Schmidt K, Klatt P, Mayer B
Institut für Pharmakologie und Toxikologie, Universität Graz, Austria.
Arterioscler Thromb. 1993 Aug;13(8):1159-63. doi: 10.1161/01.atv.13.8.1159.
A diminished relaxant response of atherosclerotic arteries to nitrovasodilators has been frequently observed in advanced stages of hypercholesterolemia. In the present study, we investigated whether this effect might be a result of reduced activity of smooth muscle guanylyl cyclase. Experimental atherosclerosis was induced by feeding rabbits a cholesterol-rich diet (1%) over a period of 4 months. Aortas were removed and homogenized, and guanylyl cyclase activity was measured in the 100,000 g supernatants. Sodium nitroprusside, which stimulated cyclic GMP (cGMP) formation in control tissues almost 200-fold (from 3 to 585 pmol cGMP.mg-1 x min-1), increased enzyme activities in atherosclerotic aortas only approximately 90-fold (from 3 to 257 pmol cGMP.mg-1 x min-1). Similarly, the maximal stimulatory effects of S-nitroso-glutathione were reduced from 200-fold (controls) to 114-fold in atherosclerotic tissues. Basal guanylyl cyclase activities were identical in both atherosclerotic and control vessels. Hypercholesterolemia also reduced the activity of smooth muscle adenylyl cyclase. In control aortas, basal and NaF-stimulated enzyme activities were 24 and 349 pmol cAMP.mg-1 x min-1, respectively, whereas cAMP formation was reduced in atherosclerotic aortas to 7 (basal) and 96 (NaF) pmol cAMP.mg-1.min-1. The stimulatory effect of NaF (approximately 14-fold) remained unchanged. Since adenylyl and guanylyl cyclase have important functions in regulating vascular tone, reduced activities of both enzymes may contribute to the diminished relaxant and/or enhanced vasoconstricting effects of vasoactive compounds in atherosclerotic blood vessels.
在高胆固醇血症的晚期阶段，经常观察到动脉粥样硬化动脉对硝基血管扩张剂的舒张反应减弱。在本研究中，我们调查了这种效应是否可能是平滑肌鸟苷酸环化酶活性降低的结果。通过给兔子喂食富含胆固醇的饮食（1%），持续4个月来诱导实验性动脉粥样硬化。取出主动脉并匀浆，在100,000g的上清液中测量鸟苷酸环化酶活性。硝普钠在对照组织中刺激环磷酸鸟苷（cGMP）形成近200倍（从3至585 pmol cGMP·mg-1·min-1），而在动脉粥样硬化主动脉中仅使酶活性增加约90倍（从3至257 pmol cGMP·mg-1·min-1）。同样，S-亚硝基谷胱甘肽的最大刺激作用在动脉粥样硬化组织中从200倍（对照）降低到114倍。动脉粥样硬化血管和对照血管中的基础鸟苷酸环化酶活性相同。高胆固醇血症还降低了平滑肌腺苷酸环化酶的活性。在对照主动脉中，基础和氟化钠刺激的酶活性分别为24和349 pmol cAMP·mg-1·min-1，而在动脉粥样硬化主动脉中cAMP形成减少至7（基础）和96（氟化钠）pmol cAMP·mg-1·min-1。氟化钠的刺激作用（约14倍）保持不变。由于腺苷酸环化酶和鸟苷酸环化酶在调节血管张力方面具有重要功能，两种酶活性的降低可能导致动脉粥样硬化血管中血管活性化合物的舒张作用减弱和/或血管收缩作用增强。
