JP2003531114A - Use of protein kinase alpha inhibitors - Google Patents

Abstract

  (57) [Summary] The present invention relates to the use of PKIα and / or derivatives thereof for hypotension, as a β-antagonist, and for the manufacture of a medicament for the prevention and / or treatment of diseases in which the β-antagonist can be used. The invention also relates to the use of PKIα inhibitors and / or derivatives thereof as β agonists and for the manufacture of a medicament for the prevention and / or treatment of diseases for which β agonists may be used.

Description

Detailed Description of the Invention

The present invention relates to a protein kinase inhibitor α (PKI-α), use of an inhibitor of the protein kinase inhibitor α, and a screening method for β-agonists and β-antagonists.

[0002] In 1975, the phenomenon of "myocardial stunning" was first reported. It was prolonged after a short period of ischemia caused by coronary artery occlusion,
It means that the characteristic of the myocardium showing reversible myocardial damage, that is, the myocardium does not show the expected contractility. This reversible symptom persists for hours and denies the view generally accepted by experts, that ischemic symptoms of 45 minutes or longer are always accompanied by cardiomyocyte necrosis.

The formation of oxygen radicals, calcium overload, sarcoplasmic reticulum dysfunction, and troponin proteolysis have been discussed as pathogenic mechanisms of "myocardial contractile failure" (Bo
lli; Mechanism of Myocardial "Stunning" Circulation 1990: 723-38; and Wijns, Vatner, Camici. Hibernating Myocardium. New England Journal of
Medicine. 1998. 173-81.). However, neither of these mechanisms is suitable to completely explain the phenomenon (Duncker et al .; Myocardial Stunning R
emaining Questions. Cardiovasc Res 1998; 38; 549-558).

The protein kinase A (hereinafter also referred to as PKA) present in the heart regulates myocardial contraction due to phosphorylation of phospholamban and troponin I, which is regulated by a receptor that is coupled to adenylate cyclase. And is regulated by catecholamines. The enzyme activity is regulated by both protein kinase inhibitor (hereinafter referred to as PKI) and cAMP. Two types of protein kinase inhibitors have been found in the heart: alpha and beta (PKIα and P
KIβ). They act as competitive inhibitors by the Cα and Cβ subunits of active protein kinase A being inhibited. In this case, the α type is 6 more than the β type.
It is more than twice as effective.

The protein kinase inhibitor known in the prior art is the protein kinase inhibitor α (also referred to herein as PKIα). PKIα has a length of 76 amino acids, and the part of the primary sequence essential for inhibitory action seems to be restricted to the amino acid region at positions 14-22. This sequence is 100% identical in humans, pigs, chickens, rats and mice. At the mRNA level, the 5'end of total porcine mRNA shows about 90% sequence homology compared to that of human, mouse, rat and chicken. Recombinant PKIα comprising only amino acids 14 to 22 of the complete PKIα amino acid sequence is cell permeable and Calbiochem (Catalog # 47648).
It is available from 5).

At its 5'end, the porcine cDNA encoding PKIα has a second open reading frame encoding a polypeptide having 9 amino acids, and at its 3'end it contains a number of different poly ( A) -has a signal sequence (gene bank # bankit256111AF132737).

The object of the present invention is to provide new uses of PKIα and PKIα inhibitors.

The object according to the invention is achieved by the use of PKIα and / or its derivatives for lowering blood pressure.

In another aspect of the invention, the object according to the invention is achieved by the use of PKIα and / or its derivatives as β antagonists.

In yet another aspect of the invention, the object is achieved by the use of PKIα and / or a derivative thereof for the manufacture of a medicament for the prevention and / or treatment of diseases in which a β antagonist can be used. .

PK for use in accordance with the invention, comprising the amino acid sequence set forth in SEQ ID NO: 2
Iα may be provided.

In an embodiment of the use according to the invention, PKIα is encoded by a nucleic acid corresponding to the coding sequence of the sequence shown in SEQ ID NO: 1, or a nucleic acid produced therefrom by the degeneracy of the genetic code, or a nucleic acid which hybridizes therewith. It

[0013]   For use according to the invention, PKIα used in truncated form may also be provided.

