JPH09151134A - Cardiac muscle protective solution - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a myocardial protective fluid capable of protecting hypertrophic myocardium getting easily ischemic or morbid myocardium, enabling safe operation in bloodless visual field without the need of using any local hypothermia, and enabling favorable cardiac function recovery, by combining histidine with a specific compound in specified proportions. SOLUTION: This myocardial protective fluid contains a combination of 90-110 (esp. 100) mM/L of histidine with 0.05-2 (esp. 0.1) mM/L of adenosine. Owing to the combination, the necessary amount of the histidine to be used becomes minimum and production of histamine can be suppressed to a minimum. Besides, it is preferable that the fluid contains glucose serving as the substrate of glycolytic system (9-12mM/L), insulin to raise glucose intake into cells (7.1-121U/L) and lidocaine as a Na channel blocker (60-120mg/L). This fluid is optimum for preserving hypertrophic myocardium, and pref. has its pH at 7.7-7.9.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a cardioplegia solution,
In particular, the present invention relates to a cardioplegia solution suitable for protecting hypertrophic myocardium and myocardium in a pathological state.

[0002]

2. Description of the Related Art Generally, a heart is stopped during an open-heart surgery, and the heart is held by using a cardioplegic solution, and at the same time, an assisting means called a heart-lung machine is used.

The action of this myocardium as a pump is that the energy state in cells and various ions (especially Ca ²⁺ , N
intracellular concentration of a ⁺ , Pi) or intracellular pH, c
It is determined by the affinity of onactile protein for Ca ²⁺ ions. Therefore, in order to protect the myocardium, maintaining a good balance between them is extremely important.

[0004]

However, the central concept of myocardial protection at the present time is to hold the myocardium at an extremely low temperature and suppress its metabolism. In other words, the energy consumption and the accumulation of hydrogen ions (H ⁺ ) and lactate caused by the hydrolysis of ATP that occur during ischemia are minimized to prepare for reperfusion after surgery. Therefore, at the time of open heart surgery, the body temperature is kept low (28 to 30 ° C) by the heart-lung machine.
Local cooling of myocardium (4
It is necessary to carry out (about ° C).

However, in the conventional method of cooling the myocardium with ice, the surgical field of view is narrowed, which hinders the smooth progress of the surgery. Further, since the above-mentioned ice is generally made of lactate Ringer's solution, the heart remains immersed in the lactate solution during the operation. However, it is said that in such a state, the solution diffusing ability during ischemia is high, an imbalance in ion concentration gradient is caused, and an injury upon reperfusion after amplification of ischemia is amplified.

[0006] In recent years, a warm heart surg has been proposed in which, using a warm blood, it is possible to chemically achieve cardiac arrest without creating ischemia and safely perform surgery.
The method called ery is becoming popular. However, this method is very cumbersome, and it is 150-minutes per minute.
Since 200 cc of cardioplegic solution is administered, it is difficult to secure a visual field for surgery, and since the body temperature is not maintained at a low temperature, there is a high risk of causing injury to other organs, particularly brain injury. Not a method.

The present invention has been proposed in order to solve the above-mentioned problems of the prior art, and its purpose is to protect hypertrophic myocardium and pathological myocardium which are vulnerable to ischemia, without using local cooling. Another object of the present invention is to provide a cardioplegic solution that enables safe operation in a bloodless visual field and can obtain good cardiac function recovery.

[0008]

[Means for Solving the Problems] In order to achieve the above-mentioned object, the cardioplegic solution according to claim 1 contains 9 histidine.
0 mM / L to 110 mM / L, adenosine 0.05 m
It is characterized by containing M / L to 2 mM / L.

The cardioplegic solution according to claim 2 contains histidine at 90 mM / L to 110 mM / L and adenosine at 0.05 mM / L to 2 mM / L, and is used for preservation of hypertrophic myocardium. To do.

The invention according to claim 3 is the cardioplegic solution according to claim 1 or 2, wherein glucose serving as a glycolytic substrate is 9 mM / L to 12 mM / L, and glucose is taken up into cells. Insulin to increase the amount of 7I. U. /
L-12I. U. / L and lidocaine, which is a Na channel blocker, in an amount of 60 mg / L to 120 mg / L.

