Effects of calcium antagonists on vascular endothelial, smooth muscle and sympathetic nerve functions

本文观察了钙拮抗剂对犬动脉条对直接缩血管药(前列腺素F_2α)、EDRF释放剂(P物质)和神经刺激的机械反应的影响。尼卡地平(L型钙通道阻滞剂)、氟桂利嗪和AE0047(一种新的二氢吡啶衍生物)可抑制前列腺素F_2α和前列腺素F_2α的收缩，但不能被N型钙通道阻滞剂欧米茄毒素所抑制。P物质引起的内皮依赖性松弛不被尼卡地平、欧米茄毒素或T型通道阻滞剂四氯氰菊酯所抑制。血管周围神经刺激引起大脑动脉的松弛，而肠系膜动脉的收缩，这种松弛和收缩分别被一氧化氮合酶抑制剂和α-肾上腺素能受体拮抗剂所阻断，表明大脑动脉和肠系膜动脉释放的神经递质分别是NO和去甲肾上腺素。尼卡地平和t-…高剂量的溴氰菊酯不影响大鼠大脑动脉的神经源性松弛，但欧米茄毒素、氟桂利嗪和AE0047可抑制这种松弛。虽然AE0047和尼卡地平都能抑制神经刺激和去甲肾上腺素引起的收缩，但尼卡地平不能抑制去甲肾上腺素的释放，但AE0047能抑制去甲肾上腺素的释放。非选择性钙拮抗剂镉可抑制前列腺素F_2α、P物质和神经刺激引起的机械反应。这些结果表明，钙内流在血管平滑肌中主要受L通道的调节，在血管周围神经中主要受N型通道的调节，但由于特异性的L、N和T型钙通道抑制剂不能抑制钙依赖的内皮功能，因此对血管内皮细胞钙内流的调节尚不清楚。氟桂利嗪而不是尼卡地平对神经源性脑血管松弛的抑制作用可能是其抗偏头痛作用的原因。此外，还发现一些新的脱氢吡啶类化合物不仅具有直接的血管扩张作用，而且还具有抑制交感神经功能的作用。钙/钙调蛋白依赖的蛋白激酶II也参与了神经NO的产生。较少

Effects of calcium antagonists on the mechanical responses of isolated dog artery strips to the direct vasoconstrictor (prostaglandin F_<2alpha>), EDRF releaser (substance P) and nerve stimulation were examined. Contraction induced by prostaglandin F_<2alpha> was inhibited by nicardipine (L-type calcium channnel inhibitor), flunarizine and AE0047 (a new dihydropyridine derivative), but not by omega-conotoxin (N-type channel inhibitor). Endothelium-dependent relaxation caused by substance P was not suppressed by nicardipine, omega-conotoxin nor tetramethrin (T-type channel inhibitor). Perivascular nerve stimulation produced relaxations in the cerebral artery whereas contractions in the mesenteric artery ; the relaxation and contraction were abolished by nitric oxide (NO) synthase inhibitors and alpha-adrenoceptor antagonists, respectively, indicating that neurotransmitters mainly released from the cerebral and mesenteric arteries are NO and noradrenaline, respectively. Nicardipine and t … More etramethrin did not affect the neurogenic relaxation in the cerebral artery, but omega-conotoxin, flunarizine and AE0047 inhibited the relaxation. Although contractions induced by nerve stimulation and noradrenaline were suppressed by both AE0047 and nicardipine, noradrenaline release caused by nerve stumulation was not inhibited by nicardipine but by AE0047. Cadmium, a non-selective calcium antagonist, inhibited the mechanical responses to prostaglandin F_<2alpha>, substance P and nerve stimulation. These results indicate that calcium influx is mainly regulated by L-type channel in the vascular smooth muscles and by N-type channel in the perivascular nerves, but that in the endothelial cells has not been determined since specific L-, N- and T-type calcium channel inhibitors failed to inhibit the calcium-dependent endothelial function. Suppression by flunarizine, but not by nicardipine, of the neurogenic cerebroarteial relaxation may explain its anti-migraine action. Further, it is found that some of the new dehydropyridine derivatives possess not only direct vasodilator action but also inhibitory action on sympathetic nerve function. Involvement of calcium/calmodulin-dependent protein kinase II in the production of neural NO has also been suggested. Less