In a preferred embodiment of the use according to the invention, a PK comprising the amino acids 14 to 22 of the PKIα sequence, in particular the sequence of PKIα according to SEQ ID NO: 1 or SEQ ID NO: 2.
Iα may be provided.

In a particularly preferred embodiment of the use according to the invention, arrhythmias, pulsatile heart syndrome, angina, myocardial infarction, acute myocardial infarction, heart failure, arterial hypertonia, essential and adrenal hypertonia, portal hypertension. , Bleeding from esophageal varices, pheochromocytoma, overdose of sympathomimetics and cholinergic blockers, monoglaucoma, hyperthyroidism, thyrotoxicosis, migraine, essential tremor, motor tremor There is provided PKIα or a derivative thereof for use in treating and / or preventing a disease selected from the group comprising warfare and alcohol withdrawal syndrome.

In another particularly preferred embodiment of the use according to the invention, there is provided PKIα or a derivative thereof for use in post-infarction drug therapy, for the prevention of recurrence and / or as an analgesic.

The object according to the invention is achieved by the use of a PKIα inhibitor or a derivative thereof for increasing blood pressure.

The object in another aspect is achieved by the use of a PKIα inhibitor or a derivative thereof as a β agonist.

In yet another aspect, an object is to treat and / or treat diseases for which β agonists can be used.
Alternatively, it is achieved by the use of a PKIα inhibitor or a derivative thereof for the manufacture of a prophylactic drug.

In a preferred embodiment of the use according to the invention, an inhibitor is provided which affects the transcription of PKIα.

[0021]   A PKIα as described herein may further be provided for use according to the invention.

In another aspect of use according to the invention there is provided a PKIα inhibitor comprising an amino acid sequence selected from the group comprising the sequences of SEQ ID NO: 3 and SEQ ID NO: 4.

In a particularly preferred embodiment of the use according to the invention there is provided a PKIα inhibitor for use in the treatment and / or prophylaxis of a disease selected from the group comprising heart failure, myocardial infarction, chronic and acute heart failure and hypotension. To be done.

In another aspect, the object is according to the invention for screening agents for lowering blood pressure, β antagonists, and / or agents for the treatment and / or prevention of diseases in which β antagonists can be used. A method, wherein the mixture is prepared from a beta receptor, a beta agonist of the beta receptor, and a candidate beta antagonist, and-how the binding behavior of the beta agonist to the beta receptor depends on the use of the candidate beta antagonist Deciding what to change is accomplished by a method comprising:

In an embodiment of the method according to the invention, the altered binding behavior of β agonists to β receptors observed under the influence of a candidate β antagonist is described in β herein.
Compared with the changes in binding behavior of β agonists to β receptors observed under the influence of antagonists.

In a preferred embodiment of the method according to the invention there is provided a β receptor selected from the group comprising β1 and β2 receptors.

In yet another embodiment of the method according to the invention the beta agonist is selected from the group comprising sympathomimetics, in particular noradrenaline, adrenaline, dopamine and dobutamine.

Finally, in a method according to the invention there is provided a beta agonist as described herein.

[0029] An object in yet another aspect is a method for screening a drug for lowering blood pressure, a β agonist and / or a drug for treating and / or preventing a disease for which a β agonist can be used. A transcription system is provided for the beta antagonist, a candidate beta agonist is added to the transcription system, and-determining how transcription for the beta antagonist is altered by the beta agonist. Is achieved by a method comprising:

In a preferred embodiment of the method according to the invention, the alteration in transcription of the β antagonist observed under the influence of the candidate β agonist is of the β antagonist observed under the influence of the β agonist described herein. Compared to transcriptional changes.

In another aspect of the method, there is provided a β antagonist as described herein.

In yet another aspect of the method according to the invention there is provided a beta antagonist obtainable according to one of the methods according to the invention.

The present invention is based on the surprising discovery that PKIα has a negative muscle contractile action, that is, an action of reducing myocardial function. This effect occurs through the inhibition of protein kinase A, which is important for phosphorylation of phospholamban and troponin (so-called β-adrenergic signaling). Due to the negative muscle contractile action of PKIα, myocardial function is inversely improved by inhibition of PKIα, especially in the case of heart failure.

