动物模型,高血压 z-bo 2020-08-05 692

　　Hypertension is a direct consequence of the increase in peripheral resistance caused by the spasm of small arteries throughout the body. The spasm of the arterioles is related to many factors such as genetic/mental stimulation, stress, renal ischemia, the role of the adrenal cortex and the role of sodium. The replication of blood pressure models is mostly formed by simulating the risk factors of hypertension from different angles.

　　The animal models used are spontaneously hypertensive rats (SHR), neural prototypes, renal outsourcing type and deoxycorticosterone acetate (DOCA) salt-induced hypertensive rats, renal vascular hypertensive dogs, salt sensitivity and salt resistance Hypertensive rats and so on.

　　(1) Neural prototype hypertension model:

　　Can use dogs, rats, rabbits, etc., to induce conditioned reflex hypertension and cortical hypertension models by acting on the animal nervous system through functional or physical methods.

　　1. Neuropsychiatric stimulation: strong sound, shopping, electrical stimulation, conditioned reflex conflict, etc. can cause strong thunder excitement and blood pressure increase in the animal's advanced nerve center. The disadvantage is that this increase in blood pressure cannot be sustained. At the same time, animals have a tendency to adapt to the same stimulus, so a durable hypertension model cannot be established.

　　2. Removal of the baroreceptor nerve: using electricity to damage the solitary tract of an animal or destroy the catecholamine neurons in the nucleus of the solitary tract with 6-hydroxydopamine, so that the decompression reflex center loses the function of adjusting blood pressure, which can establish a chronic hypertension model, but there are some Animals may die shortly after surgery.

　　(2) Spontaneously hypertensive rat model

　　Okamoto et al. mated male Wistar rats with blood pressure of 19.3~23.3KPa with female rats of the same species with blood pressure of 17,3~18.6KPa. Their offspring selected high blood pressure as inbreeding. After three generations, most animals had blood pressure exceeding 24KPa. They called it spontaneously hypertensive rats (SHR). Through continuous selection, the inbred line SHR was obtained in 1969, and by 1986 the line had reached the 80th generation.

　　100% of the offspring of SHR develop hypertension. Generally, blood pressure gradually increases with age after birth. According to statistics from the 30th to 32nd generation, the average blood pressure of male rats is 24.5±2.3KPa and female rats is 23.7±1.9KPa in the 10th week after birth. It will continue to increase thereafter. It can exceed 26.6KPa.

　　The mechanism of blood pressure increase: In the early stage of growth of hypertensive rats, the vascular resistance continues to increase, blood pressure rises, myocardial hypertrophy, and the body's renin-angiotensin system is activated. This process continues to the late stage of survival and develops more Severe myocardial hypertrophy and congestive heart failure. With the continuous development of hypertension, hypertensive rats have similar complications to human hypertensive patients-brain and myocardial damage, and nephrosclerosis.

　　Advantages: Spontaneously hypertensive rats are similar to human hypertensive patients in many aspects, such as pathogenesis, cardiovascular complications of hypertension, changes in peripheral vascular resistance, and sensitivity to salt. It is currently internationally recognized as the closest An animal model of human essential hypertension. Therefore, it is widely used in medical basic experimental research, such as the research on the electro-growth of SHR hypertension, the research on the renin angiotensin system, the research on endothelin, the research on mitogen-activated protein kinase, Research on the structure and function of blood vessels has made some progress. Another example is blocking the renin-angiotensin aldosterone system at the receptor level to explore the possible mechanism of hypertensive myocardial remodeling. Rat model of hypertension. In addition, this model is especially used for human hypertension research and hypertension drug screening. For example, the study of the neuroprotective effect of candesartan on cerebral ischemia in hypertensive rats also uses a spontaneous hypertension model.

　　Disadvantages: high breeding conditions, relatively expensive, troublesome genetic breeding, need a certain time, and easy to mutate or cut off, if it is used in large quantities, there will still be certain difficulties.

　　(3) Renal outsourcing hypertension model

　　Mechanism of increased blood pressure: foreign body bandaging outside the kidney can cause peri-nephritis, forming a fibrous sheath outside the kidney, compressing the kidney parenchyma and causing renal tissue ischemia, increasing the formation of renin and increasing blood pressure.

　　Use 120～150g rats. After anesthesia, fix in the prone position, put a sandbag about 2 to 3 cm high on the lower back, cut the hair of the surgical field, disinfect the skin with 0.05% chlorhexidine alcohol, and cut along the midline of the spine from the 10th thoracic vertebra to the third lumbar vertebra. Cut the skin, separate the muscle with small vascular forceps 1.5-2cm below the left quarter rib and 1cm from the spine. Use two fingers to squeeze the kidney from the lower part of the abdomen. Carefully peel off the kidney from the surrounding tissues and remove the double layer. The latex film is cut into an "X" shape, and the kidney is cross-wrapped around the kidney door, and then cut on the opposite side, the right kidney is taken out, removed after separation, and the muscle and skin wounds are sutured separately. Inject 10,000 to 20,000 units of penicillin G subcutaneously. The instruments used for surgery must be autoclaved, as long as they are immersed in 75% ethanol for 30 minutes, rinsed with boiled saline before use, and immersed in ethanol after use. After the operation, 1% sodium chloride solution can be added as a promoting factor.

　　(four), renal hypertension model

　　Gold-blatt hypertension model has double kidney and single kidney model. The double-kidney model means that the animal retains both kidneys but narrows one or two kidney arteries, so it is also called two-kidney one-clamp or two-kidney double-clamp type. The single-kidney model consists of removing one side of the kidney, narrowing the renal artery that preserves the kidney, and one kidney one clip type. Animals of these three models can develop long-term stable hypertension.

