WO2012011572A1

WO2012011572A1 - Therapeutic agent for diastolic heart failure

Info

Publication number: WO2012011572A1
Application number: PCT/JP2011/066707
Authority: WO
Inventors: 一博山本; 敏昭真野; 泰史坂田; 洋介大森; 朋義曽我; 朋仁大谷
Original assignee: 国立大学法人大阪大学
Priority date: 2010-07-23
Filing date: 2011-07-22
Publication date: 2012-01-26

Abstract

It has been discovered that carnitine, a derivative thereof or a pharmaceutically acceptable salt thereof is useful as an active ingredient of a prophylactic or therapeutic agent for diastolic heart failure. The present invention is capable of providing a pharmaceutical agent that is effective for prophylaxis or treatment of diastolic heart failure, on which an effective therapeutic method has not been established yet.

Description

Treatment for diastolic heart failure

The present invention relates to a therapeutic agent for diastolic heart failure.

It is estimated that there are more than 2 million heart failure patients in Japan. Heart failure is a leading cause of death in industrialized countries, including Japan, and it reduces the quality of life for patients. Heart failure is categorized as systolic heart failure, in which the left ventricle expands and movement decreases (lower left ventricular ejection fraction), and diastolic heart failure, in which the left ventricle does not expand and left ventricular ejection fraction is maintained. The The ratio of heart failure patients is about 3: 2, and both have a poor prognosis.

複数 Multiple treatments that have a prognostic improvement effect have been revealed for systolic heart failure. Treatment guidelines (see Non-Patent Documents 1 to 3) prepared by the Japanese, American and European Cardiovascular Society have also described some standard treatments, and the prognosis has been improving over the past 20 years. . However, no effective treatment has been established for diastolic heart failure, and life prognosis has not improved over the past 20 years. In addition, since diastolic heart failure is more common among the elderly and women, the proportion of patients in total heart failure is increasing year by year in developed countries, and establishment of a treatment for this condition is urgent.

Patent Document 1 describes a medicine containing acylcarnitine as an active ingredient for the prevention and / or treatment of a disease involving the production of inflammatory cytokines, and is one of the diseases involving the production of inflammatory cytokines. As heart failure is described. However, according to the results of a large-scale clinical trial for contractile heart failure conducted before the filing of Patent Document 1, it has been reported that suppressing inflammatory cytokines is not necessarily effective as a treatment for heart failure ( It is not scientifically supported that the invention described in Patent Document 1 is effective for heart failure.

Patent Document 2 describes that propionyl L-carnitine suppresses left ventricular hypertrophy in end-stage renal disease dialysis patients. However, since diastolic heart failure indicates a pathological condition in which the left ventricle does not dilate as described above, it cannot be inferred from the description in Patent Document 2 that propionyl L-carnitine is effective for diastolic heart failure. .

Non-Patent Document 6 describes the use of L-carnitine for the treatment of diastolic heart failure. However, there is no “foundation for diagnosing heart failure” necessary to determine whether the target patient meets the criteria as a patient with diastolic dysfunction, and how blood pressure and pulse have changed as a result of treatment. Since there is no description about it, it is undeniable that the evaluation index has simply changed due to an antihypertensive action or the like, and that the expanded function has not been changed directly. Therefore, Non-Patent Document 6 cannot be said to scientifically demonstrate that L-carcinin is effective in the treatment of diastolic heart failure.

JP 2006-347935 A JP-T 2009-511619

As described above, an effective treatment method for diastolic heart failure has not yet been established, and early establishment of a treatment method for this disease state is desired. Therefore, an object of the present invention is to provide a medicament effective for the prevention or treatment of diastolic heart failure.

The present invention includes the following inventions in order to solve the above problems.
[1] A preventive or therapeutic drug for diastolic heart failure, comprising carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
[2] A myocardial sclerosis inhibitor comprising carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
[3] A myocardial fibrosis inhibitor comprising carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
[4] A prostacyclin increasing agent comprising carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
[5] The prostacyclin increasing agent according to the above [4], wherein the prostacyclin is a myocardial prostacyclin.
[6] A method for preventing or treating diastolic heart failure, comprising administering an effective amount of carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof to a mammal.
[7] Use of carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof for the manufacture of a preventive or therapeutic agent for diastolic heart failure.
[8] Carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of diastolic heart failure.