The uses according to the invention are all based on the finding that PKIα has a negative concentration-dependent muscle contractile effect and is involved in β-adrenergic signaling. From the above, in one aspect PKIα may be used for the purpose of lowering blood pressure or producing a medicament. In another aspect, from the above, PKIα can be used as a β antagonist. The latter represents the fact that the action of catecholamines that bind to the β receptor on protein kinase A, which regulates contractility, is attenuated by protein kinase inhibitors, and the latter shows β antagonistic action.

Due to the β-antagonistic action of PKIα, the latter is also suitable for the manufacture of medicaments for which β-antagonists are usually used. In other words, due to the β adrenergic action of PKIα, the latter or its derivatives may be used in place of or in addition to the β antagonists previously used in medicine.
In this case, there is essentially no limitation so that substitution with PKIα or a drug, including the latter, is provided for any drug that contains a β antagonist as the active ingredient of the drug.

Since PKIα is expressed not only in muscle tissue but also in nerve tissue, especially in the brain, PKI
The field of neurophysiological application for Iα and its inhibitors is also within the scope of the invention.
As an example, reference may also be made herein to migraine where a β antagonist is used, which according to the invention may be replaced by PKIα.
To those skilled in the art, in summary, any tissue that expresses PKIα and forms pathological or altered symptoms is treated therapeutically or prophylactically according to the invention with PKIα and its inhibitors. obtain.

A number of advantages are created by the use according to the invention. The use of PKIα and its inhibitors broadly explains the class of pharmaceutically active compounds, in particular to the extent that a completely new class of compounds is introduced into these therapeutically important fields of application. It Moreover, PKIα and its inhibitors also range to the extent that they are produced very early in the β-adrenergic signaling cascade and, as a result, are subject to the undesired downregulation of β-receptors with numerous drawbacks. There are advantages to These benefits are further explained below based on heart failure.

It is believed that heart failure is one of the most serious diseases in developed countries of Western Europe because of its high prevalence (1-1.5%) and morbidity in the adult population and its corresponding High cost (Sharpe, N et al .; Lancet 352 (Suppl. I), 3-7
(1998)). Although a large number of agents have been used to treat it, only a few of these are effective, ie, long term. These are mainly β
Blockers and ACE inhibitors (Cleland, J .; Lancet 352 (Suppl. I), 1-2 (199
8)). In contrast, the more commonly used calcium antagonists (eg adalate-nifedipine) are not well received (Prescrir Int 7 (35), 90-91 (
1998); and Ishibashi, Y et al .; Clin Exp Pharmacol Physiol 26 (5-6), 404-.
10 (1999)). It appears that treatment may increase patient morbidity, especially their acute effects, suggesting caution when these agents are used. In contrast, beta blockers appear to have considerable advantages, especially compared to the morbidity of patients in question. Unfortunately, these drugs act via the so-called down-regulated β1 and β2 receptors and may consequently lose their site of action (Massie, B .; Lancet 352 (Suppl I)). , 29
-33 (1998)). As a result, more and more attempts have been made to discover classes of agents with their site of action on the higher levels of the β-adrenergic signaling cascade. Due to the inhibition of protein kinase A, mainly by intracoronary administration, PKIα, and especially their amino acids 14-22, appear to belong to the desired class of substances.

In this connection, PKIα inhibitors, in particular PKIα inhibitors encoded by the second open reading frame of PKIα (PKIα-I), appear to be particularly advantageous as a result. In each case, if desired, both β-antagonistic and β-agonistic effects may flaunt the advantages of using PKIα and its inhibitors.

The amino acid sequence of PKIα is represented in SEQ ID NO: 1 together with the nucleic acid sequence encoding it and in SEQ ID NO: 2 as the amino acid sequence itself. For the person skilled in the art, in short, PKIα is not limited to PKIα having the sequences represented as the sequences SEQ ID NO: 1 and SEQ ID NO: 2. Rather, PKIα is defined herein as any protein kinase inhibitor that affects the activity of protein kinase A. In this respect, the functional definition is based on the term protein kinase inhibitor below.

Due to the functional definition of the term protein kinase inhibitor as used herein, the nucleic acid sequence shown in SEQ ID NO: 1 is also only one example of a sequence encoding a protein kinase inhibitor. Other sequences result from the degeneracy of the genetic code.