　　1. One kidney one clip (left renal artery stenosis + right nephrectomy) blood pressure increase mechanism is mainly due to sodium retention and renin angiotensin system activation and increased sympathetic nerve activity.

　　Advantages: Because of the low success rate of this model, the blood pressure cannot continue to rise, which limits its scope of use, and is currently less used.

　　2. In the two-kidney one-clip type (the left renal artery is stenosis, the right kidney is reserved), the activation of the renin angiotensin system is dominant in the increase in blood pressure. The renal artery stenosis causes renal ischemia, leading to the formation of renin in the kidney, and then Increase the content of angiotensin in the snow and raise blood pressure.

　　Advantages: This model has the advantages of simple modeling, high success rate, strong identity, and is comparable to the pathological process of human hypertension. It is the most commonly used classic animal model of hypertension in the world. It is currently used in screening antihypertensive drugs Choose a more model. It is also possible to add 2% Nacl solution on the basis of this experimental model. Sodium water retention and blood volume expansion may be important reasons for increased blood pressure.

　　3. The increase in blood pressure in the double-kidney double-clamp model is mainly due to the continuous ischemia of both kidneys that activates the renin-angiotensin system. The increase in angiotensin level not only directly constricts blood vessels, but also increases the release of sympathetic neurotransmitters and aldosterone and The release of active substances such as endothelin eventually leads to the formation of high blood pressure.

　　Advantages: The peak blood pressure of this model is high and stable. With the extension of the observation time, the blood pressure level continues to rise steadily, which is basically the same as the blood pressure evolution process of human hypertension. In the above-mentioned other types of renal vascular hypertension rats, the peak blood pressure is mostly around 180mmHg, and with the prolongation of the observation time, the blood pressure level has dropped, and even returned to the normal level. The blood pressure of double-kidney and double-clamped renal vascular rats rose sharply two weeks after the operation, and the blood pressure trend was consistent with that of male spontaneous hypertensive rats. The blood pressure of spontaneously hypertensive rats was stable for a long time and gradually increased with the growth of the rats. specialty. Double-kidney double-clamp renovascular hypertensive rats can produce blood pressure peaks and cardiovascular and cerebrovascular complications similar to those of spontaneous hypertensive rats. If the experiment is only considered from the single factor of hypertension which causes complications in other organs of the body, the double-kidney double-clamp renovascular rats can make up for the deficiencies in some aspects of spontaneously hypertensive rats, and there are also a wide range of animal sources. It has the advantages of low price, easy breeding, and simple model copy method.

　　(5), DOCA salt-induced hypertension model

　　DOCA salt: The method of using DOCA salt to cause high blood pressure is widely used, but the dosage and duration are different. Generally, one side of the kidney is removed, and then DOCA oil or suspension is injected subcutaneously or intramuscularly. The dose ranges from 15 to 50 mg for several weeks; it is also possible to embed 40 to 75 mg of DOCA pills under the skin; all use 1% Nacl solution. Such animals have pathological changes in the kidneys and blood vessels.

　　Mechanism of blood pressure increase: A large dose of DOCA (precursor of aldosterone) was used in the production process, which has a similar physiological effect as aldosterone, feedback inhibition of circulating renin-angiotensin system, resulting in low plasma renin activity. A low-renin hypertension model.

　　This model is a secondary hypertension model, which is similar to the primary hyperaldosteronism in human hypertension. Therefore, it can be used in the study of hypertension caused by primary aldosterone. In addition, the literature uses DOCA salt-induced hypertensive rats to study the kidneys, such as the study of the protective effect of bosentan on the kidneys of hypertensive rats.

　　In addition, Ben-Ishay et al. selected high blood pressure and low blood pressure among animals treated with DOCA salt and one side of nephrectomy for inbreeding respectively. By the 20th generation, two lines of animals were established, which was later named Israel Hypertension. Rats (SBH) and Israeli normal blood pressure rats (SBN), the former has slightly higher blood pressure than the latter, and are very sensitive to DOCA salt.

　　(6). Salt-sensitive and salt-resistant hypertensive rat models

　　Dahl et al. treated rats with a high-salt diet (8% sodium chloride) and triiodothyroxine, and found that the blood pressure of some rats increased, while the blood pressure of the other animals did not change significantly. They inbred the rats with the highest and lowest blood pressure respectively. After three generations, they separated salt-sensitive (DS) and salt-resistant rats (DR). Hypertension occurs in DS rats taking a high-salt diet, but not in DR rats. DS rats are a typical model of hypertension caused by environmental factors (salt) and genetic factors.

　　The mechanism of the increase in blood pressure is not yet clear. It may be due to the increase in extracellular fluid volume caused by sodium retention, and therefore the increase in cardiac output. Increased intracellular sodium level in vascular smooth muscle cells leads to an increase in intracellular calcium ion concentration and enhances the vasoconstriction response, so peripheral vascular resistance increases, which can promote the formation of hypertension.

　　For further purification, Rapp et al. screened and inbreeded DS and DR rats for 20 generations, and obtained two inbred animals, namely salt-sensitive hypertensive rats (SS/Jr) and salt-resistant hypertensive rats. (SR/Jr).

　　SS/Jr rats were fed high-salt (8% Nacl) and low-salt (0.3% Nacl) after weaning, and the development process of hypertension was different. The blood pressure of the high-salt group increased rapidly, and animals died after 3 weeks, and all died at 8 weeks; the blood pressure of the low-salt group rose slowly, and it took 6 months for animals to die.

　　SR/Jr rats have little response to high salt and low salt blood pressure.