Rossi Noreen F, Beierwaltes William H
Dept. of Medicine, Wayne State Univ. School of Medicine and John D. Dingell VA Medical Center, 4160 John R #908, Detroit, MI 48201, USA.
Am J Physiol Regul Integr Comp Physiol. 2006 May;290(5):R1208-15. doi: 10.1152/ajpregu.00701.2005. Epub 2005 Dec 15.
Endothelin (ET) peptides stimulate vasopressin (AVP) secretion via ET(B) receptors at hypothalamic loci. Nitric oxide modulates the actions of ET in the cardiovascular system and also influences neurotransmission and specifically suppresses firing of magnocellular neurons. The purpose of these studies was to ascertain whether nitric oxide, generated in response to ET(B) receptor stimulation, buffers the stimulatory effect of ET and suppresses AVP release. Studies were performed using a pharmacological approach in hypothalamo-neurohypophyseal explants from rats, and an alternative strategy using explants from mice with an inactivating mutation of neuronal NOS (nNOS-/-) and their wild-type parent strain. Whole explants in standard culture or only the hypothalamus of compartmentalized explants was exposed to the ET(B) selective agonist, IRL 1620 (10(-13) to 10(-8) M). Rat and wild-type mouse explants displayed similar responses, although absolute basal release rates were higher from murine explants. Maximal AVP release at 0.1 nM IRL 1620 was 311 +/- 63 (rat) and 422 +/- 112% basal x explant(-1) x h(-1) (mouse). Sodium nitroprusside (SNP; 0.1 mM) suppressed maximal AVP release to basal values. N(omega)-nitro-L-arginine methyl ester (L-NAME, 0.1 microM), which did not itself stimulate AVP secretion, more than doubled the response to 1 pM IRL 1620, from 136 +/- 28 to 295 +/- 49% basal x explant(-1) x h(-1) (P < 0.05) by rat explants. Explants from wild-type mice responded similarly. Explants from nNOS-/- mice had higher basal AVP secretory rate in response to 1 pM IRL 1620: 271 +/- 48 compared with 150 +/- 24% basal x explant(-1) x h(-1) (P < 0.05) from wild-type murine explants. In the nNOS-/-, SNP suppressed stimulated release, and L-NAME exerted no additional stimulatory effect: 243 +/- 38% basal x explant(-1) x h(-1). Thus nitric oxide inhibits the AVP secretory response induced by ET(B) receptor activation within the hypothalamo-neurohypophyseal system and is generated primarily by the nNOS isoform. The modulation of AVP secretion by ET and also nitric oxide can take place independently from their effects on cerebral blood flow, systemic hemodynamics, or the arterial baroreflex.
内皮素（ET）肽通过下丘脑位点的ET（B）受体刺激血管加压素（AVP）分泌。一氧化氮调节ET在心血管系统中的作用，也影响神经传递，并特别抑制大细胞神经元的放电。这些研究的目的是确定响应ET（B）受体刺激而产生的一氧化氮是否缓冲ET的刺激作用并抑制AVP释放。研究采用药理学方法在大鼠下丘脑 - 神经垂体外植体中进行，并采用另一种策略，使用来自具有神经元型一氧化氮合酶（nNOS-/-）失活突变的小鼠及其野生型亲本品系的外植体。将标准培养中的完整外植体或仅分隔外植体的下丘脑暴露于ET（B）选择性激动剂IRL 1620（10^-13至10^-8 M）。大鼠和野生型小鼠外植体表现出相似的反应，尽管小鼠外植体的绝对基础释放率更高。在0.1 nM IRL 1620时最大AVP释放量为311±63（大鼠）和422±112％基础×外植体^-1×小时^-1（小鼠）。硝普钠（SNP; 0.1 mM）将最大AVP释放抑制至基础值。N（ω）-硝基-L-精氨酸甲酯（L-NAME，0.1 microM）本身不刺激AVP分泌，但使对1 pM IRL 1620的反应增加一倍以上，从136±28增加到295±49％基础×外植体^-1×小时^-1（P <0.05），大鼠外植体反应类似。野生型小鼠的外植体也有类似反应。来自nNOS-/-小鼠的外植体对1 pM IRL 1620的基础AVP分泌率更高：271±48，而野生型小鼠外植体为150±24％基础×外植体^-1×小时^-1（P <0.05）。在nNOS-/-中，SNP抑制刺激释放，L-NAME没有额外的刺激作用：243±38％基础×外植体^-1×小时^-1。因此，一氧化氮在下丘脑 - 神经垂体系统内抑制由ET（B）受体激活诱导的AVP分泌反应，并且主要由nNOS同工型产生。ET和一氧化氮对AVP分泌的调节可以独立于它们对脑血流量、全身血流动力学或动脉压力反射的影响而发生。