In its native form, the protein kinase inhibitor α has a length of 76 amino acids. In fact, the range of amino acid 14-22 primary sequences involved in the inhibitory effect is broadened so that protein kinase inhibitors, especially the shorter (“truncated”) forms of PKIα, can be used according to the invention. In this case, the use of PKIα, where the sequence is restricted to amino acids 14 to 22 of the complete amino acid sequence, appears to have particular advantages. This shortened PKIα is capable of crossing the membrane, or is membrane permeable, ie it crosses the cell membrane, enters the intracellular space, and into intracellular compartments, especially sarcoplasmic reticulum and protein kinase A. To reach. PKIα and preferably a shortened form and more preferably PKI as shown in SEQ ID NO: 1 or SEQ ID NO: 2
The shortened form, which comprises amino acids 14 to 22 of the complete primary sequence of α, is
It can be administered intraperitoneally or intravenously.

In this case, it is within the skill of the artisan that PKIα may exist in modified form as well as its inhibitor. Such modifications can be carried out, for example, in connection with the need for crude drugs. Other modifications may relate to pharmacological properties and toxicity.

Formulations comprising PKIα or its inhibitors may comprise commonly used herbal adjuvants and ingredients such as pharmaceutically acceptable carriers and buffers.

Β blockers, ie β antagonists, and also PKIα according to the invention
And its derivatives are, for example, 1. Antiarrhythmic drug (cardiac irregularity) 1. Hyperactive heart syndrome 3. Anti-angina drug (angina) 4. 4. Improvements in myocardial infarction (post myocardial infarction drug therapy), prognosis of patients with acute myocardial infarction and prevention of recurrent myocardial infarction. Treatment of heart failure 6. Antihypertensive drugs (arterial hypertonicity, essential and renal hypertonicity) 7. 7. Portal hypertension, bleeding from esophageal varices, 8. Pheochromocytoma (only available after prior alpha inhibition) 9. Overdose of β-sympathomimetics and m-choline receptor enceptor blockers 10. Glaucoma (single glaucoma) 11. 12. Hyperthyreosis and thyroid poisoning It is used as or for the treatment of central nervous diseases such as migraine, and as an analgesic (central sedative) (essential tremor, motor tremor and alcohol withdrawal syndrome).

The use of a PKIα inhibitor according to the invention (hereinafter also referred to as PKIα-I) is
It is based on the surprising finding that Iα has a concentration-dependent, myocardial contractile effect and is involved in β-adrenergic signaling. Given these properties of PKIα, PKIα inhibitors may result in modification and reversal of the action of PKIα. Thus, PKIα inhibitors may be used for increasing blood pressure or in drugs suitable for this purpose. As PKIα inhibitors act on inhibitors of β-adrenergic signal transducers, they themselves act as β-agonists and can therefore be used. This use usually comprises the use for the manufacture of a medicament for the treatment and prophylaxis of diseases in which β agonists can be used, so that PKIα inhibitors have been previously used as medicaments in β. It can be used in addition to agonists. In this case, there is basically no limitation in any case, so that a substitute for any drug containing a β agonist as a pharmaceutically active ingredient can be newly prepared by the PKIα inhibitor.

In this case, the functional definition is based on the term PKIα inhibitor. PKIα
An inhibitor is thus any compound that inhibits the action of PKIα, whereby to what extent PKIα inhibition is carried out, to which class of compounds the PKIα inhibitor may be assigned, and on the basis of this mechanism PKIα It does not matter if the inhibitor exerts its effect.

On the basis, the mechanism by which a PKIα inhibitor can act is the inhibition of PKIα transcription. For example, the gene product of the second open reading frame of the PKIα gene acts in that sense as an inhibitor. In this case, the fact that the gene product of interest may be an activator is the fact that Wang, X. et al .; Mol Pharm 54, 514-524 (
1998). The amino acid sequence of this gene product in humans is Met Trp Ile Phe Gly Ser Asn Asp, and together with the encoding nucleic acid sequence, is recorded as SEQ ID NO: 3 hereinafter.

[0049]   The corresponding sequence in pigs is         Met Trp Ile Phe Val Ser Asn Asp And, together with the encoding nucleic acid sequence, is recorded hereafter as SEQ ID NO: 4.

