Louden C, Nambi P, Branch C, Gossett K, Pullen M, Eustis S, Solleveld H A
Department of Toxicology-US, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939, USA.
J Cardiovasc Pharmacol. 1998;31 Suppl 1:S384-5. doi: 10.1097/00005344-199800001-00109.
Structurally and pharmacologically diverse vasodilators are known to lower blood pressure, increase heart rate, and produce acute injury to right coronary arteries in the dog. Administration of low concentrations of endothelin-1 (ET-1) to anesthetized dogs causes coronary vasoconstriction and reductions in coronary blood flow. Therefore, pharmacologic blockade of endothelin receptors (ETA and ETB) with the mixed ET receptor antagonist SB 209670 could lead to coronary vasodilatation. In toxicology studies, continuous administration of SB 209670 to dogs for 5 days at 50 micrograms/kg/min was associated with minor but sustained increases in heart rate (10-30 beats/min), slight decreases in mean arterial pressure (10-15 mm Hg), and medial hemorrhage and necrosis of extramural coronary arteries in the right atria. Doses of 10 micrograms/kg/min had no effect. The lesions in the right atrium were associated with the highest density of ET receptors, approximately 470 fmol/mg compared to 170-200 fmol/mg in the ventricles and septum. Because changes in systemic cardiovascular parameters are minimal, the coronary arterial lesion is most likely due to a local vasodilatory effect in the coronary bed.
已知结构和药理作用各异的血管扩张剂可降低血压、增加心率，并对犬的右冠状动脉造成急性损伤。给麻醉的犬注射低浓度的内皮素 -1（ET -1）会导致冠状动脉收缩并减少冠状动脉血流量。因此，使用混合内皮素受体拮抗剂SB 209670对内皮素受体（ETA和ETB）进行药理阻断可能会导致冠状动脉扩张。在毒理学研究中，以50微克/千克/分钟的剂量连续5天给犬注射SB 209670，会导致心率出现轻微但持续的增加（10 - 30次/分钟），平均动脉压略有下降（10 - 15毫米汞柱），以及右心房壁外冠状动脉出现中层出血和坏死。10微克/千克/分钟的剂量则没有效果。右心房的病变与内皮素受体的最高密度相关，约为470飞摩尔/毫克，而心室和隔膜中的密度为170 - 200飞摩尔/毫克。由于全身心血管参数的变化很小，冠状动脉病变很可能是由于冠状动脉床的局部血管扩张作用所致。