A cardioplegic solution according to a fourth aspect is characterized by containing histidine at 100 mM / L and adenosine at 0.1 mM / L.

The cardioplegic solution according to claim 5 is characterized in that it contains histidine at 100 mM / L and adenosine at 0.1 mM / L and is used for preservation of hypertrophic myocardium.

The cardioplegic solution according to claim 6 is L-Hi.
Stidine was 100 mM / L and KH ₂ PO ₄ was 2.
5 mM / L, the _{KCl 20mM / L, MgSO 4 ·} 7H
₂ O 6 mM / L, NaCl 80 mM / L, CaCl
₂ 0.1 mM / L, Adenosine 0.1 mM
/ L, D-glucose 11 mM / L, Manni
20 mM / L for tol and 100 m for Lidocaine
g / L, NaOH 3.6 mM / L, Insulin 10I. U. / L is contained.

The invention described in claim 7 is the same as claim 1.
The cardioplegic solution according to any one of claims 6 to 6 has a pH of 7.7 to 7.9.

According to the cardioplegic solution having the above-mentioned constitution, by containing a predetermined amount of histidine, intracellular hydrogen ions (H ⁺ ) and lactate are buffered to the outside of the cell. As a result, glycolysis is suppressed by these ions, the glycolysis reaction is promoted, and energy production occurs. Further, by containing a predetermined amount of adenosine, an appropriate dilating action of blood vessels can be obtained.

As a result, good myocardial protection is possible under a wide temperature range of 13 ° C to 37 ° C. In addition, since ice is not required during the operation and blood is not used as the cardioplegia solution, a good visual field can be secured. Furthermore, the administration method is simple, the basic composition is amino acid, and other contents are conventionally used, so that the safety is very high.

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION Embodiments of the cardioplegic solution according to the present invention will be specifically described below. Table 1 shows the composition of the cardioplegia solution in this embodiment.

[0018]

[Table 1] One of the features of the cardioplegic solution in the present embodiment is that adenosine is contained at 0.1 mM / L and histidine, which is a basic amino acid, is contained at 100 mM / L.

The reason for having such a composition is as follows. That is, due to ischemia, the TCA circuit or electron transfer system, which is an aerobic energy production system in cardiomyocytes, is stopped, and along with this, energy production via these systems is also stopped. On the other hand, in the anaerobic myocardial cells, only glycolysis is working, and although it is a small amount, ATP (2
Mol) is produced and reduced nicotinamide adenine
Dinucleotide (nicotinamide ade
Nine dinucleotide (NAD) is reoxidized. However, even in this system,
Accumulation of lactate and hydrogen ion (H ⁺ ) which are the final metabolites in the cell lowers the intracellular pH,
Energy production stops.

The accumulation of cations in such ischemic cardiomyocytes causes cell swelling, enzyme inactivation, and denaturation of myocardial contractile proteins, and buffers these cations in vivo. However, it is known that there are buffers that try to keep the cell environment constant, and amino acids are one of them. Among the amino acids, histidine has a strong buffering effect, and when histidine is administered externally,
The intracellular hydrogen ion (H ⁺ ) is buffered to the outside of the cell along with anion such as lactate. As a result, the glycolysis system is suppressed by these ions, the glycolysis system reaction is promoted, and energy production occurs.

Such administration of histidine has already been performed in B
It has been tried by retchneider et al.
Since histidine is used at a low temperature of 4 ° C, the amount of histidine that passes through the cell membrane is limited, and a relatively large amount of histidine outside the cell is converted to histamine by decarboxylation and affects cells. It was very dangerous. Further, since the cardioplegic solution of Brettchneider et al. Does not contain glucose as a substrate, energy production could not be expected even if the glycolysis was suppressed by administering histidine.

In the cardioplegic solution of the present embodiment, paying attention to these points, and making the amount of histidine effective and the necessary minimum amount, it is possible to suppress the production amount of histamine to an extremely small amount. .

Further, the cardioplegic solution of this embodiment contains glucose as a glycolytic substrate, insulin for increasing glucose uptake into cells, and lidocaine as a Na channel blocker.

