DE4410997A1 - Pharmaceutical preparations and drugs for the prevention and treatment of endothelial dysfunctions - Google Patents

Abstract

The present invention describes the use of compounds which release or transfer nitrogen monoxide, of endogenous nitrogen monoxide formation stimulators, and of guanylate cyclase stimulators for preventing, treating and eliminating endothelial dysfunctions and diseases associated with or caused by said dysfunctions. The invention further describes the use of said compounds for preparing pharmaceutical products for said areas of application.

Description

Field of application of the invention

The present invention relates to the use of nitrogen monoxide releasing agents and / or transmitting compounds, from stimulators of endogenous Nitric oxide formation and stimulators of guanylate cyclase for prevention, Treatment and elimination of endothelial dysfunctions and diseases which caused by or associated with endothelial dysfunction. According to the invention, the provision of pharmaceutical preparations is simultaneous for the named indications.

Known technical background

Organic nitric acid esters such as glycerol trinitrate (GTN) (Murrel, Lancet; 80, 113, 151 (1879)), Pentaerythrityl tetranitrate (PETN) (Risemann et al., Circulation, Vol. XVII, 22 (1958), US Pat. No. 2,370,437), 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, EP-PS 45 076, EP-PS 57 847, EP-PS 59 664, EP-PS 64 194, EP-PS 67 964, EP-PS 143 507, US-PS 3 886 186, US-PS 4 065 488, US-PS 44 17 065, U.S. Patent 4,431,829), Isosorbide Dinitrate (ISDN) (L. Goldberg, Acta Physiolog. Scand. 15, 173 (1948)), propatyl nitrate (M'dard, Mem. Poudres 35; 113 (1953)), trol nitrate (FR-PS 984 523) or Nicorandil (US-PS 4,200,640) and similar compounds Vasodilators, some of which have been primarily used in the indication angina for decades pectoris or ischemic heart disease (IHK) find the widest therapeutic use (Nitrangin®, Pentalong®, Monolong®, Isoket®, Elantan® and others). Comparable and improved pharmacological effectiveness when used in the above Indications show newer organic nitrates such as SPM 3672 (N- [3-nitratopivaloyl] -L-cysteine-ethyl ester) (US Pat. No. 5,284,872) and its derivatives. The use of organic nitrites such as isoamyl nitrite as coronary dilators is also long known (Brunton, Lancet; 97 (1867)). Other nitrogen monoxide releasing agents or -transmitting compounds such as thionitrites, thionitrates, S- Nitrosothiols or nitrosoproteins (Harrison et al., Circulation 87; 1461-1467 (1993))  as well as substituted furoxanes (1,2,5-oxadiazole-2-oxides, furazan-N-oxides) (Feelisch et al., Biochem. Pharmacol. 44; 1149-1157 (1992)) or substituted sydnonimines, in particular Molsidomine (DE-AS 16 95 897, DE-AS 25 32 124, DD-PS 2 44 980) are also considered potent coronary dilators are described. All of these substances are capable of themselves or in Form of their pharmacologically active metabolites, e.g. B. the molsidomine metabolites "SIN 1" and "SIN-1A" (Noack, Nitroglycerin VII, Walter de Gruyter & Co., Berlin 1991, 23-28) as well as their derivatives and structural analogues (Noack and Feelisch, Molecular mechanism of nitrovascular bioactivation; in "Endothelial Mechanisms of Vasomotor Control" (ed. Drexler et al.), Pp. 37-50, Steinkopff Verlag, Darmstadt, F.R.G (1991)), in vivo Liberate or transfer nitric oxide.

The pharmaceutical processing of organic nitrates or nitrites and others Nitrogen monoxide liberating or transferring compounds to pharmaceutical Preparations for the treatment of angina pectoris or ischemic heart disease are generally known. It is carried out in accordance with the pharmaceutical expert in general familiar working methods and rules, whereby the selection of the applicable ones Technologies and pharmaceutical additives used primarily according to the processing agent aimed. Here are questions of its chemical-physical Properties, the chosen form of application, the desired duration of action and the Avoidance of drug-excipient incompatibilities of particular importance. For Medicinal product with the indication angina pectoris or ischemic heart disease is available all the oral, parenteral, sublingual or transdermal application in the form of Tablets, coated tablets, capsules, solutions, sprays or plasters are described (DD-PS 2 93 492, 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, JP application 59/10513 (1982)).

