HU220165B - Pharmaceutical preparations for the prevention and treatment of endothelial dysfunction - Google Patents

Description

FIELD OF THE INVENTION The present invention relates to the use of organic nitrate compounds as nitric oxide releasing and / or transporting compounds and as nitric oxide endogenous stimulating agents in the manufacture of a medicament for the treatment and cure of endothelial disorders or diseases associated with endothelial disorders.

Organic nitric acid esters such as glycerol trinitrate (GTN) [Murrel, Chain 80, 113, 151 (1879)], pentaerythrityl tetranitrate (PETN) [Riseman et al., Circulation, XVII. Vol. 22, 1958, US-PS 2 370437], Isosorbide-5-mononitrate (ISMN) (DE-OS 22 21 080, DE-OS 27 51 934, DE-OS 30 28 873, DE-PS 29 03) 927, DE-OS 31 02 947, DE-OS 31 24 410, EPPS 45 076, EP-PS 57 847, EP-PS 59 664, EP-PS 64 194, EP-PS 67 964, EP-PS 143 507, U.S. Pat. No. 3,886,186, U.S. Pat. No. 4,065,488, U.S. Pat. No. 4,417,065, U.S. Pat. No. 4,431,829), Isosorbide Dinitrate (ISDN) [L. Goldberg, Acta Physiolog. Scand. 15, 173 (1948)], propathyl nitrate [Medard, Mem. Poudres 35: 113 (1953)], trnitrate (FR-PS 984 523) or nicorandil (U.S. Pat. No. 4,200,640) and the like are vasodilators and some have been widely used for decades in the treatment of angina pectoris and ischemic heart disease. for use (Nitrangin®, Pentalong®, Monolong; Isoket®, Elantan®, etc.). Newer types of organic nitrates, such as SPM 3672 [N- (3-nitropropivaloyl) -L-cysteine ethyl ester] (US-PS 5,284,872) and their derivatives, show similar and better therapeutic effects in the said indications. The use of organic nitrites such as isoamyl nitrite as coronary vasodilators has long been known (Brunton, Chain 97 (1857)). Other nitric oxide releasing or transporting compounds, such as thionitrites, thionitrates, S-nitrosothiols or nitroso proteins (Harrison et al., Circulation 87: 1461-1467 (1993)) and furoxanes (1,2,5-oxadiazole-2). oxides, furazane N-oxides) [Feelisch et al., Biochem. Pharmacol. 44: 1149-1157 (1992)] or substituted sidnoimines, in particular molydidomine (DE-AS 16 95 897, DE-AS 25 32 124, DD-PS 244 980), have also been reported to be effective coronary vasodilators. These substances, alone or in the form of their pharmacologically active metabolites, such as the "SIN 1" and "SIN-1A" metabolites of molydidomine (Noack, Nitroglycerin VII, Walter de Gruyter & Co., Berlin 1991, 23-28), and their derivatives; their structural analogs [Noack and Feelisch, Molecular mechanism of nitrovascular bioactivation; in "Endothelial Mechanisms of Vasomotor Control," published by Drexler et al., 37-50. (Steinkopff Verlag, Darmstadt, Germany, 1991)] are all capable of in vivo release and transport of nitric oxide.

Galenic processing of organic nitrates or nitrites, and other compounds that release or transmit nitric oxide, into pharmaceutical compositions for the treatment of angina pectoris and ischemic heart disease is well known and is known to those skilled in the art of pharmacology; in doing so, the technology to be used and the choice of the pharmaceutical excipients to be used will depend primarily on the active ingredient to be processed. Of particular importance here is the chemical-physical properties of the active ingredient, the application form, the desired duration of action and the prevention of incompatibility between the active ingredient and the excipient. In particular, oral, parenteral, sublingual or transdermal administration in the form of tablets, dragees, capsules, solutions, sprays or patches have been described for the treatment of angina pectoris and pharmaceutical compositions for the treatment of ischemic heart disease (DD-PS 293 492; DE-AS 26 23 800; DE-OS 33 25 652, DE-OS 33 28 094, DE-PS 40 07 705, DE-OS 40 38 203, 59/10513 (1982)].

