CN110278941B - Isolated heart protection solution containing natriuretic peptide - Google Patents
Isolated heart protection solution containing natriuretic peptide Download PDFInfo
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- CN110278941B CN110278941B CN201910625360.3A CN201910625360A CN110278941B CN 110278941 B CN110278941 B CN 110278941B CN 201910625360 A CN201910625360 A CN 201910625360A CN 110278941 B CN110278941 B CN 110278941B
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N1/00—Preservation of bodies of humans or animals, or parts thereof
- A01N1/02—Preservation of living parts
- A01N1/0205—Chemical aspects
- A01N1/021—Preservation or perfusion media, liquids, solids or gases used in the preservation of cells, tissue, organs or bodily fluids
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N1/00—Preservation of bodies of humans or animals, or parts thereof
- A01N1/02—Preservation of living parts
- A01N1/0205—Chemical aspects
- A01N1/021—Preservation or perfusion media, liquids, solids or gases used in the preservation of cells, tissue, organs or bodily fluids
- A01N1/0226—Physiologically active agents, i.e. substances affecting physiological processes of cells and tissue to be preserved, e.g. anti-oxidants or nutrients
Abstract
The invention discloses an isolated heart protection solution containing natriuretic peptide, which is a mixture of natriuretic peptide and HTK solution. The natriuretic peptide is one of atrial natriuretic peptide, brain natriuretic peptide, C-type natriuretic peptide and artificially synthesized blood vessel natriuretic peptide. The concentration of the atrial natriuretic peptide, the brain natriuretic peptide, the C-type natriuretic peptide and the synthetic vascular natriuretic peptide in HTK solution is 10‑8mol/L～10‑6mol/L. The pH value of the in vitro heart protection solution is 7.2-7.4. The natriuretic peptide-containing isolated heart protection solution can effectively maintain isolated heart activity, improve cardiac function and inhibit myocardial inflammatory reaction.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an in vitro heart protection solution containing natriuretic peptide.
Background
HTK (thymine-tryphane-Ketoglutarate, HTK) cardioprotective solution is also called constett protective solution, is a crystalloid solution imitating intracellular fluid developed by Bretschneider et al, germany in 1975, is mainly used for preserving transplanted donor organs such as liver, kidney, heart, lung and pancreas at present, and can also be used as a cardioprotective solution in cardiac surgery or a pulmonary protective solution perfused through pulmonary artery. As cardioplegic solution, "equilibrium" is a remarkable feature of HTK solution, it can make the vascular lacuna be completely filled, finally realize the balance of ion, temperature and oxygen metabolism inside and outside the cell. Meanwhile, a strong buffer system in the HTK liquid can effectively prevent myocardial cell acidosis, and the amino acid can provide energy for ischemic myocardium for a long time, so the HTK liquid has the advantages of long acting time, no influence on operation field operation, reduction of pre-blood charging amount and the like. However, the HTK liquid has no obvious improvement effect on the inflammatory response of the ischemia reperfusion injury myocardium.
Therefore, there is a need to find an effective improved HTK solution, which can not only protect the heart for a long time, does not affect the operation of the operative field, reduces the effects of pre-hyperemia, etc., but also inhibit the myocardial inflammatory reaction of myocardial ischemia reperfusion injury, so as to further improve the activity of the isolated heart.
Natriuretic Peptides (NPs) are a group of polypeptides that are important in maintaining water-salt balance, blood pressure stability, cardiovascular and renal functions of the body. There are three major types of research that are currently more and more clear: atrial Natriuretic Peptide (ANP), Brain Natriuretic Peptide (BNP), and C-type natriuretic peptide (CNP), wherein the molecular weight of ANP is 3080Da, the molecular weight of BNP is 3466Da, and the molecular weight of CNP is 2360 Da. In recent years new members have been discovered, such as ventricular natriuretic peptides found in ventricles of eel (eel) and rainbow trout (rainbow trout), DNP isolated and purified from Dendroaspis angusticeps snake venom, and synthetic Vascular Natriuretic Peptide (VNP) of Wei et al 1993, wherein the molecular weight of VNP is 2837Da, which together constitute the natriuretic peptide family.
