Homaidan F R, Donowitz M, Weiland G A, Sharp G W
Department of Pharmacology, New York State College of Veterinary Medicine, Cornell University, Ithaca 14853.
Am J Physiol. 1989 Jul;257(1 Pt 1):G86-93. doi: 10.1152/ajpgi.1989.257.1.G86.
The actions of three different types of calcium channel blockers on short-circuit current (Isc) in rabbit ileum were studied. These included the phenylalkylamines, verapamil and (l)-desmethoxyverapamil (D888); the dihydropyridines, nifedipine and nitrendipine; and the benzothiazepine, diltiazem. All of the drugs decreased Isc, a change associated with increased Na and Cl absorption. Verapamil and D888 had the largest effects. The dihydropyridine, BAY K 8644, a calcium channel activator, increased Isc and decreased Na and Cl absorption, effects not inhibited by tetrodotoxin. The phenylalkylamines had an additional effect on Isc in the presence of a maximally inhibitory concentration of the dihydropyridines, suggesting the possibility of two distinct calcium channels, one of which is the L-type voltage-activated, dihydropyridine- and phenylalkylamine-sensitive channel, and the other is a channel only sensitive to phenylalkylamines but not to dihydropyridines. [3H]nitrendipine and [3H]D888 binding to an enriched preparation of basolateral membranes from ileal epithelial cells was characterized. Each ligand bound specifically and saturably to an apparently single population of high-affinity sites with [3H]D888 having three times as many binding sites as [3H]nitrendipine. [3H]nitrendipine binding was partially inhibited by verapamil and D888 and was increased by diltiazem; whereas [3H]D888 binding was inhibited completely by verapamil but only partially by nitrendipine and diltiazem. These transport and binding studies suggest the presence of two types of Ca2+ channels in ileal epithelial cells, one of which interacts with the dihydropyridines, the phenylalkylamines, and the benzothiazepines at three different sites and the other channel that only binds the phenylalkylamines.
研究了三种不同类型的钙通道阻滞剂对兔回肠短路电流（Isc）的作用。这些阻滞剂包括苯烷基胺类的维拉帕米和（l）-去甲氧基维拉帕米（D888）；二氢吡啶类的硝苯地平和尼群地平；以及苯并硫氮䓬类的地尔硫䓬。所有这些药物均降低了Isc，这种变化与钠和氯吸收增加有关。维拉帕米和D888的作用最大。二氢吡啶类的BAY K 8644是一种钙通道激活剂，可增加Isc并减少钠和氯的吸收，其作用不受河豚毒素抑制。在二氢吡啶类药物达到最大抑制浓度时，苯烷基胺类对Isc还有额外作用，这表明可能存在两种不同的钙通道，其中一种是L型电压激活的、对二氢吡啶类和苯烷基胺类敏感的通道，另一种通道仅对苯烷基胺类敏感而对二氢吡啶类不敏感。对[3H]尼群地平和[3H]D888与回肠上皮细胞基底外侧膜富集制剂的结合进行了表征。每种配体均特异性且饱和地结合到一个明显单一的高亲和力位点群体，[3H]D888的结合位点数量是[3H]尼群地平的三倍。[3H]尼群地平的结合受到维拉帕米和D888的部分抑制，并被地尔硫䓬增强；而[3H]D888的结合被维拉帕米完全抑制，但仅被尼群地平和地尔硫䓬部分抑制。这些转运和结合研究表明，回肠上皮细胞中存在两种类型的Ca2+通道，其中一种在三个不同位点与二氢吡啶类、苯烷基胺类和苯并硫氮䓬类相互作用，另一种通道仅结合苯烷基胺类。