Here, the reason why the lidocaine is contained is as follows.
It is as follows. That is, during ischemia, intracellular Na ⁺ is accumulated, and as a result, Na ⁺ / H ⁺ channel or Na ⁺ / Ca ²⁺ channel is activated, and intracellular acidosis is promoted by increase of intracellular H ^+. Alternatively, it causes an increase in intracellular Ca ²⁺ , and an imbalance of these ions causes cytotoxicity. However, when lidocaine is administered, intracellular Na ⁺ accumulation is suppressed, so that the above-mentioned cytotoxicity can be reduced.

The cardioplegic solution of this embodiment contains 0.1 mM / L of adenosine in order to prevent vasodilatory action and decomposition of high-energy phosphate. The reason why adenosine was set to 0.1 mM / L is as follows. That is, as described above, the heart is stopped during the open-heart surgery, and at the same time, an assisting means called a heart-lung machine is used, but during the use of the heart-lung machine, the blood flow in the kidney is not in a physiological state, so Metabolic excretion is greatly delayed. Further, since the perfusion pressure in the heart-lung machine is reduced, the blood flow to other organs such as the brain, liver, and kidney is reduced, and various complications are highly likely to occur after surgery. Therefore, when a large amount (for example, about 5 mM / L) of adenosine is contained in the cardioplegia solution, the blood vessel dilating action is too strong, the blood pressure is significantly lowered, and the period of hypotension is prolonged. Is.

The action and effect of the cardioplegia solution of the present invention will be described below with reference to more specific examples.

Example 1 In this example, by using the cardioplegic solution according to the present invention, lactate and hydrogen ions (H ⁺ ) accumulated in cells can be removed from the cells, and anaerobic metabolism is achieved. This was done to verify that the glycolysis system can be promoted even in the inside.

(Method) 13 hybrid adult dogs (weight 18 to 2)
6 kg) was intubated after pentobarbital (30 mg / kg) intravenous anesthesia, and the heart was removed under respirator control. After performing a median sternotomy, a catheter was inserted and placed from the brachiocephalic artery into the ascending aorta. After collecting blood used for a perfusion device from this catheter, the aorta was blocked, and a myocardial protective solution (30 ml / kg) was injected from the catheter to obtain cardiac arrest. As the cardioplegia solution, the cardioplegic solution (HBS) according to the present invention having the composition shown in Table 2 and the University of Wisconsin (UW) solution were used after being cooled to 4 ° C.

Thereafter, the heart was excised and simply immersed in a storage solution (HBS) containing histidine (4 ° C.) for 24 hours (HBS-24, n = 5) or 30 hours (HBS-).
30, n = 4) Conserved group and University of Wisconsin (U
W) solution stored for 24 hours (4 ° C) in a group (UW-24, n
= 4) and compared the cardiac function between these groups.

Cardiac function was measured 2 hours after reperfusion, and a lower concentration of dobutamine (2 μg / kg / min: DOB) was measured.
-L) and a high concentration of dobutamine (10 μg / kg / mi
The response of the preserved heart to the (n: DOB-H) load was also examined. In addition, as a control for examining the cardiac function of these preserved hearts, three new dogs were used, blood was collected in the same manner as above, the aorta was blocked, and Ringer's solution (K ⁺ : 20 mM was used.
(30 ml / kg, control group) after cardiac arrest,
The heart was removed.

[0031]

[Table 2] Immediately after sewing the left ventricle balloon for cardiac function measurement, blood perfusion was performed with a perfusion device, and cardiac function was evaluated 2 hours later. As the perfusate, Ringer's solution is added to autologous blood to use a perfusate having a hematocrit value adjusted to a range of 20 to 25%.
Albumin was added to keep the oncotic pressure above 300 Osm / L. Glucose 18 as energy substrate
00 mg and at the same time 20 IU regular insulin were also added.

Immediately before the end of preservation, the isolated heart was inserted and fixed with a catheter for perfusion pressure monitoring after reperfusion from the left common carotid artery,
The left subclavian artery and the distal end of the aorta were closed respectively. Then, the mitral valve was excised, the chordae tendineae was excised at the papillary muscle attachment site, and a balloon catheter for cardiac function measurement was inserted into the left ventricle transvaginally and sewn to the mitral valve annulus. Ventt in the left ventricular apex
ube was inserted. The perfusion device is one in which blood ejected by a centrifugal pump passes through a membrane lung and then a heat exchanger, and then is sent from a catheter placed in the ascending aorta to perfuse the heart. The perfusate flowing out from the pulmonary artery was stored again in the reservoir and oxygenated, and then used as the perfusate.