In addition to the long-known applications of nitrosating substances, there is their Use for the treatment and prevention of diseases described their Cause in pathologically increased concentrations of sulfur-containing amino acids in Have body fluids. These disease states, caused by congenital ones or acquired defects in the metabolisin of these amino acids and caused by increased blood and urine concentrations of said amino acids (homocystinuria) are characterized, are summarized under the term homocysteinemia (WO 92/18002).

The anti-ischemic effectiveness of the organic nitrates and the other substance classes mentioned above is explained by hemodynamic effects, in particular a heart-relieving effect, which leads to a reduction in the oxygen consumption of the heart or corrects the mismatch between the O₂ supply and demand at the Chamber of Industry and Commerce. The cause is a preferred expansion of the venous capacity vessels (venous pooling) or reduction in preload and a direct coronary dilatation effect, particularly in the area of coronary stenoses. This may have a positive influence on post-stenotic perfusion (positive steal effect), since the organic nitrates in atherosclerotic vascular areas are obviously more potent than in healthy vascular sections (Kojda et al., Endothelium 1 (Suppl.); Abstr. 299, p. s76 (1993)), especially in the area of coronary stenoses. This purely hemodynamic effect is mediated by radical nitrogen monoxide, NO ·, which is released uniformly from all nitrovasodilators despite the very different chemical structure of the compounds. The bioactivation pathways that ultimately lead to the provision of NO · on site, i.e. in the endothelial cell and smooth muscle cell of the vessel, are very different (Noack and Feelisch, Molecular mechanism of nitrovascular bioactivation; in "Endothelial Mechanisms of Vasomotor Control" (ed. Drexler et al.), Pp. 37-50, Steinkopff Verlag, Darmstadt, FRG (1991)). This could be clarified beyond doubt by direct NO measurement using different techniques in recent years (method Noack et al., Neuroprotocols 1; 133-139 (1992)). NO has a vasodilatory effect by activating the soluble guanylate cyclase. This stimulates the formation of cGMP from GTP. For its part, cGMP leads to various phosphorylation reactions (eg on protein kinases) which require intracellular Ca storage (Karczewski et al., Z. Kardiol. 79 (Suppl. 1): 212 (1990)). The relaxation of the intracellular free Ca ²⁺ level then occurs. It has been known since 1987 that the endothelium derived relaxing factor (EDRF) is identical to NO or a substance containing NO (Palmer et al., Nature, 327: 524-526 (1987), Ignarro et al., Proc. Natl. Acad. Sci. 84; 9265-9269 (1987)) and has an important meaning for local blood circulation.

The endothelial cells form a complete gap in the area of the inner wall of the blood vessels Monolayer. This results in a total surface area for the adult human approx. 800 m² with its own weight, that with 1.5 to 2 kg that of human Liver equivalent. The functions performed by endothelial cells relate to today's Two things: one mechanical and one functional. For one thing, they practice a kind Barrier function with which the penetration of blood components such. B. from Low density lipoproteins (LDL) in the lumen near the wall of the vessel (intima) should be prevented. On the other hand, they have an endocrine function. Comes through different stimuli it for the increased synthesis of bioactive substances such as EDRF / NO and prostaglandin-I₂ (PGI₂), with which the function of the flowing cells (Pohl and Busse, Eur. Heart J .: 11 (Suppl. B) 35-42 (1990)), regional hemodynamics (Furchgott, Circ. Res. 53: 557-573 (1983)) and the structural structure of the vessel wall (Di Corleto, Exp. Cell Res. 153: 167- 172 (1984)) are fundamentally influenced. This explains at the same time that it is at damage to the endothelium, for whatever reason (endothelial damage from  Hypercholestemic anemia (T.J. Verbeuren et al., Circ. Res. 58: 552-564 (1986), Endothelial damage in the post-infarction phase (M.R. Sigreid et al., Circ. 86 (Suppl. 1); 21 (1992)), comes to a pathological influence on the endothelial function, which can have different consequences. This includes a regional vasoconstriction or a Vasospasm and remodeling or growth processes in the vascular wall, which as initial Processes of atherogenesis are considered.