According to the present invention, it is possible to provide a preventive or therapeutic agent for diastolic heart failure, for which there has been no effective treatment until now. Carnitine, which is an active ingredient of the present invention, is a compound synthesized in vivo and is already commercially available as a pharmaceutical product for other purposes, so it is very useful in terms of low safety concerns.

It is a figure which shows the free carnitine density | concentration in plasma. It is a figure which shows the free carnitine density | concentration in a heart. It is a figure which shows the Azan-Mallory dyeing | staining image of the left ventricular papillary muscle of the rat of each group. FIG. 3 shows OCTN2 mRNA and protein expression levels in the heart. It is a figure which shows the mRNA and protein expression level of OCTN2 in a kidney. It is a figure which shows the free carnitine excretion rate (FE) in the kidney of a control group and a non-treatment group. It is a figure which shows the measured value of [< ³ > H] proline uptake | capture to a cultured cardiac fibroblast. It is a figure which shows the measured value of 6-keto-PGF1α concentration in the heart. It is a figure which shows the measured value of 6-keto-PGF1α concentration in the culture supernatant of cultured cardiac fibroblasts. It is a figure which shows the mRNA expression level of FADS1 in the heart. It is a figure which shows the mRNA expression level of FADS2 in the heart. It is a figure which shows the mRNA expression level of FADS1 in a cultured cardiac fibroblast. It is a figure which shows the mRNA expression level of FADS2 in a cultured cardiac fibroblast. It is a figure which shows the arachidonic acid (AA) density | concentration measured value in a heart. FIG. 6 is a graph showing measured values of 6-keto-PGF1α concentration in cultured cardiac fibroblasts knocked down by FADS1 or FADS2. It is a figure which shows the AA density | concentration measured value in the cultured cardiac fibroblast which knocked down FADS1 or FADS2.

The present invention provides a preventive or therapeutic agent for diastolic heart failure containing carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof as an active ingredient. The present invention also provides a myocardial sclerosis inhibitor, a myocardial fibrosis inhibitor, and a prostacyclin-increasing agent containing carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

The present inventors conducted comprehensive metabolomic analysis on blood and urine samples collected from diastolic heart failure model rats (Dahl salt-sensitive rats) and control rats. As a result, it was found that L-carnitine was contained in a substance in which various changes were observed, and in the heart tissue of a diastolic heart failure model rat, it was confirmed that the carnitine concentration decreased during the heart failure stage. Accordingly, the present inventors conducted an experiment in which L-carnitine was administered to a diastolic heart failure model rat. As shown in Example 1, L-carnitine was fibrotic to the myocardium accompanied by an increase in myocardial prostacyclin concentration. Based on the suppression, it was found that the myocardial sclerosis was suppressed, and as a result, the onset of diastolic heart failure could be suppressed.

Carnitine or a derivative thereof is not particularly limited as long as it is carnitine, an isomer thereof, or a derivative thereof (for example, a derivative that is converted into carnitine in vivo). Examples thereof include L-carnitine, DL-carnitine, acyl-L-carnitine, acetyl-L-carnitine, propionyl-L-carnitine, carnitine chloride, carnitine orotate and the like.
The pharmaceutically acceptable salt thereof is not particularly limited, and examples thereof include metal salts such as sodium salt and calcium salt, inorganic acid salts such as hydrochloride, carbonate and sulfate, acetate, malate and succinate. And organic acid salts such as Specific examples include DL-carnitine hydrochloride, L-carnitine hydrochloride, L-carnitine fumarate, L-carnitine tartrate, L-carnitine magnesium citrate, N-acetyl-L-carnitine hydrochloride, and the like. .

Carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof used in the present invention is preferably L-carnitine, carnitine chloride, L-carnitine hydrochloride, L-carnitine fumarate, L-carnitine tartrate, acyl-L -Carnitine, acetyl-L-carnitine and propionyl-L-carnitine, more preferably L-carnitine, carnitine chloride, L-carnitine hydrochloride, L-carnitine fumarate and L-carnitine tartrate.

