Pearce W J, Reynier-Rebuffel A M, Lee J, Aubineau P, Ignarro L, Seylaz J
Department of Physiology, Loma Linda University School of Medicine, California.
J Pharmacol Exp Ther. 1990 Aug;254(2):616-25.
The present studies were conducted to examine the role of cerebrovascular guanylate cyclase in hypoxic cerebral vasodilatation. In arteries mounted in vitro for measurements of isometric tension, 20 min of hypoxia (bath oxygen partial pressure, approximately 15 Torr) significantly increased cyclic GMP levels from 16 to 32, from 15 to 25 and from 20 to 38 pmol/g in rabbit common carotid, internal carotid and basilar arteries. These increases were blocked either by pretreatment with 3 microM methylene blue, or by removal of the vascular endothelium. Methylene blue also significantly delayed hypoxic relaxation in the basilar and internal carotid arteries, and blocked transient hypoxic vasoconstriction in the common carotid. Together, these in vitro results demonstrate that vascular cytosolic guanylate cyclase participates in an endothelium-dependent manner in the direct effects of hypoxia on cerebral arteries, and that the nature of this participation varies significantly between arteries. When methylene blue (20 mg/kg) was administered in vivo, however, it had no effect on the magnitude of hypoxic cerebral vasodilatation as determined by both local (mass spectrometry) and global (venous outflow) methods of blood flow measurement. This latter finding suggests that: 1) large and small cerebral arteries may differ significantly in terms of either endothelial function or sensitivity to methylene blue; or 2) feedback regulation of other mechanisms of hypoxic cerebral vasodilatation compensate for the effects of guanylate cyclase inhibition. Additional experiments using other inhibitors of cytosolic guanylate cyclase and/or vessels isolated from the cerebral microcirculation will be necessary to distinguish between these possibilities.
进行本研究以检验脑血管鸟苷酸环化酶在缺氧性脑血管舒张中的作用。在体外安装用于测量等长张力的动脉中，20分钟的缺氧（浴氧分压约为15托）使兔颈总动脉、颈内动脉和基底动脉中的环磷酸鸟苷（cGMP）水平显著升高，分别从16升高至32、从15升高至25以及从20升高至38 pmol/g。这些升高可通过用3 microM亚甲蓝预处理或去除血管内皮来阻断。亚甲蓝还显著延迟了基底动脉和颈内动脉的缺氧性舒张，并阻断了颈总动脉的短暂缺氧性收缩。这些体外实验结果共同表明，血管胞质鸟苷酸环化酶以依赖内皮的方式参与缺氧对脑动脉的直接作用，并且这种参与的性质在不同动脉之间有显著差异。然而，当在体内给予亚甲蓝（20 mg/kg）时，通过局部（质谱分析）和整体（静脉流出）血流测量方法确定，它对缺氧性脑血管舒张的幅度没有影响。后一发现表明：1）大脑动脉和小动脉在内皮功能或对亚甲蓝的敏感性方面可能存在显著差异；或者2）缺氧性脑血管舒张的其他机制的反馈调节可补偿鸟苷酸环化酶抑制的作用。需要使用胞质鸟苷酸环化酶的其他抑制剂和/或从脑微循环分离的血管进行额外实验，以区分这些可能性。