Endothelial dysfunction is generally due to a limitation or loss of characterized by endothelial-mediated physiological vasodilation. At the same time is one Reduction or abolition of the NO-mediated vascular relaxation caused by NO mediated vascular protection and the growth processes suppressed by NO in the Watch intima and media. Endothelial dysfunction is also characterized due to proliferative processes in the vascular wall due to increased mitogenesis, an increased endothelial adhesion and migration of leukocytes and macrophages as well as a increased oxidation of low-density lipoproteins (LDL), which are endothelial-damaging. It is regularly used for pathophysiological conditions in the context of atherosclerosis, Hypertension, hypercholesterolemia, diabetes mellitus and heart failure observed (Creager et al., J. Clin. Invest. 86: 228-234 (1990); Linder et al., Circulation 81: 1762-1769 (1990); Zeiher et al., Circulation 83: 391-401 (1991)). Likewise, hypoxia and low shear forces triggering moments for endothelial dysfunction. It leads u. a. to, that vasoactive substances like acetylcholine or serotonin, which are normally a Cause vasorelaxation because of their direct vasoconstrictive effects on the smooth vascular muscles cause a vasoconstriction, which negatively affects the clinical picture influence (Golino et al., N. Engl. J. Med. 324: 641-648 (1991)). The physiological In endothelial dysfunction, vasomotor regulation is not only disturbed but the opposite. These changes are even more pronounced atherosclerotic remodeling of the inner wall of the vessel (Ludmer et al., N. Engl. J. Med. 315: 1046-1051 (1986)).

The endothelium not only contributes with its autocrine and paracrine activity Keeping the wall of the blood vessel healthy, but also affects the effect exogenous NO-Liberators such as PETN or GTN in that it itself forms EDRF / NO. If you remove the endothelium z. B. mechanically from the arterial wall (at invasive catheter diagnosis or extracorporeally on isolated vascular segments) or Suppressing endothelial NO formation by specific inhibitors, the vasodilatory effect of nitrovasodilators such as GTN or PETN enhanced (buses et al., Cardiovasc. Pharmacol. 14 (Suppl. 11): S81-S85 (1989), Kojda et al., J. Vasc. Res. 29: 151 (1992A)). Pharmacological inhibition of endothelial NO synthesis leads to same effect on coronary veins (Kojda et al., Naunyn-Schmiedeberg Arch. Pharmacol.  346: R35 (1992B)). It is known that the action of calcium channel blockers, especially those of 1,4-dihydropyridine type (DHP's) after removal of the endothelium is weakened (Kojda et al., Bas. Res. Cardiol. 86: 254-256 (1991)). Further Research has shown that these substances are likely to stimulate the endothelial NO formation and release are (Günther et al., Basic Res. Cardiol. 87: 452-460 (1992)). Kinins such as bradykinin also contain their biological activity on the increased endothelial formation and release of EDRF / NO (V.A. Briner et al., At the. J. Physiol. 264: F322-F327 (1993); Kelm et al., Biochem. Biophys. Res. Commun. 154: 236-244 (1988)).

Statement of the invention

Endothelial dysfunctions are more common and pathophysiological today significant cardiovascular diseases such as atherosclerosis. Prevention, treatment and elimination of these dysfunctions and related or diseases caused by them are therefore important therapeutic Necessities.