The difference in amino acid morphology is the substitution of the amino acid sequence at position 5 present in the two human and porcine forms, which is based on the substitution at the nucleic acid level, which results in the second position of the 5th codon. Changes. For the human sequence, glycine is the 5th amino acid, while for the porcine sequence, the latter is valine. The corresponding base substitution is a G (human) to T (pig) change.

It will be clear to the person skilled in the art that modifications from the sequences disclosed in SEQ ID NOs: 3 and 4 are possible and at the same time derivatives derived from said sequences also show an inhibitory effect on PKIα, in particular its transcription.

The β agonists and PKIα inhibitors disclosed herein include: Increased myocardial contraction (desirably in the case of patients with severe heart failure or myocardial infarction (chronic and acute heart failure) 2. Hypotension, may be used for or in.

It will be apparent to the person skilled in the art that the use according to the invention can be utilized within the treatment of diseases to be treated and prevented, in particular in individuals in need of such treatment.

The method according to the invention is used as PKIα, ie as an inhibitor of protein Kinner A, or as an inhibitor thereof, especially in connection with a range of one or more diseases or indications disclosed herein. Can be done. In this case, the method may also be applied starting from a wide range of compounds such that one or more of them having corresponding properties are determined (“screening”). Compounds that are likely to have corresponding properties are also referred to hereinafter as "candidate" compounds.

In a broad aspect, in a method according to the invention for determining or screening compounds having β-antagonistic action, the presenting receptor is present as an isolated molecule, eg in solution or immobilized. Can exist. However, it is also within the scope of the present invention that the receptor is present in biological systems. Such biological system may be an in vitro system or an in vivo system. The typical in vitro system in this case is a translation or transcription system. Typical in vivo in this case
System is a cellular system, such as a cell, in particular a cardiomyocyte or neuron that contains the genetic information for PKIα. However, the cell system may be a cell into which a nucleic acid encoding PKIα or a part thereof or a nucleic acid controlling its expression is preferably introduced using a genetic engineering method. When using in vivo or in vitro systems, the stress-inducing use of PKIα further disclosed herein may be made.

In the method according to the present invention, the effect of the candidate antagonist may also be evaluated based on comparison with the effect of PKIα and its derivatives, as disclosed herein. As a result, quantification of the effects of test compounds can be performed even at very early times in the screening or development of new β antagonists and β agonists. In this case, the method according to the present specification may also provide a β agonist used as described herein.

In a broad aspect, in a method according to the invention for determining or screening compounds having β-agonist action, the presenting β-agonist is present as an isolated molecule, eg in solution or immobilized. Can exist However, it is also within the scope of the present invention that the receptor is present in biological systems. Such biological system may be an in vitro system or an in vivo system. The typical in vitro system in this case is typically a cell-free translation or transcription system. Typical in vivo systems in this case are cellular systems, such as cells, especially cardiomyocytes or neurons, which contain the genetic information for PKIα. However, the cell system may also be a cell into which a nucleic acid encoding a candidate β agonist or a part thereof or a nucleic acid controlling its expression is introduced using a genetic engineering method.

The transcription system for the β antagonist used within the method according to the invention is
In this case, it may be an in vivo system or an in vitro system. Typical in this case in
The in vitro system is a translation or transcription system. Typical in vivo systems in this case are cellular systems, such as cells, especially cardiomyocytes or neurons, which contain the genetic information for PKIα. However, the cell system may be a cell into which a nucleic acid encoding PKIα or a part thereof or a nucleic acid controlling its expression is preferably introduced using a genetic engineering method. When using in vivo or in vitro systems, the stress-inducing use of PKIα further disclosed herein may be made.

It is also within the scope of the method according to the invention that the transcription system for the β-antagonist further comprises a candidate β-agonist or a nucleic acid which encodes it or which regulates its expression. Further, beta antagonists and beta agonists that may be, or may be determined according to one of the methods disclosed and described herein, or as a result thereof are It may also be used within the scope of the method according to the invention.

