Catecholamine biosynthesis and blood pressure

我们发现，苯乙醇胺N-甲基转移酶（PNMT），合成 肾上腺素参与肾上腺以外的许多功能。PNMT在心脏发育的早期表达，并且可以在心脏中被糖皮质激素诱导。PNMT也存在于大脑的特定神经细胞中，其参与血压控制和交感神经系统的情绪激活。研究人员已经开发出PNMT敲除小鼠。该小鼠在心脏和脑中提供了PNMT表达细胞的极好的组织学定位。该小鼠将用于绘制个体发育期间PNMT的胎儿表达图，并确定发育期间表达PNMT的心脏细胞。将小鼠杂交以产生PNMT表达细胞中的儿茶酚胺产生的条件性敲除。将研究这种条件性基因敲除动物，以确定这些细胞中儿茶酚胺的心脏表达是否对胎儿心脏发育至关重要，因为不能产生任何儿茶酚胺的动物会因心脏异常而死亡。初步研究发现PNMT敲除小鼠是高血压。研究将确定这些小鼠的慢性和应激血压，并将调查肾上腺素治疗失败的假设。 脑中的产生使交感神经活动失去抑制，导致高血压。 最初的研究发现，携带PNMT启动子多态性的人类受试者的交感神经活动增加，导致该基因的低水平表达。人体研究将确定具有PNMT基因的高和低表达多态性的受试者的自主活动的基础和应激水平，并测量这些受试者的基础血压和对应激源的血压反应。平行的人类和动物研究应该提供一个互补的理解PNMT基因在自主神经和心血管生理学中的重要作用。

We found that phenylethanolamine N-methyltransferase (PNMT), the enzyme that synthesizes epinephrine, is involved in many functions outside the adrenal. PNMT is expressed early in cardiac development, and can be induced in the heart by glucocorticoids. PNMT is also present in specific nerve cells of the brain which participate in blood pressure control and temper activation of the sympathetic nervous system. The investigators have developed a PNMT knockout mouse. This mouse provides excellent histologic localization of PNMT expressing cells in both heart and brain. This mouse will be used to map the fetal expression of PNMT during ontogeny and to define the cardiac cells that express PNMT during development. The mouse will be cross-bred to develop a conditional knock-out of catecholamine production in PNMT expressing cells. This conditional knockout animal will be studied to determine if cardiac expression of catecholamines in these cells is essential for fetal cardiac development, since animals that cannot make any catecholamines die with abnormal hearts. Initial studies find the PNMT knockout mouse to be hypertensive. Studies will define chronic and stress blood pressures of these mice and will investigate the hypothesis that a failure of epinephrine production in the brain disinhibits sympathetic nerve activity leading to hypertension. Initial studies find increased sympathetic nervous activity in human subjects who carry a polymorphism of the PNMT promoter that leads to low levels of expression of the gene. Human studies will define basal and stressed levels of autonomic acitivity in subjects with high and low expressing polymorphisms of the PNMT gene and measure basal blood pressures and blood pressure responses to stressors in these subjects. The parallel human and animal studies should provide a complementary understanding of the important role of the PNMT gene in autonomic and cardiovascular physiology.