(Details of examination) The cardiac function was measured by increasing the left ventricular balloon volume by 10 ml, and measuring the systolic pressure at each volume.
The diastolic pressure was calculated from the average of every 5 heartbeats. In addition, End-systemic elastance
(Ees) is obtained when the systolic pressure is 70 mmHg
d-systemic pressure-volume
It was determined as the slope of the e relationship ship (ESPVR). In addition, the ventricular volume (equilibrium volume) Vo when the ventricular pressure is zero
Was also obtained from the ESPVR curve. In addition, the end-diastolic volume (Ved) is 15 mmHg in diastolic pressure and the end-systolic volume (V
es) was the value at systolic pressure of 70 mmHg. Furthermore, the stroke volume (SV) was obtained from Ved-Ves, and the left ventricular ejection fraction (EF) was obtained from SV / Ved. Cardiac output (C
O) is SVx heart rate, and pulse pressure is left ventricular diastolic pressure 15 m
It was calculated from the systolic pressure at mHg-the diastolic pressure.

(Result 1 ... Cardiac function after 2 hours of reperfusion) The above-mentioned End-systemic elastance (Ee)
s), as shown in Table 3 and FIG. 1, no significant difference was observed between the groups.

[0035]

[Table 3] Also, the above-mentioned equilibr which is a systolic parameter.
As for the ium volume (Vo), as shown in Table 4 and FIG. 2, no significant difference was observed between the groups.

[0036]

[Table 4] On the other hand, the above-mentioned end-diastolic volume (Ved), which is also a systolic parameter, was measured by HBS as shown in Table 5 and FIG.
UW-24 showed a significantly lower value than -30 and HBS-24.

[0037]

[Table 5] Moreover, as shown in Table 6 and FIG. 4, the cardiac output (CO) was most recovered in HBS-24, and the cardiac output was 0 in 2 cases in HBS-30, but UW -24 was worse, and cardiac output was obtained in only one case.

[0038]

[Table 6] As shown in Table 7, the stroke volume (SV) is
Similar to HBS-24 (11 ± 3.0 ml), HBS-
30 (2 ± 1.0 ml / min) and UW-24 were good in this order. In UW-24, only one case recovered cardiac function.

[0039]

[Table 7] The left ventricular ejection fraction (EF) is as shown in Table 8 and FIG.
Recovery was best with HBS-24, but was significantly reduced with HBS-30, and only one with UW-24 recovered cardiac function.

[0040]

[Table 8] The pulse pressure measured at a diastolic pressure of 15 mmHg is shown in Table 9 and FIG.
HBS-24 is the best and HBS-3
0, significantly better than UW-24.

[Table 9] (Result 2 ... Changes in cardiac function due to dobutamine loading) UW-
At 24, 2 due to low concentration DOB (DOB-L) load
Only the examples reacted, and only 3 cases reacted due to the high concentration of DOB (DOB-H) loading.

The above-mentioned End-systemic elas
For stance (Ees), the results shown in Table 10 and FIG. 7 were obtained.

[0042]

[Table 10] In addition, equilibrium volume (Vo)
Also, the results shown in Table 11 and FIG. 8 were obtained.

[0043]

[Table 11] As shown in FIG. 9, the end-diastolic volume (Ved) was not significantly changed by DOB-L and DOB-H in each group.

The stroke volume (SV) is shown in Table 12 and FIG.
As shown in, the recovery of UW-24 was poor even for DOB-H. On the other hand, in HBS-24, it increased significantly according to the amount of DOB. Also, HBS-30 DO
The response to B was good and was significantly elevated compared to UW-24. No significant difference was observed between HBS-30 and HBS-24.

[0045]

[Table 12] In addition, the cardiac output (CO) is, as shown in FIG.
In W-24, 329 ± 150m due to the load of DOB-H
increased to 1 / min. With no DOB load,
Although HBS-30 was significantly lower than HBS-24, cardiac output was observed in all cases due to DOB loading, CO in both groups was elevated, and no significant difference was observed between the groups.

