Takayasu M, Suzuki Y, Shibuya M, Asano T, Kanamori M, Okada T, Kageyama N, Hidaka H
J Neurosurg. 1986 Jul;65(1):80-5. doi: 10.3171/jns.1986.65.1.0080.
The authors have examined the effects of the HA compounds HA1004(N-(2-guanidinoethyl)-5-isoquinolinesulfonamide) and HA 1077(1-(5-isoquinolinesulfonyl)homopiperazine), which are intracellular calcium antagonists, on delayed cerebral vasospasm from subarachnoid hemorrhage (SAH). The modes of action of these compounds were compared with those of the more commonly used calcium entry blockers. Calcium ionophore A23187 (4.8 X 10(-6) M)-induced contraction of a canine basilar artery strip was completely antagonized by the HA compounds (10(-5) M) but not by the entry-blocking calcium antagonists nicardipine, diltiazem, and verapamil (10(-5) M), suggesting that the HA compounds act differently. Delayed cerebral vasospasm was induced by a "two-hemorrhage" canine model. The magnitude of the vasospasm and the effects of the HA compounds were determined angiographically. On SAH Day 7, a significant vasospasm was observed in every dog. The diameter of the basilar artery had diminished to 59% +/- 2% (mean +/- standard error) of the control value obtained before SAH (on Day 1). The intravenous administration of HA 1004 caused a mild dilation of the basilar artery of 10% and 11% at doses of 3 and 10 mg/kg, respectively; however, HA 1077 produced a more marked dilation of 19% and 27%, respectively, at the same doses. Both of these drugs lowered mean arterial blood pressure to about 80% and 50% at doses of 3 and 10 mg/kg, respectively. Intracisternal administration of the HA compounds (6 mg) completely reversed cerebral vasospasm without much effect on the blood pressure. The intracellular calcium antagonists of the HA compound group appear to be promising agents for the treatment of intractable cerebral vasospasm.
作者研究了细胞内钙拮抗剂HA化合物HA1004（N-（2-胍基乙基）-5-异喹啉磺酰胺）和HA1077（1-（5-异喹啉磺酰基）高哌嗪）对蛛网膜下腔出血（SAH）后迟发性脑血管痉挛的影响。将这些化合物的作用方式与更常用的钙通道阻滞剂的作用方式进行了比较。钙离子载体A23187（4.8×10⁻⁶ M）诱导的犬基底动脉条收缩被HA化合物（10⁻⁵ M）完全拮抗，但未被钙通道阻滞剂尼卡地平、地尔硫卓和维拉帕米（10⁻⁵ M）拮抗，这表明HA化合物的作用方式不同。采用“两次出血”犬模型诱导迟发性脑血管痉挛。通过血管造影确定血管痉挛的程度和HA化合物的作用。在SAH第7天，每只犬均观察到明显的血管痉挛。基底动脉直径已缩小至SAH前（第1天）获得的对照值的59%±2%（平均值±标准误差）。静脉注射HA1004，剂量为3和10 mg/kg时，分别使基底动脉轻度扩张10%和11%；然而，HA1077在相同剂量下分别产生更明显的扩张，为19%和27%。这两种药物在剂量为3和10 mg/kg时，分别将平均动脉血压降至约80%和50%。脑池内注射HA化合物（6 mg）可完全逆转脑血管痉挛，而对血压影响不大。HA化合物组的细胞内钙拮抗剂似乎是治疗难治性脑血管痉挛的有前景的药物。