In the method according to the invention, the effect of the candidate β-agonist further is the change in transcription of the β-antagonist observed under the influence of the candidate β-agonist, and the effect of the β-agonist, as disclosed herein. It may be assessed on the basis of comparison to the changes in transcription of β antagonists observed below. As a result, quantification of the action of test compounds can be performed even at very early times in the screening or development of new β agonists.

The invention is further described in the following figures, in which further features and advantages of the invention are described,
It is further exemplified by the examples and the sequence listing.

[0062] Example Example 1: excised hearts from all six animals Sprague Dawley rats with a body weight of research about 300g of the action of PKIα against heart functioning and rats, and described by Schulze, etc. (Schulze et
al .; Circulation 1990: 959-69). Hemodynamic parameters such as contractility, external heart work (EHW), coronary flow and arterial flow were recorded approximately 15 minutes after antegrade perfusion. Cell-permeable recombinant PKIα
(Amino acids 14 to 22; Calbiochem # 476485) was subsequently administered. The compound was injected directly into the atrial cannula using a motor pump. The infusion rate was continuously adapted to the output (total of arterial and coronary flow) and 0.5
, 1.0, and 2.0 μmol / L perfusate was increased at 5 minute intervals to reach the final PKIα concentration. External heart volume and d under these test conditions
The results for the plot of p / dt _max are shown in FIG.

Infusion of reduced PKIα was markedly reversible, concentration-dependent (maximum 2) of myocardial function.
μmol), which was comparable to the dysfunction observed after short coronary artery occlusion. External heart activity and a decrease in dp / dt _max measurements are
It was significant for all tested concentrations in the paired t-test. Reduced type PKI
Perfusion with α reduced the external cardiac work by 43% and by 53%, dp /
It resulted in diminished left ventricular function, expressed as dt _max .

From these studies it is derived that the reduced form of PKIα is suitable for use in lowering blood pressure and as a novel form or substance class of β antagonists.

Example 2 Cell Culture Studies A protein kinase inhibitor truncated from amino acid positions 14 to 22 was added to cell cultures of cardiomyocytes (eg C9H2 cells available from the American Type Culture Collection). , And protein kinase A activity was determined. A dose-dependent reduction in activity was noted.

A 9 amino acid long PKIα inhibitor (the gene product of the second open reading frame of the human and porcine PKI genes) was added to cardiomyocyte cell cultures,
Then, the expression of PKIα and the activity of protein kinase A were determined. PKIα
An increase in the activity of PKA depending on the dose of inhibitor was noted.

For cell cultures of cardiomyocytes, for example as described by Olsen (Olsen
et al .; Endocrinology 5; 1246-1256 (1991)), was transfected with an expression plasmid having the sequence of PKIα, and the expression of PKIα was determined. At the same time, PK
The activity of protein kinase A, which is specifically inhibited by Iα, was determined (protein kinase A is contained in both striated and smooth muscle cells (Wang, X.
et al .; Mol Pharm 54, 514-524 (1998))). Various concentrations of protein kinase inhibitor alpha inhibitor were added to these cell cultures. The expression of PKIα is PK
It decreased depending on the concentration of Iα.

The disclosures of various references cited herein are incorporated herein by reference.

The features of the invention disclosed in the above detailed description of the invention, the claims and the drawings can be used individually and in any combination for implementing the invention in its various aspects. , And both are important.

[Table 1]

[Table 2]

[Table 3]

[Table 4]

[Table 5]

[Brief description of drawings]

FIG. 1 shows protein kinases A and P in β-adrenergic signaling.
Demonstrate the function of KIα: of the β1 and β2 receptors (β1 and β2AR), which protein kinase A activates through elevation of α, β, and γ-G protein subunits and adenylate cyclase (AC) and cAMP. The signaling cascade is shown in more detail. Protein kinase A may be inhibited by PKIα, which may antagonize the effects of protein kinase A. Protein kinase A phosphorylates, in particular, phospholamban, which may explain its positive muscle contractile action.

FIG. 2. PK, expressed as dp / dt and external cardiac activity (EHW).
Shows a decline in left ventricular function after administration of Iα.