In addition to the known use of nitrosating agents for a long time, their use in the treatment and prophylaxis of diseases caused by the abnormal concentration of sulfur-containing amino acids in body fluids has been described. These diseases are caused by congenital or acquired deficiencies in the metabolism of sulfur-containing amino acids, characterized by high levels of these amino acids in the blood and urine (homocystinuria; cystine crystals in urine), collectively referred to as homocysteinemia (WO 92/18).

The effect of organic nitrates and other substance classes mentioned above anti-ischemic hemodynamic effect (related to blood flow), mainly explain the heart relief have the effect of reducing the cardiac oxygen consumption and in case of cardiac ischemia relationship between the O ₂ -készlet and O ₂ -szükséglet adjust the difference. This is due to the expansion of large volume veins (venous pooling), reduction of preload and direct dilation of coronary arteries, particularly in the area of coronary artery stenosis. This is thought to have a positive effect on reduced post-stenosis flow (positive steal effect), since the effect of organic nitrates is more pronounced in atherosclerotic areas, particularly in coronary artery stenosis than in healthy vascular sections [Kojda et al., Endothelium 1 (Suppl. : Abstr. 299, p.76 (1993)] This purely hemodynamic effect is mediated by the nitric oxide radical (NO), which, despite the very different chemical structures of each compound, liberates this radical. however, the pathways of bioactivation at the site of action, i.e., endothelial cell and vascular smooth muscle cell, are very different [Noack and Feelisch, Molecular Mechanism of Nitrovascular Bioactivation; Drexler et al., 37-50, Steinkopff Verlag, Darmstadt, Germany (1991) In recent years, direct NO measurements by various methods have undoubtedly been clarified (Method Noack et al., Neuroprotocols 1: 133-139 (1992)). NO acts as a vasodilator because it activates soluble guanylate cyclase. This stimulates the formation of cGMP from GTP, whereas cGMP (for example on protein kinases)

HU 220 165 Β, which promote intracellular Ca accumulation [Karczewski et al., Z. Kardiol. 79 (Suppl. 1): 212 (1990)]. Through the decrease of free Ca + ⁺ levels in the cell eventually occurs in relaxation. It has been known since 1987 that Endothelium derived relaxing factor (EDRF) is identical to NO or NO-containing material [Palmer et al., Natura, 327: 524-526 (1987); Ignarro et al., Proc. Natl. Acad. Sci. 84: 9265-9269 (1987)] and plays an important role in local blood supply.

Endothelial cells form a continuous monolayer of epidermis on the inner wall of blood vessels. In adult humans, the total surface area of this squamous epithelium is approximately 800 m ² and its weight is 1.5-2 kg, which corresponds to the weight of the liver. To our knowledge, endothelial cells have two functions: mechanical and endocrine. On the one hand, they form a kind of barrier that makes it impossible for blood constituents, such as low-density lipoprotein (LDL), to penetrate into the layer close to the inner vessel wall (Intima). On the other hand, they also have endocrine (endocrine) function. For a variety of triggers, bioactive substances such as EDRF / NO and prostaglandin- ₁₂ (PGI ₂ ), which flow into cells, are progressively produced [Pohl and Busse, Eur. Heart. J: 11 (Suppl. B) 35-42 (1990)], local flow conditions [Furchgott, Circ. Gap. 53: 557-573 (1983)] and the structure of the vessel wall (Di Corleto, Exp. Cell Slit. 153: 167-172 (1984)]. This also provides a good explanation for any endothelial damage [high cholesterol-induced endothelial damage: TJ Verbeuren et al., Circ. Gap. 58: 552-564], [Endothelial damage after infarction: MR Sigreid et al., Circ. 86 (Suppl. 1): 21 (1992)], with abnormal changes in endothelial function, which may have various consequences, such as vasoconstriction, vascular spasms and vascular remodeling and growth processes, which are considered to be the cause of atherosclerosis.