The preventive or therapeutic agent for diastolic heart failure, myocardial sclerosis inhibitor, myocardial fibrosis inhibitor, and prostacyclin-increasing agent of the present invention comprises the above active ingredient, a pharmaceutically acceptable carrier, and an additive as appropriate. It can be formulated. Specifically, oral agents such as tablets, coated tablets, pills, powders, granules, capsules, solutions, suspensions, emulsions, parenterals such as injections, infusions, suppositories, ointments, patches, etc. can do. What is necessary is just to set suitably about the mixture ratio of a carrier or an additive based on the range normally employ | adopted in the pharmaceutical field | area. Carriers or additives that can be blended are not particularly limited. For example, various carriers such as water, physiological saline, other aqueous solvents, aqueous or oily bases, excipients, binders, pH adjusters, disintegrants, absorption Various additives such as an accelerator, a lubricant, a colorant, a corrigent, and a fragrance are included.

Additives that can be mixed into tablets, capsules and the like include binders such as gelatin, corn starch, tragacanth and gum arabic, excipients such as crystalline cellulose, corn starch, gelatin, alginic acid and the like. Leavening agents, lubricants such as magnesium stearate, sweeteners such as sucrose, lactose or saccharin, flavoring agents such as peppermint, red mono oil or cherry. When the dispensing unit form is a capsule, a liquid carrier such as fats and oils can be further contained in the above type of material. Sterile compositions for injection can be formulated according to conventional pharmaceutical practice, such as dissolving or suspending active substances in vehicles such as water for injection, naturally occurring vegetable oils such as sesame oil, coconut oil and the like. As an aqueous liquid for injection, for example, isotonic solutions containing physiological saline, glucose and other adjuvants (for example, D-sorbitol, D-mannitol, sodium chloride, etc.) are used. For example, alcohols (eg, ethanol), polyalcohols (eg, propylene glycol, polyethylene glycol), nonionic surfactants (eg, polysorbate 80 ^™ , HCO-50) and the like may be used in combination. As the oily liquid, for example, sesame oil, soybean oil and the like are used, and they may be used in combination with solubilizing agents such as benzyl benzoate and benzyl alcohol. Buffers (eg, phosphate buffer, sodium acetate buffer), soothing agents (eg, benzalkonium chloride, procaine, etc.), stabilizers (eg, human serum albumin, polyethylene glycol, etc.), storage You may mix | blend with an agent (for example, benzyl alcohol, phenol, etc.), antioxidant, etc.

Since the preparation thus obtained is safe and has low toxicity, for example, it is administered to humans and other mammals (eg, rats, mice, rabbits, sheep, pigs, cows, cats, dogs, monkeys, etc.) By doing so, diastolic heart failure can be effectively prevented or treated.
In addition, prostacyclin can be increased to suppress myocardial fibrosis and to suppress myocardial sclerosis.

The dose varies depending on the patient's condition, symptom, administration method and the like, but in the case of oral administration, for example, generally about 0.01 g to 40 g as an active ingredient per day for a human body weight of about 60 kg, preferably Is about 0.1 to 10 g, more preferably about 0.3 to 4 g. When administered parenterally, the single dose varies depending on the patient's condition, symptom, administration method, etc. For example, in the case of an injection, it is usually about 0.01 to 100 g in a human body weight of 60 kg, for example. It is convenient to administer about 0.1 to 20 g, more preferably about 0.5 to 10 g by intravenous injection. The total daily dose may be a single dose or divided doses.

Hereinafter, the present invention will be described in detail by way of examples, but the present invention is not limited thereto.

[Example 1: Suppression of diastolic dysfunction by administration of carnitine]
1-1 Experimental Method (1) Administration of L-carnitine to a diastolic dysfunction model (Dahl salt-sensitive rats) Male Dahl salt-sensitive rats were bred on a high salt diet (8% NaCl-containing diet) from day 1 of 6 weeks of age. This was used as a model for diastolic dysfunction (reference 1: Doi R, et al. J Hypertens 2000; 18: 111-120. Reference 11: Masuyama T, et al. J Am Coll Cardiol 2000; 36: 2333- 2338). Control group (male Dahl salt-sensitive rats with normal diet (0.3% NaCl-containing diet) continued), no treatment group of diastolic dysfunction model (high salt diet = 8% NaCl-containing diet from day 1 of 6 weeks old) Start), group in which carnitine was administered to the diastolic dysfunction model (in the diastolic dysfunction model, 1% L-carnitine (Wako Pure Chemical Industries, Japan) mixed high-saline diet from 17 weeks of age) (salt content is 8% NaCl It was divided into 3 groups.