The left ventricular ejection fraction (EF) is shown in Table 13 and FIG.
As shown in, both HBS-30 and HBS-24 are DO
The response to B was good and no significant difference was observed between the two groups.

[0047]

[Table 13] As for the pulse pressure measured at a diastolic pressure of 15 mmHg, as shown in FIG. 13, both HBS-30 and HBS-24 showed a good response to DOB, and no significant difference was observed between the two groups.

(Discussion) As described above, the cardioplegic solution of the present invention was stored for 24 hours in HBS or 30 hours.
In the myocardium after storage for a long time, better cardiac function recovery than that of UW solution was obtained. In the HBS-preserved heart, at the time of 2 hours of reperfusion, the 24-hour preservation group showed significantly better functional recovery than the 30-hour preservation group. However, even in the 30-hour storage group, the reactivity to dopamine was good and 2
It showed almost the same cardiac function as the 4-hour preservation group, and the possibility of preservation for 24 hours or longer was confirmed.

[Embodiment 2] In this embodiment, the cardioplegic solution according to the present invention is used as a cardioplegic solution for hypertrophic myocardium.

In general, a hemodynamic ove
Left ventricular hypertrophic heart caused by rload (clinically, congenital heart disease, acquired valve disease, or hypertrophic cardiomyopathy)
Is vulnerable to ischemia, which is mainly intracellular calcium ((Ca
²⁺ ) i) It is considered to be related to changes in regulatory ability and changes in the energy substrate used.

First, intracellular calcium ((Ca ²⁺ ) i
) Explain the change in adjustability. That is, (Ca
²⁺ ) i is important for cardiomyocyte contraction, but it is mainly a voltage-dependent Ca ²⁺ channel in the cell membrane,
sarcoplastic reticulum (S
R) Ca ²⁺ channel (ryanodine r)
regulated by the eceptors). And
Normally, Ca ²⁺ channels in SR play an important role in Ca ²⁺ regulation, but in hypertrophic myocardium, vo
It is largely dependent on the lage-dependent Ca ²⁺ channel.

Further, even during ischemia, energy is used for the regulation of ions inside and outside the cell. Therefore, when the energy supply from the glycolytic system is stopped, the ion distribution collapses (particularly,
Ca ²⁺ , Na ⁺ ), injury after reperfusion is greater.

It is considered that 2/3 of this energy substrate depends on fatty acid metabolism, and the glucose-dependent portion is 20% or less, but in hypertrophic myocardium, this depends on glycolysis. It is shifting. for that reason,
Glycolysis (anaerobic) is enhanced in hypertrophic myocardium exposed to ischemia, but accumulation of its metabolite lactate and intracellular acidosis immediately stop glycolysis and cut off energy supply. . Therefore, it is thought that by removing lactate and H ⁺ , which are glycolytic suppressors, it is possible to promote glycolysis and enable good energy production during ischemia even in hypertrophic myocardium. To be Based on this idea, the basic amino acid histidine was used to protect hypertrophic myocardium.

The effects of using the cardioplegic solution (HBS) of the present invention on hypertrophic myocardium during ischemia will be described below.

(Method) A rabbit on the 10th day of life was anesthetized by intramuscular injection of ketamine hydrochloride, and then thoracotomy was performed.
It was used for the experiment as a model of hypertrophic myocardium after 5 to 7 weeks. After the anesthesia with ketamine again, the hypertrophic heart was extracted and perfused with the Langendorff perfusion model. As the perfusate, oxygenated Krebs-Henseleit
(KH) solution was used, and after 30 minutes, the items described below were measured, and then the K ⁺ concentration of the KH solution was adjusted to 20 mM (KC).
1) 30 ml or 30 ml of HBS was injected, warm ischemia at 37 ° C. was added for 40 minutes, and reperfusion was performed for 30 minutes.
The same item was measured at 30 minutes of reperfusion.

