Catecholamine biosynthesis and blood pressure

我们发现苯乙醇胺N-甲基转移酶(PNMT)是合成 肾上腺素参与肾上腺以外的许多功能。PNMT在心脏发育早期表达，并可在心脏中被糖皮质激素诱导。PNMT也存在于大脑中特定的神经细胞中，这些神经细胞参与血压控制和交感神经系统的温和激活。研究人员开发了一种PNMT基因敲除小鼠。该小鼠在心脏和脑中都能很好地定位表达PNMT的细胞。这只小鼠将被用来定位PNMT在个体发育过程中的胎儿表达，并确定在发育过程中表达PNMT的心肌细胞。将对小鼠进行杂交，使其在表达PNMT的细胞中产生儿茶酚胺的有条件的敲除。将对这种有条件的基因敲除动物进行研究，以确定这些细胞中的儿茶酚胺在心脏中的表达是否对胎儿心脏发育至关重要，因为无法使任何儿茶酚胺产生的动物会死于心脏异常。初步研究发现，PNMT基因敲除小鼠患有高血压。研究将定义这些小鼠的慢性和应激性血压，并将调查肾上腺素失效的假设 大脑中的产物会抑制交感神经活动，从而导致高血压。 初步研究发现，携带PNMT启动子多态导致该基因表达水平低的受试者交感神经活动增加。人类研究将确定PNMT基因高表达和低表达的受试者的基础和应激水平的自主神经活性，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对PNMT基因在自主神经和心血管生理学中的重要作用的补充理解。

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.