(2) Echocardiography and cardiac catheterization SONOS 5500 (Philips Medical System, Inc.) was applied to 20-week-old Dahl salt-sensitive rats under general anesthesia with Ketamine HCl (50 mg / kg, intraperitoneal injection). (Netherlands) was used for echocardiography (see Reference 1).
After echocardiography, a 1.5-Fr high-fidelity, manometer tipped catheter (SPR-407; Millar Instruments, USA) was inserted into the left ventricle from the right carotid artery for cardiac catheterization. In cardiac catheterization, left ventricular end-diastolic pressure, left ventricular relaxation time constant (Tau), and myocardial stiffness constant were measured (Reference 2: Yoshida J, et al. Hypertension 2004; 43: 686-691.).

(3) Collection and storage of blood, urine and organs After cardiac catheterization, urine collection by bladder puncture and blood collection by inferior vena cava puncture were performed, and the urine supernatant and plasma after centrifugation were stored at -80 ° C.
The heart was retroperfused from the aorta, frozen with liquid nitrogen after perfusion with 4 ° C. saline, and stored at −80 ° C. The kidney was perfused with 4 ° C. physiological saline from the abdominal aorta where the proximal and distal portions of the renal artery were blocked by clipping, frozen with liquid nitrogen, and stored at −80 ° C. A part of the heart was fixed with 10% formalin and then embedded in paraffin.

(4) Left ventricular fibrosis area An Azan Mall-stained specimen of the left ventricular papillary muscle level was prepared from a paraffin-embedded heart sample, and the left ventricular fibrosis area was measured (see Reference 1).

(5) Collection and culture of cardiac fibroblasts Cardiac fibroblasts were collected from neonatal Wistar rats on the first day of life (Reference 3: Kinugawa KI, et al. Am J Physiol. 1997; 272: H35). -47.) The collected cardiac fibroblasts were cultured in a 5% CO ₂ incubator using Dulbecco's modified Eagle's medium (DMEM; Invitrogen, USA) containing 10% fetal calf serum (FCS; Invitrogen, USA). . Thereafter, subculture was performed every 48 hours, and cardiac fibroblasts after the second passage were used for the experiment.
The culture medium was replaced with DMEM without FCS 24 hours before introduction of the drug or [ ³ H] proline. Moreover, DMEM without drug introduction was used as a control group for each experiment. The collected cardiac fibroblasts and culture supernatant were stored at −80 ° C.

(6) Measurement of free carnitine concentration Free carnitine concentration in plasma, urine and heart was measured using enzyme cycling method (Reference 4: McGarry JD, Foster DW. Free and esterified carnitine. Radiometric method. In: Bergmeyer J, editors. Methods of analytical analysis. New York, Academic Press; 1981. p. 474-88.).
Renal free carnitine excretion rate (FE) was determined using the following formula (Reference 5: Luci'a Go 'mez-Amores, et al. Pharmaceutical Research. 2003; 20 (8): 1133-1140.) .

(7) Quantitative real-time RT-PCR method RNA was extracted from heart, kidney or cardiac fibroblasts stored at -80 ° C., and reverse transcription reaction was performed using oligo d (T) 16 as a reverse primer to obtain cDNA ( Reference 6: Yamamoto K, et al. Cardiovasc Res. 2000; 46: 421-432.). The cDNA was subjected to RT-PCR using ABI PRISM 7900 HT Sequence Detection System and Software (Applied Biosystems, USA), and the amount of mRNA was measured. GAPDH primers and TaqMan® probes were used as previously described (Ref. 7: Nishikawa N, et al. Cardiovasc Res. 2003; 57: 766-774.). Solute carrier family 22 (organic cation transporter), member 5 (OCTN2), fatty acid desaturase 1 (FADS1), fatty acid desaturase 2 (FADS2), TaqMan Gene Expression Assay (respective assay IDs are Rn00570533_m1, Rn01759794_g1, Rn00580220_m1; RT-PCR was performed using Applied Biosystems, USA. Each mRNA amount was corrected using the GAPDH mRNA amount as an internal control.

(8) Western blotting Using the OCTN2 antibody (Cat. No. ab79964; Abcam, USA), Western blot analysis was performed to evaluate the protein expression level (Reference 8: Sakata Y, et al. Cardiovasc Res 2003). ; 57: 757-765.).

