Schoeffter P, Miller R C
Mol Pharmacol. 1986 Jul;30(1):53-7.
Acetylcholine relaxes rat aorta and increases aortic cyclic GMP levels by a mechanism (or mechanisms) dependent on the endothelium and on extracellular calcium. Therefore, the effects of representatives of different subclasses of calcium entry blockers, verapamil, nifedipine, diltiazem, and bepridil, on maximal acetylcholine (1 microM)-induced increases in cyclic GMP levels were investigated in rat isolated aorta. None of these compounds, at a concentration (3 microM) sufficient to maximally inhibit agonist-stimulated Ca2+ influx into vascular smooth muscle cells, significantly affected either the basal or the acetylcholine-stimulated tissue cyclic GMP levels. On replacing all but 20 mM Na+ by choline, a condition that might be expected to limit or even abolish Na+-Ca2+ exchange, or in the presence of amiloride (1 mM), an inhibitor of Na+-Ca2+ exchange, acetylcholine-stimulated increases in tissue cyclic GMP levels were abolished or inhibited by about 80%, respectively. In choline containing solution acetylcholine relaxant responses were abolished. The presence of amiloride, or the replacement of Na+ by choline, had no effect on increases in cyclic GMP levels evoked by sodium nitroprusside (0.3 microM), an agent that stimulates cyclic GMP formation in smooth muscle without intervention of the endothelium. Replacement of Na+ by Li+ but not the other treatments depressed basal tissue cyclic GMP levels by about 45% but did not abolish either acetylcholine- or sodium nitroprusside-induced relaxant responses. However, the time course of relaxant responses elicited by both these relaxant agonists in precontracted rat aortic rings with endothelium was altered by Li+ replacement; the half-time to relaxation to acetylcholine was increased by about 70-fold. It is concluded that calcium channels, as characterized in smooth muscle and cardiac tissue, are not involved in the stimulated liberation of an endothelial-derived relaxant factor by acetylcholine, but that an Na+-Ca2+ exchange process may be of importance.
乙酰胆碱可使大鼠主动脉舒张，并通过一种或多种依赖于内皮和细胞外钙的机制增加主动脉环磷酸鸟苷（cGMP）水平。因此，研究了不同亚类钙通道阻滞剂（维拉帕米、硝苯地平、地尔硫䓬和苄普地尔）对大鼠离体主动脉中最大乙酰胆碱（1μM）诱导的cGMP水平升高的影响。这些化合物在足以最大程度抑制激动剂刺激的Ca2+流入血管平滑肌细胞的浓度（3μM）下，均未显著影响基础或乙酰胆碱刺激的组织cGMP水平。用胆碱替代除20 mM Na+以外的所有离子，这种情况可能会限制甚至消除Na+-Ca2+交换，或者在存在amiloride（1 mM）（一种Na+-Ca2+交换抑制剂）的情况下，乙酰胆碱刺激的组织cGMP水平升高分别被消除或抑制了约80%。在含胆碱的溶液中，乙酰胆碱的舒张反应被消除。amiloride的存在或用胆碱替代Na+，对硝普钠（0.3μM）引起的cGMP水平升高没有影响，硝普钠是一种在不依赖内皮干预的情况下刺激平滑肌中cGMP形成的药物。用Li+替代Na+，而不是其他处理，使基础组织cGMP水平降低了约45%，但并未消除乙酰胆碱或硝普钠诱导的舒张反应。然而，Li+替代改变了这两种舒张激动剂在有内皮的预收缩大鼠主动脉环中引起的舒张反应的时间进程；乙酰胆碱舒张的半衰期增加了约70倍。结论是，平滑肌和心脏组织中所描述的钙通道不参与乙酰胆碱刺激内皮衍生舒张因子的释放，但Na+-Ca2+交换过程可能很重要。