Previous researches show that NPs not only have the effects of benefiting sodium, promoting urination, relaxing blood vessels and reducing blood pressure, but also have direct protective effects of resisting apoptosis, improving cell activity and the like on myocardial cells, thereby becoming a hotspot for developing heart protection medicaments. In 2001, the FDA approved SCIOS recombinant BNP (trade name nesiritide) to be marketed for treating acute congestive heart failure, and the recombinant BNP has good curative effect. BNP (brand name neomycin) is also on the market in 2005 in China. The HTK liquid and the NPs are combined, and the effect of the isolated heart protective liquid is improved.
Disclosure of Invention
The invention aims to provide an isolated heart protection solution containing natriuretic peptide, which can prolong the heart protection time and inhibit myocardial cell inflammatory reaction induced by ischemia-reperfusion injury.
The technical scheme adopted by the invention is as follows: an isolated heart protective solution containing natriuretic peptide is a mixture of natriuretic peptide and HTK solution.
The present invention is also characterized in that,
the natriuretic peptide is any one of atrial natriuretic peptide, brain natriuretic peptide, C-type natriuretic peptide, and synthetic vascular natriuretic peptide.
The concentrations of atrial natriuretic peptide, brain natriuretic peptide, C-type natriuretic peptide, and synthetic blood vessel natriuretic peptide are all 10-8mol/L～10-6mol/L。
The pH value of the isolated heart protection solution is 7.2-7.4.
The invention has the beneficial effects that:
1. the invention has the function of improving the cardiac function. The isolated heart protection solution containing natriuretic peptide obviously increases left ventricular systolic pressure LVSP, left ventricular diastolic end pressure LVEDP, the maximum rising rate (+ dp/dtmax) of left ventricular systolic pressure, the maximum falling rate (-dp/dtmax) of left ventricular diastolic pressure and Coronary Flow (CF), and has an effect of improving heart function higher than 7% compared with the existing HTK solution.
2. Compared with the prior HTK solution, the isolated heart protective solution containing natriuretic peptide of the invention has the advantage that the levels of lipid peroxides MDA and superoxide dismutase SOD of heart tissues are reduced by more than 5%.
3. Compared with the prior HTK liquid, the isolated heart protective liquid containing natriuretic peptide of the invention has the content ratio of myocardial creatine kinase isoenzyme CK-MB and lactate dehydrogenase LDH reduced by more than 20 percent.
4. Compared with the prior HTK solution, the isolated heart protective solution containing natriuretic peptide of the invention has the advantage that the levels of inflammatory factors TNF-alpha and IL-6 in the isolated heart perfusion solution are reduced by more than 30%.
Drawings
FIG. 1 is a graph comparing the extent of reduction of MDA levels in heart tissue for an ex vivo cardioprotective solution comprising a natriuretic peptide of the invention with a control group;
FIG. 2 is a graph comparing the reduction in SOD activity in heart tissue of an isolated cardioprotective solution of the present invention containing natriuretic peptides to a control group;
FIG. 3 is a graph comparing the reduction of CK-MB activity in isolated heart perfusion fluid by isolated cardioprotective solutions containing natriuretic peptides of the present invention and control groups;
FIG. 4 is a graph comparing the decrease in LDH activity levels in isolated heart perfusate for an isolated cardioprotective solution of the present invention and a control group containing natriuretic peptides;
FIG. 5 is a graph comparing the effect of an ex vivo cardioprotective solution comprising a natriuretic peptide of the present invention and a control on cardiomyocyte apoptosis;
FIG. 6 is a comparison graph of the measurement of the apoptosis rate of an isolated cardioprotective solution containing natriuretic peptide of the present invention and a control group;
FIG. 7 is a comparison graph of the concentration measurement of inflammatory mediator TNF-alpha in isolated heart perfusion fluid of the isolated heart protection fluid containing natriuretic peptide and a control group according to the present invention;
FIG. 8 is a comparison graph of the concentration measurement of the inflammatory mediator IL-6 in isolated heart perfusion fluid of the isolated heart protection fluid containing natriuretic peptide and a control group.