(9) Measurement of [ ³ H] proline incorporation into cultured cardiac fibroblasts [ ³ H] proline incorporation was measured for the purpose of evaluating collagen production in cultured cardiac fibroblasts. Angiotensin II (5 μmol / L; Peptide Institute, Japan), [ ³ H] proline was introduced simultaneously with L-carnitine (30 mmol / L), and liquid scintillation counter (LS 6500; Beckman Coulter, USA) 48 hours after introduction [ ³ H] proline uptake was measured using (Reference 9: Villarreal F, et al. Am J Physiol Cell Physiol. 2009; 296 (5): C1178-C1184.).

(10) 6-keto-prostaglandin F1α (6-keto-PGF1α) concentration measurement 6-keto-PGF1α (stable metabolite of prostacyclin) in the culture supernatant of the heart and cultured cardiac fibroblasts was enzyme immunoassay kit. (Cat. No. 900-004; Assay Design, USA).

(11) AA concentration measurement The AA concentration in the heart and in cultured cardiac fibroblasts was measured by gas chromatography (Reference 10: Metcalfe LD, et al. Anal Chem. 1961; 33: 363-64.).

(12) Knockdown of FADS1 or FADS2 in cultured cardiac fibroblasts For cultured cardiac fibroblasts, siRNAs against FADS1 or FADS2 (Cat. No. SRF27A-2134 and SYD21-325, respectively; both Cosmo Bio, Japan) ) Knocked down FADS1 or FADS2.

(13) Statistical processing The measured values were displayed as an average value ± standard deviation. For testing between multiple groups, one-factor analysis of variance was used, and when a significant difference was observed, analysis was performed using Fisher protected least significant difference as a post hoc test. A P value <0.05 was considered statistically significant.
In the figures and tables, the case where P <0.05 was indicated for the control group, and the case where P <0.05 was indicated for the untreated group or the Angiotensin II group.

1-2 Experimental Results (1) Systolic blood pressure, pulse and weight Table 1 shows the systolic blood pressure, pulse and weight at the age of 19 weeks. In the untreated group (diastolic dysfunction model), the systolic blood pressure and pulse were significantly increased compared with the control group by administration of the 8% high NaCl diet, but in the carnitine group, the systolic blood pressure and pulse were increased by L-carnitine administration. There was no significant effect. There was no difference in body weight among the three groups.

(2) Plasma Free Carnitine Concentration in Heart The free carnitine concentration in plasma is shown in FIG. 1 (a), and the free carnitine concentration in the heart is shown in FIG. 1 (b). As is clear from FIGS. 1 (a) and 1 (b), the free carnitine concentrations in plasma and heart are both decreased in the untreated group (diastolic dysfunction model). Significantly increased. From these results, it was confirmed that the carnitine concentration decreased in the diastolic dysfunction model was improved by administration of L-carnitine.

(3) Echocardiographic examination and cardiac catheter examination Table 2 shows the results of the echocardiographic examination and cardiac catheter examination. As a result of echocardiography, the increase in relative wall thickness was reduced in the carnitine group compared with the untreated group. The other echocardiographic indices showed no change due to L-carnitine administration, and the left ventricular diameter shortening rate was maintained in both the untreated group and the carnitine group.
Lung weight and left ventricular end-diastolic pressure increased significantly in the untreated group, but these increases were not observed in the carnitine group, indicating that the onset of diastolic dysfunction was prevented.
In the carnitine group, there was no change in Tau compared to the untreated group, but the increase in myocardial stiffness constant was reduced, and L-carnitine suppressed diastolic dysfunction by improving myocardial stiffness. It was considered a thing. In addition, an increase in left ventricular weight was also suppressed in the carnitine group compared to the untreated group.
FIG. 2 shows Azan Mall stained images of the heart of each group of rats. The left ventricular fibrosis area was significantly increased in the untreated group, but the increase was suppressed in the carnitine group (see Table 2). L-carnitine was thought to have improved myocardial stiffness constant by inhibiting left ventricular fibrosis.

(4) OCTN2 expression level in heart and kidney OCTN2 mRNA and protein expression levels in heart are shown in FIG. 3 (a), and OCTN2 mRNA and protein expression levels in kidney are shown in FIG. 3 (b). In either case, the upper graph shows the mRNA expression level, and the lower graph shows the protein expression level (western blotting result).
Moreover, the free carnitine excretion rate (FE) in the kidneys of the control group and the untreated group is shown in FIG.
As is apparent from FIGS. 3 (a) and 3 (b), in the untreated group, the expression of OCTN2, which is a specific transporter of free carnitine, decreased at both the mRNA level and the protein level in the untreated group. It was.
Moreover, with the decrease in OCTN2 expression in the kidney, the free carnitine excretion rate (FE) increased in the untreated group (see FIG. 4), which was considered to be the cause of the decrease in blood free carnitine concentration. It was considered that the decrease in OCTN2 expression in the heart tissue and the decrease in blood free carnitine concentration in the untreated group contributed to the decrease in free carnitine concentration in the heart tissue.

