Diz D I, Westwood B, Bosch S M, Ganten D, Ferrario C
Hypertension Center, Division of Surgery, Wake Forest University, Winston-Salem, NC 27157-1032, USA.
Hypertension. 1998 Jan;31(1 Pt 2):473-9. doi: 10.1161/01.hyp.31.1.473.
Angiotensin (Ang) II increases substance P (SP) efflux from perfused slices of medulla oblongata, and a peptide antagonist of SP, [Leu11,psiCH2NH10-11]SP, blocks the acute hypotension and bradycardia caused by Ang II injected into the nucleus tractus solitarii (nTS) of Harlan Sprague-Dawley (SD) rats. We investigated whether the same relationships exist in (mRen2)27 renin transgenic (TG) rats, which have chronic elevations of medullary tissue Ang II levels. Ang II increased SP efflux (48% above control; P<0.01) from slices of medulla prepared from 8- to 12-week old male TG rats. Injections of Ang II (250 fmol in 30 nL) into the nTS of chloralose-urethane anesthetized TG rats produced a significant increase in pressure of 7+/-2 mm Hg before a 13+/-3 mm Hg fall in pressure. Ang II induced similar depressor responses in Hannover SD rats but no increase in pressure. After nTS injection of the NK1-selective SP antagonist CP-96,345 (30 pmol in 60 nL), Ang II-induced hypotension was blocked in both groups, as was the pressor component in hypertensive rats. Hypotensive and bradycardic effects of glutamate (0.6 nmol in 30 nL) injected into the nTS were not altered by CP-96,345. In vitro receptor autoradiography showed that the SP antagonist (10 or 100 microM) did not compete for 125I-Ang II binding in the dorsal medulla, a result suggesting that it did not interact directly with Ang II receptors. Thus, the nTS cardiovascular effects of Ang II are mediated by SP in both normotensive rats and a model of hypertension with altered endogenous levels of Ang II. These findings link Ang II-induced effects on SP release from brain slices of the medulla oblongata to acute cardiovascular actions of the peptide through an NK1 receptor.
血管紧张素（Ang）II可增加延髓灌流切片中P物质（SP）的流出，而SP的一种肽拮抗剂[Leu11,psiCH2NH10 - 11]SP可阻断注入哈兰斯普拉格 - 道利（SD）大鼠孤束核（nTS）的Ang II所引起的急性低血压和心动过缓。我们研究了在（mRen2）27肾素转基因（TG）大鼠中是否存在相同的关系，这类大鼠的髓质组织Ang II水平长期升高。Ang II可使8至12周龄雄性TG大鼠制备的延髓切片中的SP流出增加（比对照组高48%；P<0.01）。向用氯醛糖 - 乌拉坦麻醉的TG大鼠的nTS中注射Ang II（250飞摩尔，溶于30纳升），在血压下降13±3毫米汞柱之前，压力显著升高7±2毫米汞柱。Ang II在汉诺威SD大鼠中诱导出类似的降压反应，但未使血压升高。在nTS注射NK1选择性SP拮抗剂CP - 96,345（30皮摩尔，溶于60纳升）后，两组中Ang II诱导的低血压均被阻断，高血压大鼠中的升压成分也被阻断。注入nTS的谷氨酸（0.6纳摩尔，溶于30纳升）的降压和心动过缓作用未被CP - 96,345改变。体外受体放射自显影显示，SP拮抗剂（10或100微摩尔）在延髓背侧不与125I - Ang II结合竞争，这一结果表明它不直接与Ang II受体相互作用。因此，在正常血压大鼠和内源性Ang II水平改变的高血压模型中，Ang II对nTS的心血管作用均由SP介导。这些发现通过NK1受体将Ang II对延髓脑片SP释放的诱导作用与该肽的急性心血管作用联系起来。