Detailed Description
The present invention will be described in detail below with reference to the accompanying drawings and specific embodiments.
An isolated heart protective solution containing natriuretic peptide is a mixture of natriuretic peptide and HTK solution.
The natriuretic peptide is any one of atrial natriuretic peptide, brain natriuretic peptide, C-type natriuretic peptide, and synthetic vascular natriuretic peptide.
The concentration of atrial natriuretic peptide, brain natriuretic peptide, C-type natriuretic peptide, and synthetic blood vessel natriuretic peptide in HTK liquid is 10-8mol/L～10-6mol/L。
The pH value of the in vitro heart protection solution is 7.2-7.4.
The preparation method of the HTK liquid comprises the following steps: 0.8766g of sodium chloride, 0.6710g of potassium chloride, 0.1842g of 2-ketoglutaric acid-hydrogen-potassium, 0.8132g of magnesium chloride hexahydrate, 3.7733g of histidine monohydrochloride monohydrate, 27.9289g of histidine, 0.4085g of tryptophan, 5.4651g of mannitol and 0.0022g of calcium chloride dihydrate were dissolved in 1000mL of ultrapure water to obtain an HTK solution.
Example 1
An isolated heart protection solution 1 containing natriuretic peptide is specifically prepared according to the following steps:
step 1, 0.2837g of synthetic natriuretic peptide (VNP) was dissolved in 100mL of ultrapure water to obtain a solution with a concentration of 10-3mol/L。
Step 2, according to the method for preparing the HTK solution, 0.8766g of sodium chloride, 0.6710g of potassium chloride, 0.1842g of 2-ketoglutaric acid-hydrogen-potassium, 0.8132g of magnesium chloride hexahydrate, 3.7733g of histidine monohydrochloride monohydrate, 27.9289g of histidine, 0.4085g of tryptophan, 5.4651g of mannitol and 0.0022g of calcium chloride dihydrate are dissolved in 1000mL of ultrapure water to obtain the HTK solution.
And 3, adding 100 mu L of the solution obtained in the step 1 into the HTK solution obtained in the step 2, uniformly mixing, and adjusting the pH value to 7.2-7.4 to obtain the in vitro heart protection solution 1.
In the isolated heart protective solution, the concentration of the artificially synthesized angionatriuretic peptide in HTK solution is 10-7mol/L。
Example 2
An isolated heart protection solution 2 containing natriuretic peptide is specifically prepared according to the following steps:
step 1, 0.3466g of Brain Natriuretic Peptide (BNP) is dissolved in 100mL of ultrapure water, and the concentration of the obtained solution is 10-3mol/L。
Step 2, according to the method for preparing the HTK solution, 0.8766g of sodium chloride, 0.6710g of potassium chloride, 0.1842g of 2-ketoglutaric acid-hydrogen-potassium, 0.8132g of magnesium chloride hexahydrate, 3.7733g of histidine monohydrochloride monohydrate, 27.9289g of histidine, 0.4085g of tryptophan, 5.4651g of mannitol and 0.0022g of calcium chloride dihydrate are dissolved in 1000mL of ultrapure water to obtain the HTK solution.
And 3, adding 100 mu L of the solution obtained in the step 1 into the HTK solution obtained in the step 2, uniformly mixing, and adjusting the pH value to 7.2-7.4 to obtain the in vitro heart protection solution 2.
In the above isolated cardioprotective solution, the concentration of brain natriuretic peptide in HTK solution is 10-7mol/L。
Example 3
An isolated heart protection solution 3 containing natriuretic peptide is specifically prepared according to the following steps:
step 1, 0.2360gC type natriuretic peptide (CNP) is dissolved in 100mL of ultrapure water to obtain a solution with the concentration of 10- 3mol/L。
Step 2, according to the method for preparing the HTK solution, 0.8766g of sodium chloride, 0.6710g of potassium chloride, 0.1842g of 2-ketoglutaric acid-hydrogen-potassium, 0.8132g of magnesium chloride hexahydrate, 3.7733g of histidine monohydrochloride monohydrate, 27.9289g of histidine, 0.4085g of tryptophan, 5.4651g of mannitol and 0.0022g of calcium chloride dihydrate are dissolved in 1000mL of ultrapure water to obtain the HTK solution.