It has now been found that the use of nitrogen monoxide releasing and / or -transmitting compounds, from stimulators of endogenous nitric oxide formation as well as stimulators of guanylate cyclase, in particular stimulators of soluble Guanylate cyclase, for the prevention, treatment and elimination of endothelial dysfunctions as well as those associated with and / or caused by these dysfunctions Diseases is suitable. These endothelial dysfunctions and diseases are pre-existing all endothelial damage caused by hypercholesterolemia, endothelial damage caused by hypoxia, Endothelial damage from mechanical and chemical noxae, especially during and after drug and mechanical reopening of stenosed vessels e.g. B. after percutaneous transluminal angiography (PTA) and percutaneous transluminal coronary angiography (PTCA), endothelial damage in the post-infarction phase (endothelial dysfunction in Reperfusion), endothelial mediated reocclusion after bypass surgery, Circulatory disorders in peripheral arteries and cardiovascular diseases such as Atherosclerosis, hypertension, including pulmonary and portal hypertension, hypertension Heart disease, diabetic micro- and macroangiopathy, coronary heart disease, Heart failure or other diseases that are causally related to endothelial dysfunction are based.

Nitric oxide releasing and / or transmitting compounds, stimulators of endogenous nitrogen monoxide formation as well as stimulators of guanylate cyclase in the sense  of this invention are, among others, directly or indirectly acting on the guanylate cyclase Compounds, which are understood as indirect stimulators of the guanylate class which stimulators of guanylate cyclase are able to release or their otherwise increase enzyme-effective concentration and / or compared to inhibitors of Guanylate cyclase have an antagonistic effect or their enzyme-effective concentration otherwise humiliate. As indirect stimulators of the guanylate class come under other compounds that are suitable, the endogenous NO formation or -Increase release like calcium channel blockers, especially those from 1,4-dihydropyridine type, for example nifedipine, felodipine, nimodipine, amlodipine and other. The use of connections which endothelial Kinine content are able to increase. Above all, these are stimulators of the kinin receptors such as kinins or substances with an analogous effect, stimulators of endothelial kinin formation and inhibitors of kinin degradation, in particular inhibitors of angiotensin converting Enzymes (ACE inhibitors) such as captopril, enalapril, moexipril, ramipril and related Active ingredients. The use of compounds that are generally effective Develop release and / or transmission of endogenous or exogenous nitrogen monoxide the particularly preferred embodiment of the present invention. Specifically considered upcoming substance classes and compounds are organic nitrates, in particular glycerol trinitrate, pentaerythrityl tetranitrate, isosorbide-5-mononitrate, Isosorbide dinitrate, mannitol hexanitrate, inositol hexanitrate, propatyl nitrate, trol nitrate, Nicorandil newer nitrates like SPM 3672 as well as their physiologically compatible derivatives, organic nitrites such as isoamyl nitrite, thionitrites, thionitrates, S-nitrosothiols such as S-nitroso- N-acetyl-D, L-penicillamine, nitrosoproteins, nitrogen monoxide-liberating furoxane derivatives, nitrogen monoxide-liberating sydnonimine derivatives, especially molsidomine, mesocarb and their analogs, nitrosyl complex compounds, especially iron Nitrosyl compounds such as nitroprusside sodium and nitrogen monoxide itself. Because the Nitrogen monoxide release and / or transfer often in vivo pharmacologically active metabolites, these are basically also suitable in To be used according to the present invention. At the same time, the use of physiologically compatible derivatives of all the compounds mentioned above possible. Mainly common addition compounds, salts or enzymatically or Hydrolytically cleavable compounds such as esters, amides and the like are possible Variations.

The selection of the respective active ingredient is based on general pharmacological Principles and the therapeutic requirements which are familiar to the person skilled in the art. In addition to the desired pharmacological effect, the state of health, the stage of the disease, the physical condition, the known effects and Side effects, contraindications, frequency of treatment, duration of use, Consider drug interactions and parallel drug applications.  