Endothelial dysfunction is generally characterized by loss of endothelial-mediated physiological vasodilation. At the same time, NO-mediated vasoconstriction, NO-mediated vasoconstriction, and NO-suppressed growth processes in the inner and middle layers of the vessel wall are observed. In addition, endothelial dysfunction is characterized by an increased proliferation process in the vascular wall due to increased mitogenesis, increased migration and adhesion of leukocytes and macrophages to endothelium, and increased oxidation of endothelial-damaging low-density lipoproteins (LDLs). This dysfunction is usually observed in pathological conditions associated with atherosclerosis, hypertension, high blood cholesterol, diabetes and heart failure [Creager et al., J. Clin. Invest. 86: 228-234 (1990); Lindner et al., Circulation 81: 1762-1769 (1990); Zeiher et al., Circulation 83: 391-401 (1991). Similarly, hypoxia and low shear forces can cause endothelial dysfunction. Among other things, this normally results in vasoconstriction agents, such as acetylcholine or serotonin, since they act on vascular smooth muscle directly in the direction of vasoconstriction, resulting in vasoconstriction that negatively affects the disease [Golino et al., N. Engl. J. Med., 324: 641-648 (1991)]. Thus, the physiological regulation of coin motility in endothelial dysfunction is not only reversed but reversed. These changes are even more pronounced during the atherosclerotic transformation of the inner vessel wall [Ludmer et al., N. Engl. J. Med. 315: 1046-1051 (1986)].

The autocrine and paracrine activity of the endothelium not only serves to keep the blood vessel wall intact, but also influences the action of exogenously administered NO-releasing agents such as PETN or GTN by forming EDFR / NO itself. If the endothelium is removed mechanically from the artery wall (for example, in the case of intrathecal catheter diagnostics, or in an isolated vessel section outside the body), or NO inhibition of the endothelium is suppressed by special inhibitors, the vasodilator effects of nitro vasodilators such as GTN or PETN are enhanced. et al., Cardiovasc. Pharmacol. 14 (Suppl. 11): S81-S85 (1989); Code et al., J. Vasc. Gap. 29: 151 (1992A)]. Drug suppression of endothelial NO synthesis leads to a similar effect in the venous section of the coronary artery [Koodya et al., NaunynSchmiedeberg Arch. Pharmacol. 346: R35 (1992B)]. It is known that the activity of calcium antagonists, especially of the 1,4-dihydropyridine type calcium antagonists (DHPs), is reduced after removal of the endothelium [Kódja et al., Bas. Cardiol. 86: 254-256 (1991)]. Further studies have shown that these substances are believed to be endothelial NO generation and release promoters [Günther et al., Basic Slit. Cardiol. 87: 542-460 (1992)]. Similarly, the biological activity of quinines, such as bradykinin, is based on enhanced endothelial synthesis and release of EDRF / NO [V. A. Briner et al., Am. J. Physiol. 264: F322-F327 (1993); Keim et al., Biochem. Biophys. Gap. Commun. 154: 236-244 (1988)].

Endothelial dysfunction is today considered to be the cause of common and pathophysiologically significant cardiovascular diseases, including atherosclerosis. Therefore, the prevention, treatment, and eradication of this dysfunction and of the diseases it causes or causes is an important and necessary medical task.

It has been found that compounds that release and / or transfer nitric oxide, endogenous nitric oxide stimulating agents, and guanylate cyclase, particularly soluble guanylate cyclase promoters, are useful in the treatment of endothelial dysfunction and concomitant and / or for the prevention, treatment and eradication of the diseases it causes. These dysfunctions and diseases are mainly: endothelium damaged by high cholesterol in blood, endothelium damaged by hypoxia, endothelium damaged by mechanical and chemical disorders, mainly drug or mechanical reoperation of narrowed blood vessels such as transluminal angiogenic skin

EN 220 165 Β during and after transfluminal coronary angiography (PTCA) and dermal transluminal coronary angiography (PTCA), endothelial damage after infarction (endothelial dysfunction during reflux), endothelial-mediated re-occlusion after bypass surgery, peripheral arterial insufficiency and circulatory disorders such as atherosclerosis, hypertension including pulmonary and portal hypertension, hypertension-related heart disease, diabetic vascular disease, coronary heart disease, cardiac failure and other diseases caused by endothelial dysfunction.