And 3, adding 1ml of the solution obtained in the step 1 into the HTK solution obtained in the step 2, uniformly mixing, and adjusting the pH value to 7.2-7.4 to obtain the in vitro heart protection solution 3.
In the isolated cardioprotective solution, the concentration of C-type natriuretic peptide in HTK solution is 10-6mol/L。
Example 4
An isolated cardioprotective solution 4 comprising natriuretic peptide is specifically prepared by the following steps:
step 1, 0.3080g Atrial Natriuretic Peptide (ANP) was dissolved in 100mL ultrapure water to obtain a solution with a concentration of 10- 3mol/L。
Step 2, according to the method for preparing the HTK solution, 0.8766g of sodium chloride, 0.6710g of potassium chloride, 0.1842g of 2-ketoglutaric acid-hydrogen-potassium, 0.8132g of magnesium chloride hexahydrate, 3.7733g of histidine monohydrochloride monohydrate, 27.9289g of histidine, 0.4085g of tryptophan, 5.4651g of mannitol and 0.0022g of calcium chloride dihydrate are dissolved in 1000mL of ultrapure water to obtain the HTK solution.
And 3, adding 10 mu L of the solution obtained in the step 1 into the HTK solution prepared in the step 2, uniformly mixing, and adjusting the pH value to 7.2-7.4 to obtain the in vitro heart protection solution 4.
In the isolated heart protective solution, the concentration of atrial natriuretic peptide in HTK solution is 10-8mol/L。
The effect verification is carried out on the isolated heart protection liquids 1and 2 containing the natriuretic peptide (blood perfusion-cold storage-reperfusion research is carried out by establishing a rat heart Langendorff model in vitro, the protection of the heart protection liquid on the cardiac muscle in the process of obtaining, storing and transplanting the heart donor by simulating the heart transplantation operation), and the isolated heart protection liquids are analyzed and compared with HTK liquid heart protection liquid (a control group).
The method comprises the following specific steps:
adult male SD rats were taken 24 and randomized into 3 groups: HTK group, HTK-B group, HTK-V group (number n of rats per group is 8).
Rats in each group were anesthetized intraperitoneally with 50mg/kg ketamine +10mg/kg chlorpromazine and sublingually with 250U/kg heparin for anticoagulation. Opening chest through thoracic-costal triangle, taking out heart, and immediately placing into heart protecting solution of HTK solution group, HTK-V group and HTK-B group.
Using HTK-V group rats as an example, the heart was taken out by opening the chest and immediately placed in a container having a concentration of 1.0X 10-7The solution of HTK containing 1.0X 10 mol/L of synthetic angionatriuretic peptide (example 1) was gently rubbed with hand for 10s to wash the blood vessels and the residual blood in the heart chamber to prevent blood clot formation, and then placed at 4 deg.C-7Soaking in HTK solution of artificial vasonatriuretic peptide (mol/L) for 6h, fixing the heart on Langendorff isolated heart perfusion device after 6h, and perfusing with KH solution (Krebs-Henseleit buffer) at 37 deg.C via aorta for 30min at 75mmHg constant pressure. Measuring relevant indexes such as hemodynamics, myocardial enzyme, antioxidation and myocardial inflammatory factor. Data were obtained for ex vivo cardioprotective solution 1 (HTK-V) containing natriuretic peptide according to example 1 of the present invention.
In the same procedure, the synthetic vascular natriuretic peptide was replaced with brain natriuretic peptide to obtain data on isolated cardioprotective solution 2 (HTK-B) containing natriuretic peptide of the present invention.
The control group used HTK solution instead of the isolated cardioprotective solution of the invention containing natriuretic peptide for comparative experiments.
The experimental results of the change in rat cardiac function are shown in table 1 below: after 6h of storage, the LVSP at 30min is perfused; LVEDP; d +/-dp/dtmax; CF.
Compared with the control group HTK liquid group, p is less than 0.01and p is less than 0.05, (mean + -SD, n is 8).