(5) the ^{[3 H]} proline incorporation measurements to ^{[3 H]} proline incorporation cultured cardiac fibroblasts to the culture cardiac fibroblasts shown in FIG. As is apparent from FIG. 5, the uptake of [ ³ H] proline increased by administration of angiotensin II was suppressed by the addition of L-carnitine. On the other hand, for unstimulated fibroblasts, L-carnitine did not affect collagen production. From this result, it was considered that L-carnitine suppressed collagen production.

(6) 6-keto-PGF1α concentration The measured value of 6-keto-PGF1α concentration in the heart is shown in FIG. 6 (a), and the measured value of 6-keto-PGF1α concentration in the culture supernatant of cultured cardiac fibroblasts is shown in FIG. This is shown in 6 (b). As is clear from FIG. 6 (a), the 6-keto-PGF1α concentration in the heart was significantly increased in the carnitine group. As is clear from FIG. 6 (b), the 6-keto-PGF1α concentration in the culture supernatant of cultured cardiac fibroblasts was significantly increased by the addition of L-carnitine. From these results, it is considered that an increase in tissue prostacyclin concentration contributes to suppression of cardiac fibrosis, and it is clear that L-carnitine acts directly on fibroblasts to promote prostacyclin production. It was.

(7) FADS1 and FADS2 expression levels in heart and cultured cardiac fibroblasts FIG. 7 (a) shows the FADS1 mRNA expression level in the heart, and FIG. 7 (b) shows the FADS2 mRNA expression level. The FADS1 mRNA expression level in cultured cardiac fibroblasts is shown in FIG. 8 (a), and the FADS2 mRNA expression level is shown in FIG. 8 (b).
Prostacyclin is synthesized in vivo using AA as a precursor. FADS1 and FADS2 are AA synthases.
As is apparent from FIGS. 7 (a) and (b) and FIGS. 8 (a) and (b), both cardiac and cultured cardiac fibroblasts expressed FADS1 and FADS2 upon administration or addition of L-carnitine. increased. This result was thought to contribute to increased prostacyclin production by L-carnitine.
(8) AA Concentration The measured value of AA concentration in the heart is shown in FIG. As is clear from FIG. 9, the AA concentration in the heart increased significantly in the carnitine group.

(9) 6-keto-PGF1α concentration and AA concentration in FADS1 or FADS2 knockdown cells Using cultured cardiac fibroblasts, cultured cardiac fibroblasts knocked down by FADS1, or cultured cardiac fibroblasts knocked down by FADS2 The results of measuring the 6-keto-PGF1α concentration are shown in FIG. 10 (a), and the results of measuring the AA concentration are shown in FIG. 10 (b).
As is clear from FIGS. 10 (a) and (b), when one of FADS1 and FADS2 was knocked down, the increase in 6-keto-PGF1α concentration and the increase in AA concentration due to the addition of L-carnitine were both suppressed. From these results, it was considered that the increase in prostacyclin production by L-carnitine was caused by the enhanced AA synthesis due to the increased expression of FADS1 and FADS2.

The present invention is not limited to the above-described embodiments and examples, and various modifications are possible within the scope shown in the claims, and technical means disclosed in different embodiments are appropriately combined. The obtained embodiment is also included in the technical scope of the present invention. Moreover, all the academic literatures and patent literatures described in this specification are incorporated herein by reference.

Claims

A preventive or therapeutic agent for diastolic heart failure, comprising carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
A myocardial sclerosis inhibitor comprising carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
An inhibitor of myocardial fibrosis, comprising carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
A prostacyclin increasing agent characterized by containing carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
The prostacyclin increasing agent according to claim 4, wherein the prostacyclin is a myocardial prostacyclin.
A method for preventing or treating diastolic heart failure, comprising administering an effective amount of carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof to a mammal.
Use of carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof for the manufacture of a preventive or therapeutic agent for diastolic heart failure.
Carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of diastolic heart failure.