Meng W, Ayata C, Waeber C, Huang P L, Moskowitz M A
Department of Neurosurgery and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown 02129, USA.
Am J Physiol. 1998 Feb;274(2):H411-5. doi: 10.1152/ajpheart.1998.274.2.H411.
We evaluated the effects of superfusing 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), eNOS null (B) an inhibitor of soluble guanylyl cyclase, and 7-nitroindazole sodium (7-NI), a selective neuronal nitric oxide synthase (nNOS) inhibitor, on the acetylcholine (ACh) response in endothelial NOS (eNOS) null mice. Pial arteriolar diameter was measured by intravital microscopy through a closed cranial window under alpha-chloralose anesthesia. NOS activity was measured by [3H]arginine-to-[3H]citrulline conversion in subjacent cortex in vitro. The density and distribution of muscarinic receptors in the brain were determined by quantitative [3H]quinuclidinyl benzilate autoradiography and did not differ between the eNOS mutants and wild-type mice. ACh superfusion (1 and 10 microM) dose dependently dilated pial arterioles in eNOS null and wild-type mice. ODQ (10 microM) attenuated ACh-induced dilation in both eNOS mutants (41% decrease at 10 microM ACh, P < 0.01, n = 6) and wild-type strains (n = 5 per group). By contrast, topical superfusion of 7-NI (100 microM) attenuated the ACh response in eNOS mutants only (66%, P < 0.05, and 25% decrease, P < 0.05, at 1 and 10 microM ACh, respectively). Our findings suggest that nNOS-guanosine 3',5'-cyclic monophosphate (cGMP)-dependent pathways dilate pial arterioles by compensatory mechanisms after eNOS gene disruption.
我们评估了灌注1H-[1,2,4]恶二唑并[4,3-a]喹喔啉-1-酮（ODQ，一种可溶性鸟苷酸环化酶抑制剂）、eNOS基因敲除小鼠（B）以及7-硝基吲唑钠（7-NI，一种选择性神经元型一氧化氮合酶（nNOS）抑制剂）对内皮型一氧化氮合酶（eNOS）基因敲除小鼠乙酰胆碱（ACh）反应的影响。在α-氯醛糖麻醉下，通过封闭的颅骨视窗利用活体显微镜测量软脑膜小动脉直径。体外通过[3H]精氨酸向[3H]瓜氨酸的转化来测量NOS活性。通过定量[3H]喹宁环基苯甲酸酯放射自显影法测定大脑中毒蕈碱受体的密度和分布，eNOS基因敲除小鼠和野生型小鼠之间无差异。ACh灌注（1和10微摩尔）剂量依赖性地使eNOS基因敲除小鼠和野生型小鼠的软脑膜小动脉扩张。ODQ（10微摩尔）减弱了eNOS基因敲除小鼠（在10微摩尔ACh时降低41%，P<0.01，n = 6）和野生型品系（每组n = 5）中ACh诱导的扩张。相比之下，局部灌注7-NI（100微摩尔）仅减弱了eNOS基因敲除小鼠中的ACh反应（在1和10微摩尔ACh时分别降低66%，P<0.05和25%，P<0.05）。我们的研究结果表明，在eNOS基因破坏后，nNOS-鸟苷3',5'-环磷酸（cGMP）依赖性途径通过代偿机制使软脑膜小动脉扩张。