In the context of the present invention, NO-releasing and / or transferring compounds, endogenous NO-stimulating compounds, and guanylate cyclase-promoting compounds are understood to be compounds whose activity is generally based on the release and / or transfer of endogenous or exogenous nitric oxide. These include, in particular, organic nitrates, in particular glycerol trinitrate, pentaerythrityl tetranitrate, isosorbide 5-mononitrate, isosorbide dinitrate, mannitol hexanitrate, inositol hexane nitrate, propathyl nitrate, trolnitrate, nicorandil, and more nitrate. their physiologically acceptable derivatives. Given that NO release and / or transport in vivo is often via activated metabolites, these metabolites (metabolites) are also suitable for the purposes of the present invention. Finally, it is also possible to use physiologically acceptable derivatives of all the above mentioned compounds. Such variations include, in particular, the usual addition compounds, salts, or enzymatically or hydrolytically degradable compounds such as esters, amides, and the like.

The choice of the active ingredient is based on the general medical principles and therapeutic requirements known to those skilled in the art. In addition to the desired therapeutic effect, the subject's health, physical condition, stage of the disease, known effects and side effects, contraindications, frequency and duration of treatment, and compatibility with any other medications that may be taken should be considered.

Administration is in therapeutic doses, which are similar to those in which known active compounds are already used in known applications. The total daily dose may be up to 500 mg, depending on the active ingredient. Generally, a dose greater than 350 mg daily is not required. The dosage and dosage regimen should be chosen so as to maintain a constant level of active substance. The compounds of the present invention may be used alone or as part of a galenic formulation, as a single agent or in combination with other agents, such as known cardiovascular agents such as ACE inhibitors, anti-atherosclerotic agents, antihypertensive agents, cholesterol blockers, reducing agents, diuretics, calcium antagonists, coronary vasodilators, lipid lowering agents, peripheral blood flow enhancers, platelet aggregation inhibitors or other compounds also used in cardiovascular therapy.

The preparation of pharmaceutical compositions is generally known and is carried out by methods known to those skilled in the art of pharmacology; in doing so, the technology to be used and the choice of the pharmaceutical excipients to be used will depend primarily on the active ingredient to be processed. Of particular importance here are the chemical-physical properties of the active ingredient, the form of application, the desired duration of action and the prevention of incompatibility between the active ingredient and the excipient. It is the task of the skilled person to select the pharmaceutical form, excipients and manufacturing technology, having regard to the material and process parameters. Preferably, the dosage form is formulated so that the plasma level of the active ingredient is constant; this requires that the daily dose be divided into 1 or 2 divided doses for delayed release formulations and up to 10 divided doses for other formulations. Continuous dosing (infusion) is also suitable.

The compounds according to the invention can be administered mainly orally, intravenously, parenterally, sublingually or transdermally. The pharmaceutical compositions are preferably in solid or liquid form, for example, in the form of solutions, in particular droplets, injection solutions or aerosol sprays, as well as suspensions, emulsions, syrups, tablets, film-coated tablets, dragees, capsules, pellets, powders, lozenges, implants, , gels, ointments, patches or other forms that are absorbed through the skin.

Pharmaceutical formulations contain conventional, organic or inorganic carriers and excipients which are inert to the active ingredient. Without limitation, the following suitable excipients are listed: water, saline solutions, alcohols, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, highly dispersed silica, paraffin, fatty acid mono-glyceride, and the like. derivatives, polyvinylpyrrolidone and the like. The composition may be sterilized. The composition may further include excipients such as fillers and binders, lubricants, lubricants, disintegrants or anti-disintegrants, wetting agents, adsorbents, preservatives, stabilizers, emulsifiers, solubilizers, osmotic agents, buffer solutions, coloring, perfuming, flavoring or sweetening agents. One of ordinary skill in the art will select materials appropriately based on known material parameters to exclude incompatibility of the active ingredient excipient.