As the measurement items, pulse pressure and diastolic pressure were measured by a balloon inserted into the left ventricle, each cardioplegic solution (30 ml) was injected at the end of ischemia, effluent was collected, and lactate was measured. . In addition, ³¹ P-NMR spectrum
By oscopy, intracellular high energy phosphate (p
Hosphocreatine (PCr), intracellular pH
(PHi) was measured over time.

(Results) The left ventricular weight (LV / BW ratio) with respect to the body weight of the hypertrophic heart was 4.4 × 1 in the HBS group.
0 ^-3 ± 0.6 × 10 ^-3 , 4.8 × 10 ^-3 ± in KCl group
It was 0.6 × 10 ⁻³ , and there was no difference between both groups.
There was also no difference in pulse pressure between the two groups (n = 5 in each group) before ischemia, but after 30 minutes of reperfusion, the pulse pressure was significantly decreased in the KCl group and diastolic pressure was significantly decreased. Rose. On the other hand, in the HBS group, the diastolic pressure slightly increased, but the pulse pressure did not decrease significantly (FIGS. 14 (A) and (B)). Furthermore, the amount of lactate produced during ischemia was significantly high in the HBS group (Fig. 15).

In addition, intracellular pH (pHi) rapidly decreased after ischemia in the KCl group, and after 40 minutes of ischemia, the pH was 6.3 ±.
It dropped to 0.07 pH units. After reperfusion, the recovery was mild, but even at 30 minutes, 6.85 ± 0.
The value was 16 pH units and was significantly lower than that before ischemia (FIG. 16). On the other hand, in the HBS group, intracellular pH (pHi) was well maintained even after 40 minutes of ischemia (6.75 ±).
0.04), and returned to the previous value 5 minutes after reperfusion (FIG. 16).

In addition, phosphocreatine
(PCr) disappeared in the KCl group during ischemia, but about 20% of the previous value remained in the HBS group. After reperfusion, the HBS group returned to almost the previous value, whereas in the KCl group, it was about 45% before ischemia (FIG. 17).

(Discussion) From the above results, lactate and H ⁺ accumulated intracellularly in hypertrophic myocardium are buffered extracellularly, and as a result, anaerobic glycolysis is promoted and 40 minutes after warm ischemia. Is a high-energy phosphoric acid, pho
Spocreatine (PCr) remained (FIG. 17). From this, it is considered that the cardioplegic solution according to the present invention has a good effect on the energy recovery after reperfusion and brings about a good recovery of cardiac function.

[Example 3] Using the cardioplegic solution of the present invention, the heart of a rabbit was preserved and the optimum temperature was searched.

(Method) A rabbit on the 10th day of life was anesthetized by intramuscular injection of ketamine hydrochloride, and then thoracotomy was performed.
It was used for the experiment as a model of hypertrophic myocardium after 5 to 7 weeks. After the anesthesia with ketamine again, the hypertrophic heart was extracted and perfused with the Langendorff perfusion model.

As the cardioplegia solution, the cardioplegia solution (HB) according to the present invention having the composition shown in Table 14 is used.
S) and the University of Wisconsin (UW) solution were used. As for the dipping method, in consideration of heart transplantation, simple dip storage is performed only at 4 ° C storage in order to determine the suitability of long-term storage, and in other cases, intermittent administration (1 time /
1 hour). Furthermore, as the storage temperature of myocardium,
It verified about three cases, 4 degreeC, 13 degreeC, and 21 degreeC.

[0064]

[Table 14] (result)

[Table 15] The results shown in Table 15 and FIGS. 18 to 20 were obtained. That is, as shown in FIG. 18, the diastolic pressure is 4
When stored at 8 ° C for 8 hours, both HBS and UWS were excellent, but when stored at 4 ° C for 16 hours,
Good on BS, but significantly elevated on UWS.
On the other hand, when kept at 21 ° C. for 8 hours, good results were obtained with HBS, but very high values were obtained with UWS. Furthermore, with HBS, the diastolic pressure could be kept low even when kept at 21 ° C. for 16 hours. In addition, it is generally judged that irreversible cardiomyocyte damage occurs when the diastolic pressure exceeds 15 to 20 mmHg.

