动物造模,药效评价 z-bio 2024-09-25 404

　　Catecholamines include adrenaline, norepinephrine, dopamine, and their metabolites. The system of action of this type of substance includes the substance and its receptor, as well as the substances involved in its transformation process. At present, it has been found that genes related to hypertension in the system of action of such substances include tyrosine hydroxylase, adrenergic receptors, and dopamine receptors.

　　1. β 2-adrenergic receptor gene knockout mice

　　The α 2-adrenergic receptor plays an important role in regulating the release of neurotransmitters in the central and peripheral sympathetic nervous systems. It mainly inhibits the sympathetic nervous system, and knocking out the receptor gene enhances the activity of the sympathetic nervous system, leading to hypertension. The polymorphism of the β 2-adrenergic receptor gene is associated with human hypertension to some extent. Mice with β 2-adrenergic receptor gene knockout have normal blood pressure, but exercise or administration of adrenaline leads to changes in vascular tone and energy metabolism, which further leads to the occurrence of hypertension. This experimental study indicates that abnormal β 2 adrenergic receptors do not directly lead to primary hypertension (model source: Department of Pediatrics, Georgetown University Medieal Center, Washington, DC 20007, USA)。

　　2. D receptor knockout mice

　　Renal dopamine, together with the renal neuroendocrine system, participates in regulating urinary sodium excretion to regulate blood pressure. Dopamine receptors are divided into two subgroups: D1 and D2, with D1 receptors further divided into D1 and D5. These receptors couple with activating G protein receptors to activate adenylate cyclase; D2 receptors are divided into subgroups D2, D3, and D4. These receptors couple with inhibitory G protein receptors to inhibit adenylate cyclase activity and calcium channel activity, while also having a regulatory effect on potassium channels. Research has shown that any animal model with dopamine receptor gene knockout produces hypertension. D1 receptor knockout mice showed a significant increase in both systolic and diastolic blood pressure, indicating a decrease in renal sodium excretion and diuretic ability in this type of model. The increase in blood pressure in D2 receptor knockout mice is mainly due to a decrease in sympathetic nervous system excitability inhibition ability and an increase in endothelin receptor (ETB2) activity, leading to hypertension. However, their urinary sodium excretion function is enhanced and sodium transport pump activity is reduced. The elevated blood pressure in D3 receptor knockout mice is associated with abnormalities in the renin-angiotensin aldosterone system. Stimulating the D3 receptor in periglomerular cells can inhibit the protein and mRNA expression of the AT1 receptor in the renal proximal tubules. The elevated blood pressure in D4 receptor knockout mice may be related to the AT1 receptor. The systolic and diastolic blood pressure of D5 receptor knockout were significantly increased, and under high salt diet, their blood pressure further increased, indicating that renal dysfunction plays a certain role in the mechanism of blood pressure elevation in mice. Oxidative stress and abnormal interaction between AT1 receptors in the kidneys are involved in the occurrence and development of hypertension. Knockout mice with five types of dopamine receptor genes all developed hypertension, indicating the important role of dopamine receptors in regulating blood pressure. The establishment of these models is of great significance for studying the pathogenesis of different types of dopamine receptors in hypertension