The foregoing invention opens new avenues for controlling and completely reversing endothelial dysfunctional conditions such as hypoxia, high cholesterol, hypertension, diabetes, vasoconstriction (e.g., myocardial infarction, mechanical and chemical), and complete endothelial dysfunction. Regardless of the formulation, therapeutic use of the above compounds for the first time allows the pathophysiologically endothelial-related cardiovascular diseases, such as atherosclerosis and consequent

EN 220 165 Β prevention and current therapy. Pathologically related diseases include, but are not limited to, coronary artery stenosis, vasoconstriction, peripheral arterial circulatory disorders, diabetic vascular disorders, and the like. Surprisingly, the compounds described above have their own endothelial protective activity independent of, for example, the known effects of organic nitrates, mainly against purely hemodynamic and ischemic and hypercysteinemia. The use of the compounds will stop or even reverse the above pathological processes until they become irreversible. This is, therefore, a new, unexpected component of the effect that has not yet been described or expected.

The following examples are intended to illustrate the essence and embodiment of the invention without limiting it.

Execution examples

Pharmacological in vivo experiments (New Zealand rabbit)

Example 1

In animal experiments, cholesterol-rich diets are capable of causing malfunctions in the endothelium over weeks, months, allowing the efficacy and potency of therapeutic agents to be tested [Jayakody et al., Can. J. Physiol. Pharmacol. 63: 1206-1209 (1985); Verbeuren et al., Circ. Gap. 58: 552-564 (1986); Freiman et al., Circ. Gap. 58: 783-789 (1986)].

Two groups of 9-9 female New Zealand rabbits were fed standard diet and cholesterol-rich (0.75%) diet (40 g / kg / day) for 15 weeks. Cholesterol supplementation increased plasma levels from 69.8 ± 10.4 to 907.1 ± 85.5 mg / dL and produced atherosclerotic lesions in the aortic region. Lesions were stained with 35 Danish IV and their area was determined by computer-guided laser scanning. The area of the aortic lesions was 73.3 ± 1.9% in the aortic arch, 46.3 ± 2.5% in the thoracic aorta and 49.6 ± 3.5 in the abdominal aorta. This is shown in the control group (black bar) in Figure 2. (Figure 2 is explained in more detail in Example 3.)

Example 2

Atherosclerotic lesions showed vasoconstriction readily with phenylephrine, but 1 μ, acetylcholine-mediated endothelial-mediated relaxation showed a difference compared to control (standard feed), which is best described by endothelial dysfunction. Segments of the thoracic aorta of cholesterol-fed animals (±) showed significantly lower acetylcholine sensitivity than the control aortic segments (Fig. 1).

Fig. 1 shows the endothelial-dependent vasodilator effect of acetylcholine and thereby the function of the endothelium at the respective concentration of acetylcholine, expressed as a percentage of the remaining phenylephrine-induced contraction.

There was a direct correlation between measured endothelial dysfunction and atherosclerotic lesions (r = 0.67, p <0.0001). Figure 3 shows the relationship between total surface area of lesions in a vascular segment and 1 μΜ acetylcholine-induced relaxation in the same segment after cholesterol diet (0.75%, 15 weeks). It appears that the higher the surface area of the lesions, the worse the endothelial function. These data confirm that cholesterol-rich nutrition damages the endothelium.

Example 3

Two additional groups of 9-9 animals, in addition to cholesterol, received pentaerythritil nitrate at a dose of 6 mg / kg / day which was added to the diet. In animals treated with PETN concomitantly, a significant reduction in atherosclerotic lesions was observed. The area of the lesions was determined as in Example 1. Figure 2 shows the area of lesions observed at different sections of the aorta in animals fed with cholesterol (black bars) and animals treated with PETN 6 mg / kg / day (white bars). Atherosclerotic lesions were stained with Sudan IV dye and the percentage of stained areas (based on total surface area) was determined by computerized laser scanning. PETN administration resulted in a significant (p <0.05) reduction in atherosclerotic lesions (aortic arch: 58.6 ± 2.1%, thoracic aorta: 34.7 ± 2.0%, abdominal aorta: 39.3 ± 3.1%) 4 . example