The dosage is given in therapeutic doses based on those in which the respective active ingredients are already used for known indications. The total daily dose can be up to 500 mg depending on the active ingredient. In general daily doses of up to 350 mg will be sufficient. Dosage and dosing interval should be chosen so that therapeutic plasma levels that are as constant as possible are built up. The compounds used according to the invention can be used themselves or as part of a pharmaceutical preparation, as a single active ingredient or in combination with one another or with known cardiovascular therapeutics, for example ACE inhibitors, Antiatherosclerotics, antihypertensives, beta-blockers, cholesterol-lowering agents, diuretics, Calcium antagonists, coronary dilators, lipid-lowering agents, peripheral vasodilators, Platelet aggregation inhibitors or others, also as cardiac / Circulatory therapeutic substances used, combined, their use become.

The provision of galenical preparations takes place according to the pharmaceutical specialist generally familiar procedures and rules, whereby the Selection of the technologies to be used and the pharmaceutical additives used in primarily depends on the active ingredient to be processed. Here are questions of his chemical-physical properties, the chosen form of application, the desired Duration of action, the place of action and the avoidance of drug excipients Incompatibilities of particular importance. It is therefore up to the person skilled in the art on the basis of Known substance and process parameters in a trivial manner pharmaceutical form, excipients and select manufacturing technology. The drug form in question is said to be so be designed to achieve constant therapeutic plasma levels, the contains the respective active ingredient in an amount which makes it possible to add the daily dose Release-controlled systems on 1 to 2 and in other dosage forms on up to 10 Distribute single doses. Continuous application by means of is also suitable Long-term infusion.

According to the invention, the compounds mentioned can be administered orally, intravenously, can be applied parenterally, sublingually or transdermally. The respective pharmaceutical preparation is preferably provided in liquid or solid form. Solutions are suitable for this, especially for the preparation of drops, injections or aerosol sprays, furthermore Suspensions, emulsions, syrups, tablets, film-coated tablets, coated tablets, capsules, pellets, Powders, lozenges, implants, suppositories, creams, gels, ointments, plasters or others transdermal systems.

The pharmaceutical preparations contain customary, galenically usable, organic or inorganic carriers and auxiliaries, which are themselves compared to the respective Active substances are chemically indifferent. Are suitable for this, without being limited to it be water, salt solutions, alcohols, vegetable oils, polyethylene glycols, gelatin, lactose,  Amylose, magnesium stearate, talc, highly disperse silicon dioxide, paraffin, Fatty acid mono- and diglycerides, cellulose derivatives, polyvinyl pyrrolidone and the like. The preparation can be sterilized and, if necessary, with additives such as fillers, Binders, lubricants, mold separators, lubricants, disintegrants, moisturizers, adsorbents or Anti-explosives, preservatives, stabilizers, emulsifiers, Solubilizers, salts to influence the osmotic pressure, buffer solutions, Color, fragrance, aroma or sweeteners can be added. The pharmaceutical professional will based on known substance parameters, a suitable selection to avoid drug Hit excipient incompatibilities.

The invention presented opens up a new therapeutic possibility, pathological situations such as hypoxia, high serum cholesterol, increased Blood pressure, diabetes, post-stenotic reperfusion e.g. B. in myocardial infarction and mechan. and chem. Noxen, u. a. that promote endothelial dysfunction, counteract or Prevent the development of endothelial dysfunction entirely. The therapeutic Use of suitable compounds, regardless of the galenical preparation, therefore allows, for the first time, the prevention and current therapy of cardiac and Vascular diseases of this aetiology, such as and atherosclerosis, for example resulting sequelae. These include coronary artery disease, vascular stenosis and circulatory disorders of the peripheral arteries, micro- and macroangiopathies in the Framework of diabetes mellitus etc. Surprisingly, those marked above show Compounds have an independent endothelial protective effect that is independent of the previously known, especially the purely hemodynamic and anti-ischemic Properties e.g. B. the organic nitrates or their effectiveness in hypercysteinemia, is. Their use can therefore bring these pathological processes to a standstill or even undo them as long as they're not irreversible. It is about this is an unexpected, novel component of action that has not so far was described and was not expected in this form.