[Sequence list]

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Claims (25)

[Claims] 1. Use of PKIα and / or a derivative thereof for lowering blood pressure. 2. Use of PKIα and / or a derivative thereof as a β antagonist. 3. Use of PKIα and / or a derivative thereof for the manufacture of a medicament for the prevention and / or treatment of diseases for which β antagonists can be used. 4. Use according to any one of claims 1 to 3, characterized in that PKIα comprises the amino acid sequence shown in SEQ ID NO: 2. 5. A nucleic acid encoded by a nucleic acid corresponding to the coding sequence of the sequence shown in SEQ ID NO: 1 or the nucleic acid produced therefrom due to the degeneracy of the genetic code or nucleic acid that hybridizes with it. The use according to any one of 1. 6. The method according to claim 1, wherein PKIα is used in a shortened form.
Use as described in section. 7. Use according to claim 6, wherein PKIα comprises amino acids 14 to 22 of the PKIα sequence, in particular the sequence of PKIα set forth in SEQ ID NO: 1 or SEQ ID NO: 2. 8. PKIα is derived from arrhythmia, pulsatile heart syndrome, angina, myocardial infarction, acute myocardial infarction, heart failure, arterial hypertension, essential and adrenal hypertension, portal hypertension, and esophageal varices. Bleeding, pheochromocytoma, overdose of sympathomimetics and cholinergic blockers, monoglaucoma, hyperthyroidism, thyrotoxicosis, migraine,
Use according to any one of claims 1 to 7 for the treatment and / or prevention of a disease selected from the group comprising essential tremor, motor tremor and alcohol withdrawal syndrome. . 9. Use according to any one of claims 1 to 8, wherein PKIα is used for post-infarction drug therapy, for the prevention of recurrence and / or as an analgesic. 10. Use of a PKIα inhibitor or a derivative thereof for increasing blood pressure. 11. Use of a PKIα inhibitor or a derivative thereof as a β agonist. 12. Use of a PKIα inhibitor or a derivative thereof for the manufacture of a medicament for treating and / or preventing a disease for which a β agonist can be used. 13. The method according to claim 10, wherein the inhibitor affects transcription of PKIα.
Use according to any one of 2. 14. The PKIα is the PKI according to any one of claims 1 to 9.
Use according to any one of claims 10 to 13, which is α. 15. The use according to any one of claims 10-14, wherein the PKIα inhibitor is selected from the group comprising the sequences SEQ ID NO: 3 and SEQ ID NO: 4. 16. A PKIα inhibitor is used for the treatment and / or prophylaxis of a disease selected from the group comprising heart failure, myocardial infarction, chronic and acute heart failure and hypotension. The use according to item 1. 17. A method for screening agents for lowering blood pressure, beta antagonists, and / or agents for the treatment and / or prophylaxis of diseases for which beta antagonists can be used, wherein the mixture is A method prepared from beta receptors, beta agonists of beta receptors, and candidate beta antagonists, and determining to what extent the binding behavior of beta agonists to beta receptors is altered by the use of candidate beta antagonists . 18. The change in the binding behavior of the β agonist to the β receptor observed under the influence of the candidate β antagonist is observed under the influence of the β antagonist according to any one of claims 1 to 9. 18. The method according to claim 17, which is compared with the change in the binding behavior of the β agonist to the β receptor. 19. The method according to claim 17 or 18, wherein the β receptor is selected from the group comprising β1 and β2 receptors. 20. The method according to any one of claims 17 to 19, wherein the β agonist is selected from the group comprising sympathomimetics, in particular noradrenaline, adrenaline, dopamine and dobutamine. . 21. The use according to claim 17-20, wherein the β agonist is the β agonist according to any one of claims 10-16. 22. A method for screening agents for lowering blood pressure, beta agonists and / or agents for the treatment and / or prophylaxis of diseases for which beta agonists can be used, the transcription system comprising: A method provided for a β antagonist, a candidate β agonist is added to the transcription system, and-it is determined to what extent transcription for the β antagonist is altered by the β agonist. 23. The change in transcription of a β antagonist observed under the influence of a candidate β agonist is the β antagonist observed under the influence of a β agonist according to any one of claims 11 to 16. 23. The method of claim 22, which is compared to a transcriptional change. 24. The method according to claim 22 or 23, wherein the β antagonist is according to any one of claims 1-9. 25. The method according to any one of claims 22 to 24, wherein the β antagonist can be obtained according to the method according to claims 17 to 21.