The test results of the indexes related to oxidation resistance are shown in figures 1and 2: the oxidative damage of the transplanted heart was improved in the HTK solutions of example 1, example 2 and the control group after 6h cold storage and 30min reperfusion. As can be seen from fig. 1and 2: the three-dimensional heart protection solution containing natriuretic peptide can reduce the MDA level and the SOD activity of tissues remarkably. (compared with the control group of HTK solution, p is less than 0.01and p is less than 0.05, mean + -SD, and n is 8).
The results of the myocardial enzyme test experiments are shown in fig. 3 and 4, and the myocardial enzyme test parameters are as follows: after 30min of perfusion, compared with a control group, the amount of CK-MB and LDH in coronary artery effluent liquid in the isolated heart protection liquid group containing natriuretic peptide is obviously reduced. (compared with the control group of HTK solution, p is less than 0.01and p is less than 0.05, mean + -SD, and n is 8).
FIG. 5 is a graph comparing the effect of ex vivo cardioprotective solutions of the present invention containing natriuretic peptides (x 400) on cardiomyocyte apoptosis in examples 1and 2 and a control group (HTK solution group), wherein A-C represent TUNEL staining of cardiomyocytes in three groups of rats, A is staining of HTK group, B is staining of HTK-B group, and C is staining of HTK-V group (showing that bluish or bluish color is normal cardiomyocyte nuclei, and dark brown or tan nuclei are apoptotic nuclei, as indicated by arrows; clear dark brown or tan nuclei are visible in HTK solution group, and dark brown cells are significantly reduced in HTK-B group and HTK-V group compared to HTK solution group.)
FIG. 6 shows the results of the quantitative determination of the apoptosis rate of TUNEL staining between the different groups of example 1, example 2 and the control group (HTK solution group) of an ex vivo cardioprotective solution containing natriuretic peptide of the present invention (compared with the HTK group, p < 0.05and p < 0.01, mean. + -. SD, n ═ 8).
Fig. 7 and 8 show the concentrations of inflammatory mediators of cardiomyocytes and TNF-a and IL-6 in myocardial tissue (compared to HTK group, p < 0.05and p < 0.01, mean ± SD, n 8) after 6h of cold storage, 30min of reperfusion, and ELISA for example 1, example 2 and control (HTK fluid group), respectively, of an ex vivo cardioprotective solution containing a natriuretic peptide of the invention.
As can be seen from the above, the isolated cardioprotective solution containing natriuretic peptide can effectively increase the left ventricular systolic pressure LVSP, the left ventricular diastolic end pressure LVEDP, the maximum rising rate (+ dp/dtmax) of the left ventricular systolic pressure, the maximum falling rate (-dp/dtmax) of the left ventricular diastolic pressure and the Coronary Flow (CF) value to more than 7.0 percent, and can effectively improve the cardiac function; compared with a control group, the contents of lipid peroxide MDA and superoxide dismutase SOD in heart tissues in the HTK-V group and the HTK-B group are more than 5 percent, and the contents of myocardial enzyme creatine kinase isoenzyme CK-MB and lactate dehydrogenase LDH are less than 20 percent, so that myocardial damage can be effectively prevented; the HTK-V group and the HTK-B group can effectively prevent myocardial apoptosis, and the protective effect on the myocardial apoptosis rate is obviously superior to that of the control group by more than 10 percent; compared with a control group HTK liquid, the natriuretic peptide isolated heart protective liquid can effectively reduce the content of inflammatory factors TNF-alpha and IL-6 of myocardial cells by more than 30 percent.
Claims (1)
1. An isolated heart protection solution containing natriuretic peptide, which is characterized in that the isolated heart protection solution is a mixture of the natriuretic peptide and HTK solution; the natriuretic peptide is any one of atrial natriuretic peptide, brain natriuretic peptide, C-type natriuretic peptide and artificially synthesized blood vessel natriuretic peptide;
the concentration of the atrial natriuretic peptide, the brain natriuretic peptide, the C-type natriuretic peptide and the artificially synthesized blood vessel natriuretic peptide in HTK liquid is 10- 8mol/L～10-6mol/L；
The pH value of the in vitro heart protection solution is 7.2-7.4.
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