The following examples are intended to illustrate the nature and nature of the invention Explain the execution in more detail, but without restricting its scope.  

Embodiments example 1 Experiments on a pharmacological in vivo model (New Zealand rabbit)

Cholesterol feeding is suitable in animal experiments, within weeks to months to create an endothelial dysfunction that allows influences of pharmaceuticals to be investigate and quantify (Jayakody et al., Can. J. Physiol. Pharmacol. 63: 1206- 1209 (1985); Verbeuren et al., Circ. Res. 58: 552-564 (1986); Freiman et al., Circ. Res. 58: 783-789 (1986)).

Groups of 9 female New Zealand rabbits each were fed a standard diet or a cholesterol-enriched (0.75%) diet (40 g / kg / day) over a period of Lined for 15 weeks. Cholesterol feeding led to an increase in plasma levels from 69.8 ± 10.4 to 907.1 ± 85.5 mg / dl and called atherosclerotic lesions in the area of Aorta, which after staining with Sudan IV using computer-assisted laser Scanning technique were quantified. The aortic changes included on Aortic arch an area of 73.3 ± 1.9%, in the thoracic aorta an area of 46.3 ± 2.5% and in the area of the abdominal aorta 49.6 ± 3.5% (Fig. 2, control).

Example 2

The atherosclerotically damaged vessels showed no change on phenylephrine Willingness to contract, the endothelium-mediated vasorelaxation after administration of 1 µM However, acetylcholine was in function in comparison to the controls (standard diet) changed in a way that can best be described as endothelial dysfunction. The segments of the thoracic aorta of the cholesterol-fed animals (+) show one significantly weaker sensitivity to acetylcholine than the aortic segments of the Control animals (Fig. 1). The degree of endothelial dysfunction measured correlated directly with the respective severity of the atherosclerotic lesions (r = 0.67, p <0.0001) (Fig. 3). These data show that an endothelial Dysfunction developed.

Example 3

Two other groups of nine white New Zealand rabbits each received additional Pentaerythrityl tetranitrate (PETN) (6 mg / kg / day), taking the pharmon in the press feed was incorporated. There was one in the animals treated simultaneously with PETN significant reduction in atherosclerotic lesions. The extent of these lesions  was determined in accordance with Example 1. There was a significantly reduced proportion atherosclerotic damage in all parts of the aorta (aortic arch; 58.6 ± 2.1%, Thoracic aorta 34.7 ± 2.0% and abdominal aorta 39.3 ± 3.1%) (Fig. 2).

Example 4

Likewise, there was no significant difference in the maximum after PETN feeding (1 µM acetylcholine) endothelium-mediated relaxation more compared to that with Cholesterol-fed animals (endothelial dysfunction) can be observed so that these Results show a clear protective effect of the nitrovasodilator PETN, since this prevented endothelial dysfunction in the sense of the invention presented here (Fig. 3 and 4, table 1).

The comparison between Figs. 3 and 4 shows that PETN is the extent can reduce atherosclerotic lesions and improve endothelial function. Of the poorer correlation coefficient in the PETN group indicates that PETN also a dissociation of the close relationship between atherosclerotic lesions and leads to endothelial function.

Table 1 shows the influence of PETN (6 mg / kg / day) on the development of the endothelial Dysfunction in the thoracic aorta of New Zealand white rabbits caused by feeding with a cholesterol diet (0.75%; 15 weeks). The potency of the endothelium-dependent vasodilator acetylcholine is expressed as the concentration (in - logM; pD₂ value), which, when given cumulatively, is half the effect of the vasoconstrictor Phenylephrine antagonized (the higher this value, the stronger the effect of Acetylcholine). The maximum dilatation effect is expressed as the percentage of Effect of the vasoconstrictor phenylephrine, which is at the maximum effective concentration was antagonized by acetylcholine (1 µM). The only cholesterol feeding (Control) induced endothelial dysfunction can be recognized by the significantly reduced Potency and maximum potency of acetylcholine (*, p <0.05). At the same time When feeding PETN, the differences can no longer be demonstrated. Furthermore PETN significantly (#, p <0.05) improves the potency of acetylcholine and thus that Endothelial function after cholesterol feeding, while after standard feeding it becomes one there is significant deterioration in endothelial function. Overall, this shows the protective effect of PETN on endothelial function in experimentally induced Atherosclerosis. The absorption and flooding of PETN in the plasma can also be done 24 h after the last feeding of the animals based on the measured concentrations of the Demonstrate metabolites of pentaerythrityl mononitrate (PEMN) in plasma (Fig. 5).  