However, cholesterol-fed animals treated with pentaerythrityl tetranitrate did not show any difference in endothelial-mediated relaxation at the maximum dose (1 μilk acetylcholine), which clearly indicates the positive effect of PETN on the reduces dysfunction. (Figures 3 and 4, Table 1). A comparison of Figures 3 and 4 shows that PETN reduces the area of atherosclerotic lesions and improves endothelial function. The inferior correlation coefficient in the PETN group suggests that

PETN also loosens the close relationship between atherosclerotic lesions and endothelial function.

Table 1

control PETN Standard cholesterol Standard cholesterol Acetylcholine potency [pD ₂ values] 6.91 ± 0.02 6.12 ± 0.05 * 6.62 ± 0.06 # 6.47 ± 0.13 # Maximum vasodilator effect of acetylcholine [%] 84.8 ± 1.2 60.7 ± 8.5 * 74.7 ± 4.9 * 65.0 ± 4.7

HU 220 165 Β

Table 1 shows the effect of PETN (6 mg / kg / day) on the development of endothelial dysfunction in the thoracic aorta of white New Zealand rabbit for a period of 15 weeks (0.75%). The potency of its effect on endothelium-dependent acetylcholine is given as the concentration (in logM, pD2) that antagonized half of the effect of phenyl effin upon co-administration (the higher this value, the better the effect of acetylcholine). The maximal vasodilator effect is expressed as a percentage of the antagonized effect of phenylephrine at a concentration of 1 μΜ acetylcholine. Endothelial dysfunction in cholesterol-fed animals (control) can be recognized by significantly reduced potency and reduced maximal vasodilator activity of acetylcholine (*, p <0.05). There is no difference in the simultaneous administration of PETN. In addition, PETN significantly (#, p <0.05) improves the potency of acetylcholine and consequently poor endothelial function due to cholesterol diet, whereas endothelial function is significantly worse in standard-fed animals. In conclusion, pentaerythrityl tetranitrate has a positive effect on experimentally induced arteriosclerosis. Absorption and plasma levels of PETN could be detected even 24 hours after the last feeding of the animals based on the measured plasma concentration of the metabolite pentaerythrityl mononitrate (PEMN) (Figure 5).

Figure 5 shows the plasma concentration of pentaerythrityl mononitrate in white New Zealand rabbits after 24 hours of fasting. In both cases, the standard feed contained 150 mg / kg of pentaerythrityl tetranitrate and even 0.75% cholesterol for the cholesterol group. Concentrations of pentaerythrityl mononitrate after plasma samples were processed by gas chromatography and concentration.

measured spectroscopically. In the examples below, the abbreviation DAB 10 is Deutsches Represents the 10th edition of the Arzneimittelbuch (German Pharmacopoeia). Example 5 A typical tablet composition is as follows Pentaerythrityl tetranitrate ISIS PHARMA 20 mg lactose DAB 10 137 mg potato starch DAB 10 80 mg gelatine DAB 10 3 mg talc DAB 10 22 mg magnesium stearate DAB 10 5 mg high dispersion silica DAB 10 6 mg

273 mg

Example 6 A tablet containing mg pentaerythrityl trinitrate (PETriN) has the following composition:

PETriN 20 mg lactose DAB 10 137 mg potato starch DAB 10 80 mg gelatine DAB 10 3 mg talc DAB 10 22 mg magnesium stearate DAB 10 5 mg

highly dispersed silica DAB 10 6 mg

273 mg

Example 7 A tablet containing mg pentaerythrityl dinitrate (PEDN) has the following composition:

PETDN 20 mg lactose DAB 10 137 mg potato starch DAB 10 80 mg gelatine DAB 10 3 mg talc DAB 10 22 mg magnesium stearate DAB 10 5 mg high dispersion silica DAB 10 6 mg

273 mg

Example 8 A tablet containing mg erythrityl tetranitrate (ETN) has the following composition:

