Fleckenstein A, Fleckenstein-Grün G
Physiological Institute, University of Freiburg, F.R.G.
Eur Heart J. 1988 Jun;9 Suppl H:95-9. doi: 10.1093/eurheartj/9.suppl_h.95.
A transmembrane supply of Ca2+ ions is required for active tension development in both vascular smooth musculature and myocardial fibres. Ca2+ antagonists thus not only damp hyperkinetic myocardial dysfunction but also act against practically all vasoconstrictor or spastic responses of extramural coronary smooth muscle. Clinically important targets of Ca2+ antagonists include the pulmonary, cerebral, mesenteric and renal arteries, as well as the peripheral resistance vessels of the systemic circulation. Ca2+ antagonists are used increasingly to treat acute hypertensive crises as well as for long-term antihypertensive therapy. In physiological experiments, Ca2+ antagonists not only neutralize various vasoconstrictor agents but also greatly reduce the sensitivity of the systemic arteries and arterioles to mechanical stimuli such as extension of the vascular wall by a rise in intraluminal pressure. In human arterial walls, at an advanced age, cytotoxic degrees of Ca2+ overload probably play an important role in the pathogenesis of arteriosclerotic lesions. Severe diabetics and heavy smokers exhibit an even faster progression of age-dependent arterial calcinosis. In rats, the Ca2+ antagonist verapamil not only prevented arterial calcinosis due to overdoses of vitamin D and dihydrotachysterol but also counteracted age-dependent Ca2+ accumulation. Spontaneously hypertensive rats also exhibit progressive arterial Ca2+ overload which responds excellently to the Ca2+ antagonists nifedipine, nimodipine, nisoldipine, nitrendipine, as well as to verapamil and diltiazem. Suitable Ca2+ antagonists could possibly retard or even prevent premature arterial calcinosis in humans. Moreover, Ca2+ antagonists exert a direct cardioprotective effect on the myocardium by preventing intracellular Ca2+ overload.
血管平滑肌组织和心肌纤维产生主动张力都需要跨膜供应钙离子。因此，钙离子拮抗剂不仅能缓解心肌功能亢进导致的功能障碍，还能对抗几乎所有壁外冠状动脉平滑肌的血管收缩或痉挛反应。钙离子拮抗剂在临床上的重要作用靶点包括肺、脑、肠系膜和肾动脉，以及体循环的外周阻力血管。钙离子拮抗剂越来越多地用于治疗急性高血压危象以及长期抗高血压治疗。在生理学实验中，钙离子拮抗剂不仅能中和各种血管收缩剂，还能大大降低全身动脉和小动脉对机械刺激（如管腔内压力升高导致血管壁扩张）的敏感性。在人类动脉壁中，随着年龄增长，细胞毒性程度的钙离子超载可能在动脉粥样硬化病变的发病机制中起重要作用。重度糖尿病患者和重度吸烟者的年龄相关性动脉钙化进展甚至更快。在大鼠中，钙离子拮抗剂维拉帕米不仅能预防因过量服用维生素D和二氢速甾醇导致的动脉钙化，还能抵消年龄相关性钙离子蓄积。自发性高血压大鼠也表现出进行性动脉钙离子超载，对钙离子拮抗剂硝苯地平、尼莫地平、尼索地平、尼群地平等以及维拉帕米和地尔硫卓反应良好。合适的钙离子拮抗剂可能会延缓甚至预防人类过早出现的动脉钙化。此外，钙离子拮抗剂通过防止细胞内钙离子超载对心肌发挥直接的心脏保护作用。