Table 1

Example 5

A typical tablet has the following composition:

Illustration 1

Development of endothelial dysfunction after feeding white New Zealand rabbits with a cholesterol diet (0.75%; 15 weeks). The vasorelaxing effect is shown of the endothelium-dependent vasodilator acetylcholine, and thus the functionality of the Endothels expressed as a percentage of that at any given concentration remaining pre-contraction triggered by the vasoconstrictor phenylephrine has been.  

Figure 2

Extent of atherosclerotic lesions on the luminal surface of different sections of the Aorta after feeding a cholesterol diet (0.75%; 15 weeks) (without control) and simultaneous administration of PETN (6 mg / kg / day). The atherosclerotic lesions were identified with Sudan IV colored and the percentage of the colored area (based on the total area) with Determined using a computer-assisted laser scanning process. PETN causes one significant reduction in the formation of atherosclerotic lesions (p <0.05).  

Figure 3

Relationship between the extent of atherosclerotic lesions on the luminal surface of Segments of the thoracic aorta after feeding on a cholesterol diet (0.75%; 15 weeks) and the maximum relaxation previously determined in the same segment in each case induced by 1 µM acetylcholine (endothelial function). The larger the area of the lesions, the worse the Relaxation or the endothelial function.  

Figure 4

The same representation as in Fig. 3 after simultaneous feeding of cholesterol and PETN.  

Figure 5

Plasma levels of pentaerythrityl mononitrate in the plasma of white New Zealand rabbits 24 h feed deprivation prior to taking blood, which preceded the acute trial. The Standard food contained pentaerythrityl tetranitrate (150 mg / kg) in both cases and Cholesterol group additionally 0.75% cholesterol. The concentration of Pentaerythrityl mononitrate was after using the plasma samples Gas chromatography / mass spectroscopy determined quantitatively.

Claims (12)