Further, as shown in FIG. 19, the pulse pressure is 4
When kept at 8 ℃ for 8 hours, both HBS and UWS were almost good, but when kept at 4 ℃ for 16 hours, HBS
Was good, but it was significantly decreased in UWS. On the other hand, when kept at 21 ° C. for 8 hours, good results were obtained with HBS, but very low diastolic pressure was obtained with UWS. Furthermore, with HBS, a high pulse pressure could be obtained even when kept at 21 ° C. for 16 hours. In general,
Higher pulse pressure is considered to be good for cardiac function.

Further, the diastolic pressure and pulse pressure when stored at 13 ° C. for 16 hours, 20 hours, and 24 hours using HBS are shown in FIGS. 20 (A) and 20 (B). That is, FIG.
As shown in (A), using the HBS of the present invention,
If stored at, even after storing for 24 hours,
The diastolic pressure was about 20 mmHg, and it was judged that good cardiac function recovery was possible. Further, as shown in FIG. 20 (B), the pulse pressure was 70% of that before ischemia even after storage for 24 hours.
Met.

From these results, intermittent administration at 13 ° C. for 2
It was found that in the group kept at 1 ° C, long-term storage of 16 hours to 24 hours was possible.

[Embodiment 4] In this embodiment, the cardioplegic solution of the present invention is clinically applied to more than 30 patients. That is, cold blood cardioplegi
The recovery of cardiac function after surgery was examined using the conventional myocardial protection method of a (CBC ... Method of diluting and cooling blood) and the myocardial protection solution of the present invention.
The clinical use of the cardioplegic solution according to the present invention is
HBS cooled to 4 ° C. is administered every 30 minutes.

The results are as follows. That is, immediately after administration, the myocardial temperature decreased to 15 to 17 ° C, but increased to 25 to 27 ° C until the next administration (30 minutes later). In addition, the same process was followed after the second time. In the CBC-administered group, ventricular fibrillation was seen in 5 out of 34 patients and required defibrillation, but in the HBS-administered group, no ventricular fibrillation was observed in all subjects, and defibrillation was observed. Was unnecessary (ie, started self-beating). Furthermore, H
In the BS administration group, the dose of the cardiotonic agent during open heart surgery is
The amount was clearly smaller than that in the CBC administration group. Thus, the cardioplegic solution of the present invention, even when applied clinically,
Good results were shown.

[Effect of this embodiment] As described above,
According to the cardioplegic solution of the present invention, good myocardial protection can be achieved under a wide temperature range of 13 ° C to 37 ° C, and ice is not required during surgery, so that blood is not used for the cardioplegic solution. Therefore, a good field of view can be secured. Furthermore, the administration method is simple, the basic composition is amino acid, and other contents are conventionally used, so that the safety is very high. In particular, it is a cardioplegia solution that has a remarkable effect on hypertrophic myocardium and myocardium in a pathological state and is suitable for clinical application.

[Other Embodiments] The present invention is not limited to the above-described embodiments, the adenosine content is 0.05 mM / L to 2 mM / L, and the histidine content is 90 mM / L to 110 mM / L, glucose content 9 mM / L to 12 mM / L, insulin content 7I. U. / L-12I. U. / L and the content of lidocaine are in the range of 60 mg / L to 120 mg / L, it is considered that the same effect can be obtained.

[0072]

As described above, according to the present invention, it is possible to protect hypertrophic myocardium and pathological myocardium that are vulnerable to ischemia and to safely perform surgery in a bloodless field without using local cooling. It is possible to provide a cardioplegia solution that can obtain good cardiac function recovery.

[Brief description of the drawings]

FIG. 1 is an end-system according to a first embodiment of the present invention.
Diagram showing lic elastance (Ees)

FIG. 2 is an equilibri in the first embodiment of the present invention.
Diagram showing um volume (Vo)

FIG. 3 is an end-diastolic capacity (Ve) in Example 1 of the present invention.
Diagram showing d)

FIG. 4 is a diagram showing cardiac output (CO) in Example 1 of the present invention.

FIG. 5: Left ventricular ejection fraction (EF) in Example 1 of the present invention
Figure showing

FIG. 6 is a diastolic pressure of 15 mmH in Example 1 of the present invention.
Diagram showing pulse pressure measured in g

FIG. 7 shows the end-systemic elastostance (Ee) by dobutamine loading in Example 1 of the present invention.
Figure showing s)

FIG. 8 is a diagram showing an equilibrium volume (Vo) by dobutamine loading in Example 1 of the present invention.

