects are shown in the right graphs, τ p <0.05 relative to Ang- (1-7) / HPCD (Two-factor ANOVA, followed by Bonferroni post-test) . Co-administration of Atenolol and Ang- (1-7) resulted in a decrease in

25 heart rate compared to control experiments.

 Example 5

 Coadministration of renin inhibitor Pepstatin and Anq- (1-7) decreases blood pressure

Lineage: Hypertensive transgenic mice overexpressing the 30 renin gene [TG (mREN2) 27]. Provider Source: CEBIO - Center for Bioterism, Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais.

 Sex and age: Males from 12 to 13 weeks (at the time of surgery). Acclimatization: The animals were housed in individual cages with free access to food and water.

 Systolic (SAP), diastolic (PAD), mean (MAP), and heart rate (HR) were invasively measured. A polyethylene catheter (PE50) was introduced into the left femoral artery to record these cardiovascular parameters via a transducer (MP150, Biopac Systems, Inc.). Another catheter was inserted into the inferior vena cava through the femoral vein for drug injection.

 The graphs in FIGURE 9 show the variation in mean arterial pressure (MAP) in males [TG (mREN2) 27] after single oral administration of Ang- (1-7) / HPCD (30pg / kg, N = 3) 120 minutes after pepstatin (300pg / kg) (lower panel) or 120 min after excipient (N = 3) (upper right graph). The upper left graph shows MAP variation after single administration of pepstatin (N = 3).

 Administration of Ang- (1-7) after pepstatin resulted in a decrease in MAP compared to control experiments.

 Example 6

 Co-administration of Verapamil and Ang- (1-7) calcium channel blocker decreases Anq II vasoconstrictor response

 Bloodline: Normotensive Wistar rats

 Provider source: CEBIO - Bioterismo Center of the Department of

Physiology and Biophysics of the Institute of Biological Sciences of the Federal University of Minas Gerais.

 Sex and age: Males from 12 to 13 weeks (at the time of surgery).

Acclimatization: The animals were housed in individual cages with free access to food and water.

The experiments were carried out on conscious male Wistar rator. Twenty-four hours before, under intraperitoneal anesthesia with 2.5% tribromoethanol (1.0 mL / 0.1 kg), a polyethylene catheter (PE-10 connected to PE-50) was implanted into the abdominal aorta through the femoral artery to measure mean arterial pressure. (MAP). Another catheter was introduced into the femoral vein for intravenous infusions and injections. After recovery from anesthesia, the rats were kept in individual cages with free access to food and water until the end of the experiments. Mean blood pressure was monitored by a strain gauge solid state transducer connected to a computer via a data acquisition system (MP 100; BIOPAC Systems, Inc., Santa Barbara, Calif).

 Ang II vasoconstrictor response was performed by sequential intravenous injection of Ang II (5, 10, 20, 40 ng). A two minute interval was allowed between each Ang II injection. Prior to the Ang II series of injections, rats were treated by intravenous infusion over 20 minutes of: excipient (isotonic saline, 0.9% NaCl); Ang- (1-7) (3 nmol / min); Verapamil (20pg / min); or Ang- (1-7) combined with Verapamil.

 Isolated Ang (1-7) did not modify the Ang II response. Verapamil reduced the Ang II vasoconstrictor response and this effect was enhanced by the co-administration of Ang (1-7) (FIGURE 10).

Claims

Pharmaceutical composition for the treatment of hypertension, characterized in that it comprises, in combination or separately, angiotensin (1-7) or other Mas receptor agonist, an antihypertensive and pharmaceutically acceptable excipients. Pharmaceutical composition for the treatment of hypertension according to Claim 1, characterized in that the antihypertensive agent is selected from a group comprising beta-blockers, calcium channel blockers, angiotensin II receptor blockers, diuretic ACE inhibitors. and renin inhibitors. Pharmaceutical composition for the treatment of hypertension according to claims 1 and 2, characterized in that the beta-blockers are selected from a group comprising Alprenolol, Carteolol, Levobunolol, Mepindolol, Metipranolol, Nadolol, Oxprenolol, Penbutolol, Pindolol, Propranolol. , Sotalol, Timolol, Acebutolol, Atenolol, Betaxolol, Bisoprolol, Esmolol, Metoprolol, Nebivolol, Carvedilol, Celiprolol, Labetalol and Butaxamine. Pharmaceutical composition for the treatment of hypertension according to Claims 1 and 2, characterized in that the calcium channel blockers are selected from a group comprising Amlodipine, Felodipine, Nicardipine, Nifedipine, Nimodipine, Nisoldipine, Nitrendipine, Lacidipine, Lercanidipine. , Isradipine, lercanidipine, Verapamil, Gallopamil and Diltiazem. Pharmaceutical composition for the treatment of hypertension according to claims 1 and 2, characterized in that angiotensin II receptor blockers are selected from a group comprising Candesartan, Eprosartan, Irbesartan, Losartan, Olmesartan, Telmisartan and Valsartan. Pharmaceutical composition for the treatment of hypertension according to claims 1 and 2, characterized in that the ACE inhibitors are selected from a group comprising Captopril, Enalapril, Ramipril, Quinapril, Perindopril, Lisazeopril, Trandolapril and Fosinopril. Pharmaceutical composition for the treatment of hypertension according to claims 1 and 2, characterized in that diuretics are selected from a group comprising chlorothiazides and hydrochlorothiazides such as Furosemide, Ethacrynic acid, Torsemide, Bumetanide, Chlortalidone, Epitizide, Indapamide, Metolazone. , Triamterena, Amiloride, Spironolactone.  Pharmaceutical composition for the treatment of hypertension according to claims 1 and 2, characterized in that the renin inhibitors are renin antibodies, synthetic derivatives of renin precursor proceeds, pepstatin or angiotensinogen analogs. Pharmaceutical composition for the treatment of hypertension according to Claims 1 and 2, characterized in that the antihypertensive agent and angiotensin (1-7) or other receptor agonist are administered orally, by inhalation, intramuscular injection, intravenously. , subcutaneous or topical or as a device that can be implanted. Pharmaceutical composition for the treatment of hypertension according to claim 9, characterized in that the antihypertensive agent and angiotensin (1-7) or other receptor agonist are applied simultaneously or within 10 minutes between one and other.  1 1. Pharmaceutical composition for treating hypertension according to Claims 9 and 10, characterized in that the antihypertensive agent and angiotensin (1-7) or other receptor agonist may be administered using the same or different forms of application. Pharmaceutical composition for the treatment of hypertension according to claims 1 and 2, characterized in that angiotensin (1-7) be administered in a formulation comprising cyclodextrins, cyclodextrin derivatives, liposomes, biodegradable polymers, biodegradable polymer derivatives or mixtures thereof. Use of the pharmaceutical composition for treating hypertension according to claims 1 to 12, characterized in that it is for lowering blood pressure in mammals, preferably humans.