ETN 20 mg lactose DAB 10 137 mg potato starch DAB 10 80 mg gelatine DAB 10 3 mg talc DAB 10 22 mg magnesium stearate DAB 10 5 mg high dispersion silica DAB 10 6mg

273 mg

Example 9 A tablet containing mg isosorbide mononitrate (ISMN) has the following composition:

ISMN 20 mg lactose DAB 10 137 mg potato starch DAB 10 80 mg gelatine DAB 10 3 mg talc DAB 10 22 mg magnesium stearate DAB 10 5 mg high dispersion silica DAB 10 6 mg

273 mg

Example 10 Tablet containing mg isosorbide dinitrate (ISDN)

letta has the following composition: ISDN 20 mg lactose DAB 10 137 mg potato starch DAB 10 80 mg gelatine DAB 10 3 mg talc DAB 10 22 mg magnesium stearate has a high dispersion DAB 10 5 mg silica Example 11 DAB 10 273 mg

Tablets containing mg pentaerythrityl tetranitrate (PETN) and 40 mg propanolol hydrochloride have the following composition:

HU 220 165 Β

PETN 40 mg propranolol hydrochloride 40 mg lactose 224 mg potato starch 80 mg gelatine 3 mg talc 22 mg magnesium stearate 5 mg highly dispersed silica 6 mg 420 mg

PATENT CLAIMS

Claims (3)

Use of organic nitrate compounds for the preparation of a medicament for the prevention, treatment and cure of endothelial disorders and / or diseases associated with and / or associated with endothelial disorders, which belong to the following group: a) endothelial damage caused by high cholesterol, b) endothelial damage due to hypoxia, (c) drug or mechanical reoperation of endothelial lesions caused by mechanical and chemical damage other than homocysteine, in particular narrowed blood vessels, such as transdermal transluminal angiography (PTA) and transcutaneous coronary angiography (PTCA); d) endothelial damage after infarction (endothelial dysfunction during reflux), (e) endothelial-mediated re-occlusion after bypass surgery, (f) circulatory disorders caused by atherosclerotic lesions of peripheral arteries and atherosclerosis in general, g) hypertension, including pulmonary and portal hypertension, (h) hypertension-related heart disease, (i) micro and macro forms of vascular disorders caused by diabetes, (j) heart failure, other than enzymatic deficiency due to genetic causes, caused or obtained by homocysteinemia and disease caused by it. 2. Glycerol trinitrate (GTN), pentaerythrityl tetranitrate (PETN), isosorbide-5-mononitrate (ISMN), isosorbide dinitrate (ISDN), mannitol hexanitrate, inositol hexanitrate, propathyl nitrate, trnitrate, nicorandil or or the use of physiologically acceptable derivatives thereof for the preparation of a medicament for the prophylaxis, treatment or cure of endothelial disorders and / or diseases associated with and / or associated with endothelial disorders, which belong to the following group: a) endothelial damage caused by high cholesterol, b) endothelial damage due to hypoxia, (c) drug or mechanical reoperation of endothelial lesions caused by mechanical and chemical damage other than homocysteine, in particular narrowed blood vessels, such as transdermal transluminal angiography (PTA) and transcutaneous coronary angiography (PTCA); d) endothelial damage after infarction (endothelial dysfunction during reflux), (e) endothelial-mediated re-occlusion after bypass surgery, (f) circulatory disorders caused by atherosclerotic lesions of peripheral arteries and atherosclerosis in general, g) hypertension, including pulmonary and portal hypertension, (h) hypertension-related heart disease, (i) micro and macro forms of vascular disorders caused by diabetes, (j) heart failure, other than enzymatic deficiency due to genetic causes, caused or obtained by homocysteinemia and disease caused by it. The use according to claim 1 or 2, wherein the compounds are active with other drugs used in the treatment of cardiovascular diseases, preferably ACE inhibitors, antiarterosclerotics, antihypertensives, beta blockers, cholesterol lowering agents, diuretics, calcium antagonists, coronary vasodilators, diluents, peripheral vasodilators, or combinations of agents belonging to the group of inhibitors of platelet aggregation.