FIG. 9 is a graph showing end-diastolic volume (Ved) by dobutamine loading in Example 1 of the present invention.

FIG. 10 is a graph showing the stroke volume (SV) by dobutamine loading in Example 1 of the present invention.

FIG. 11 is a graph showing cardiac output (CO) due to dobutamine loading in Example 1 of the present invention.

FIG. 12 is a graph showing left ventricular ejection fraction (EF) due to dobutamine loading in Example 1 of the present invention.

FIG. 13 is a graph showing pulse pressure measured at a diastolic pressure of 15 mmHg due to dobutamine loading in Example 1 of the present invention.

FIG. 14 (A) is a diagram showing pulse pressure in Example 2 of the present invention, and (B) is a diagram showing diastolic pressure.

FIG. 15 is a graph showing the amount of lactate produced during ischemia in Example 2 of the present invention.

FIG. 16 shows changes in intracellular pH in Example 2 of the present invention.

FIG. 17 is a diagram showing changes in PCr in Example 2 of the present invention.

FIG. 18 is a diagram showing diastolic pressure in Example 3 of the present invention.

FIG. 19 is a diagram showing pulse pressure in Example 3 of the present invention.

FIG. 20 (A) is for 16 hours, 20 hours, 2 at 13 ° C.
Diagram showing diastolic pressure when stored for 4 hours, (B) diagram showing pulse pressure

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical display location A61K 38/28 A61K 37/26 // (A61K 31/195 31:70) (71) Applicant 595169090 Hung Cao Dan Hung Cao-Danh United States 02146 Massachusetts Brookline Aspinwall Ave 150 (71) Applicant 595169104 Francis Zeby McGowan Francis X McGowan United States 02115 Massachusetts Boston Longwood Ave 300 Vader 3 515 Napa (169) Applicant Ventura Percual Buenaventura United States 15232 Pennsylvania Pittsburgh Fifth Ave New # 302 5230 (72) Inventor Isao Takeuchi 2-23-20 Hanazono, Aomori City, Aomori Prefecture (72) Inventor Pedro Jay Del Nido, United States 02173 Massachusetts Lexington Heritage Drive 9 (72) Inventor Hunka Odan United States 02146 Massachusetts Brookline Aspinwall Ave 150 (72) Inventor Francis Zeby Magowan United States 02115 Massachusetts Boston Longwood Ave 300 Vader 3 (72) Inventor Percival Bonaventure United States 15232 Pennsylvania Pittsburgh Fifth Avenue # 302 5230

Claims (7)

[Claims] 1. Histidine at 90 mM / L to 110 mM
/ L, adenosine 0.05 mM / L to 2 mM / L, a cardioplegia solution. 2. Histidine at 90 mM / L to 110 mM
/ L, adenosine 0.05 mM / L to 2 mM / L, and used for preservation of hypertrophic myocardium. 3. Glucose serving as a glycolytic substrate is 9 mM
/ L to 12 mM / L, insulin which enhances glucose uptake into cells was added to 7I. U. / L-12I. U. / L,
60 mg of lidocaine, a Na channel blocker
/ L to 120 mg / L is contained, The cardioplegia solution of Claim 1 or Claim 2 characterized by the above-mentioned. 4. A myocardial protective solution containing 100 mM / L of histidine and 0.1 mM / L of adenosine. 5. A cardioplegic solution containing 100 mM / L of histidine and 0.1 mM / L of adenosine, which is used for preservation of hypertrophic myocardium. 6. L-Histidine is 100 mM /
L, KH ₂ PO ₄ 2.5 mM / L, KCl 20 mM
/ L, MgSO ₄ · 7H2 O and 6 mM / L, NaCl and 80 mM / L, the CaCl ₂ 0.1mM / L, Aden
osine 0.1 mM / L, D-glucose 1
1 mM / L, Mannitol 20 mM / L, Lid
ocaine 100 mg / L, NaOH 3.6 mM
/ L, Insulin 10I. U. / L-containing cardioplegic solution. 7. The cardioplegia solution according to claim 1, which has a pH of 7.7 to 7.9.