1. Use of nitrogen monoxide releasing and / or transmitting Compounds, stimulators of endogenous nitric oxide formation or Guanylate cyclase stimulators for prevention, treatment and elimination endothelial dysfunctions and associated with these dysfunctions and / or diseases caused by them. 2. Use of nitrogen monoxide releasing and / or transferring compounds, stimulators of endogenous nitrogen monoxide formation or stimulators of guanylate cyclase according to claim 1, characterized in that endothelial dysfunctions and diseases associated therewith and / or caused by them
Endothelial damage caused by hypercholesterolemia, endothelial damage caused by hypoxia, endothelial damage caused by mechanical and chemical noxae, especially during and after medicinal and mechanical reopening of stenosed vessels e.g. Example after percutaneous transluminal angiography (PTA) and percutaneous transluminal coronary angiography (PTCA), endothelial damage in the postinfarct phase (endothelial dysfunction at reperfusion) endothelial-mediated reocclusion after bypass surgery, blood supply disturbances in peripheral arteries, as well as cardiovascular diseases such as atherosclerosis, hypertension, including pulmonary and portal hypertension, hypertensive heart disease, diabetic micro- and macroangiopathy, coronary heart disease, heart failure
are. 3. Use of nitrogen monoxide releasing and / or transmitting Compounds, stimulators of endogenous nitric oxide formation or Guanylate cyclase stimulators according to Claim 1 and 2, characterized in that that the soluble guanylate cyclase is stimulated. 4. Use of nitrogen monoxide releasing and / or transmitting Compounds, stimulators of endogenous nitric oxide formation or Guanylate cyclase stimulators according to Claims 1 to 3, characterized in that that the soluble guanylate cyclase is stimulated directly and / or indirectly.   5. Use of nitrogen monoxide releasing and / or transmitting Compounds, stimulators of endogenous nitric oxide formation or Guanylate cyclase stimulators according to Claims 1 to 4, characterized in that that indirect guanylate cyclase stimulators are compounds which stimulators the guanylate cyclase or their enzyme-effective concentration otherwise increase and / or antagonistic to guanylate cyclase inhibitors act or otherwise lower their enzyme-effective concentration. 6. Use of nitrogen monoxide releasing and / or transferring compounds, stimulators of endogenous nitric oxide formation or stimulators of guanylate cyclase according to claim 1 to 5, characterized in that as indirect stimulators of guanylate cyclase
Calcium channel blockers, especially those of the 1,4-dihydropyridine type,
be used. 7. Use of nitrogen monoxide releasing and / or transmitting Compounds, stimulators of endogenous nitric oxide formation or Guanylate cyclase stimulators according to Claims 1 to 5, characterized in that that nitrogen monoxide releasing and / or transmitting compounds be used. 8. Use of nitrogen monoxide releasing and / or transferring compounds, stimulators of endogenous nitrogen monoxide formation or stimulators of guanylate cyclase according to one or more of claims 1 to 5 and 7, characterized in that nitrogen monoxide releasing and / or transferring compounds
organic nitrates, in particular
Glycerol trinitrate (GTN), pentaerythrityl tetranitrate (PETN), isosorbide 5-mononitrate (ISMN), isosorbide dinitrate (ISDN), mannitol hexanitrate, inositol hexanitrate, propatyl nitrate, tiol nitrate, nicorandil or SPM 3672 as well as their derivatives, physiologically compatible
organic nitrites such as isoamyl nitrite,
Thionitrite,
Thionitrate,
S-nitrosothiols such as S-nitroso-N-acetyl-D, L-penicillamine (SNAP),
Nitrosoproteins,
nitrogen monoxide-liberating furoxane derivatives,
nitrogen monoxide liberating sydnonimine derivatives, in particular
Mesocarb, molsidomine or their pharmacologically active metabolites,
Nitrosyl complex compounds such as
Iron nitrosyl compounds, especially nitroprusside sodium, and
Nitric oxide (NO) itself
are. 9. Use of nitrogen monoxide releasing and / or transmitting Compounds, stimulators of endogenous nitric oxide formation or Guanylate cyclase stimulators according to Claims 1 to 5, characterized in that that are used as indirect stimulators of guanylate cyclase, the increase the endothelial kinine content. 10. Use of nitrogen monoxide releasing and / or transferring compounds, stimulators of endogenous nitrogen monoxide formation or stimulators of guanylate cyclase according to claim 9, characterized in that compounds which increase the endothelial kinine content,
Stimulators of the kinin receptors such as kinins or substances with an analog effect,
Endothelial kinin formation stimulators or
Inhibitors of kinin degradation such as
Inhibitors of the angiotensin converting enzyme
are. 11. Use of nitrogen monoxide releasing and / or transmitting Compounds, stimulators of endogenous nitric oxide formation or Guanylate cyclase stimulators for the manufacture of pharmaceutical preparations for the prevention, treatment and elimination of endothelial dysfunctions as well as with these dysfunctions and / or caused by them Diseases.   12. Use of nitrogen monoxide releasing and / or transmitting compounds, stimulators of endogenous nitrogen monoxide formation or stimulators of guanylate cyclase according to claim 11, characterized in that these compounds with other active substances used for the treatment of cardiovascular diseases, in particular with those from the indication groups of the
ACE inhibitors, antiatherosclerotics, antihypertensives, beta blockers, cholesterol lowering agents, diuretics, calcium channel blockers, coronary dilators, lipid lowering agents, peripheral vasodilators or platelet aggregation inhibitors,
be combined.