Nassar Noha, Abdel-Rahman Abdel A
Department of Pharmacology and Toxicology, School of Medicine, East Carolina University, Greenville, NC 27834, USA.
J Pharmacol Exp Ther. 2008 Jan;324(1):79-85. doi: 10.1124/jpet.107.129692. Epub 2007 Oct 12.
The cellular mechanisms that underlie the enhancement of clonidine-evoked hypotension in aortic barodenervated (ABD) rats and its dependence on central adenosine A(2A) receptor (A(2A)R) are not known. We tested the hypothesis that A(2A)R-mediated phosphorylation of extracellular signal-regulated kinase (pERK)1/2 in the rostral ventrolateral medulla (RVLM) and its downstream activation of nitric-oxide synthase (NOS)-NO signaling underlie the centrally (clonidine)-mediated hypotension. We first demonstrated an up-regulation of the molecular targets for clonidine [imidazoline I(1) and alpha(2A) adrenergic receptors (alpha(2A)R)] in the RVLM of ABD compared with sham-operated (SO) rats; this finding might explain the enhanced clonidine hypotension in ABD rats. A similar anatomical up-regulation of the RVLM A(2A)R was evident and was complemented with enhanced central A(2A)R [2-[4-[(2-carboxyethyl)phenyl]ethylamino]-5'-N-ethylcarboxamidoadenosine; CGS21680]-mediated hypotension in ABD rats. The hypotension produced by intracisternal CGS21680 or clonidine, in conscious ABD rats, was associated with a significant increase in pERK1/2 level in the RVLM. Whereas selective A(2A)R blockade [5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-epsilon]-1,2,4-triazolo[1,5-c]pyrimidine; SCH58261] or NOS inhibition (N(omega)-nitro-l-arginine methyl ester) virtually abolished clonidine-evoked hypotension, clonidine-evoked enhancement of RVLM pERK1/2 production was only abrogated by SCH58261 pretreatment. These findings suggest that interventions that act centrally to increase RVLM neuronal pERK1/2 production elicit hypotension via the activation of downstream NOS-NO signaling. The findings also yield insight into a cellular mechanism that might explain the dependence of centrally (clonidine)-mediated hypotension on central A(2A)R signaling in the ABD rat.
主动脉压力感受性神经切除（ABD）大鼠可乐定诱发的低血压增强及其对中枢腺苷A2A受体（A2AR）的依赖性的细胞机制尚不清楚。我们检验了以下假设：延髓头端腹外侧区（RVLM）中A2AR介导的细胞外信号调节激酶（pERK）1/2磷酸化及其下游一氧化氮合酶（NOS）-NO信号的激活是中枢（可乐定）介导的低血压的基础。我们首先证明，与假手术（SO）大鼠相比，ABD大鼠RVLM中可乐定的分子靶点[咪唑啉I1和α2A肾上腺素能受体（α2AR）]上调；这一发现可能解释了ABD大鼠可乐定低血压增强的现象。RVLM A2AR的类似解剖学上调很明显，并且与ABD大鼠中枢A2AR [2-[4-[(2-羧乙基）苯基]乙基氨基]-5'-N-乙基羧酰胺腺苷；CGS21680]介导的低血压增强相补充。清醒ABD大鼠脑池内注射CGS21680或可乐定产生的低血压与RVLM中pERK1/2水平的显著升高有关。选择性A2AR阻断[5-氨基-7-（2-苯乙基）-2-（2-呋喃基）-吡唑并[4,3-ε]-1,2,4-三唑并[1,5-c]嘧啶；SCH58261]或NOS抑制（Nω-硝基-L-精氨酸甲酯）几乎消除了可乐定诱发的低血压，而可乐定诱发的RVLM pERK1/2产生的增强仅被SCH58261预处理消除。这些发现表明，通过激活下游NOS-NO信号，作用于中枢以增加RVLM神经元pERK1/2产生的干预措施会引发低血压。这些发现还深入了解了一种细胞机制，该机制可能解释了中枢（可乐定）介导的低血压对ABD大鼠中枢A2AR信号的依赖性。
