Kerns W D, Arena E, Morgan D G
Department of Experimental Pathology, Smith Kline and French Laboratories, King of Prussia, Pennsylvania 19406.
Am J Pathol. 1989 Aug;135(2):339-49.
Fenoldopam mesylate (FM), a selective, postjunctional, dopaminergic (DA1) vasodilator, causes a novel lesion of large caliber splanchnic arteries (100 to 800 microns) in the rat characterized by necrosis of medial smooth muscle cells and hemorrhage. FM does not induce lesions in other vascular beds of the rat or in dogs or monkeys. Dopamine, like FM, causes hemorrhagic lesions of large caliber splanchnic arteries in the rat, as well as fibrinoid necrosis of small caliber arteries (less than 100 microns) of the splanchnic, cerebral, coronary, and renal vascular beds. Dopamine, an alpha- and beta-adrenoceptor and dopaminergic agonist, is used clinically, principally as a pressor agent. Because these arterial lesions were believed to result from the pharmacologic activity of these two compounds, the role of vascular receptor subtypes in their pathogenesis was investigated. Rats were coexposed to either FM or dopamine and a variety of receptor antagonists (alpha, beta, DA1, DA2, and 5HT2). In rats coexposed to the alpha-adrenoreceptor antagonist phenoxybenzamine (PBZ) and either FM or dopamine, the incidence and severity of hemorrhagic lesions of large caliber arteries were increased; PBZ, however, prevented the formation of dopamine-induced fibrinoid lesions in arteries of small caliber. SK&F 83566-C, a selective DA1 dopaminergic receptor antagonist, prevented the induction of FM and dopamine-induced hemorrhagic lesions of large caliber arteries. Rats exposed concurrently to dopamine, phenoxybenzamine, and SK&F 83566-C were free of all arterial lesions. The other receptor antagonists tested did not prevent arterial injury. Thus, the induction of splanchnic arterial lesions in the rat by dopamine and FM is caused by stimulation of, and interaction between, alpha-adrenoceptors and dopaminergic DA1 receptors. Activation of the postjunctional, dopaminergic (DA1) receptor is causally associated with the induction of novel hemorrhagic lesions of large caliber splanchnic arteries in the rat.
甲磺酸非诺多泮（FM）是一种选择性、作用于节后的多巴胺能（DA1）血管扩张剂，可导致大鼠大口径内脏动脉（100至800微米）出现一种新型病变，其特征为中膜平滑肌细胞坏死和出血。FM不会在大鼠的其他血管床或狗或猴子身上诱发病变。多巴胺与FM一样，会导致大鼠大口径内脏动脉出现出血性病变，以及内脏、脑、冠状动脉和肾血管床的小口径动脉（小于100微米）出现纤维蛋白样坏死。多巴胺是一种α和β肾上腺素能受体及多巴胺能激动剂，主要作为升压药用于临床。由于认为这些动脉病变是由这两种化合物的药理活性导致的，因此研究了血管受体亚型在其发病机制中的作用。将大鼠同时暴露于FM或多巴胺以及多种受体拮抗剂（α、β、DA1、DA2和5HT2）。在同时暴露于α肾上腺素能受体拮抗剂酚苄明（PBZ）和FM或多巴胺的大鼠中，大口径动脉出血性病变的发生率和严重程度增加；然而，PBZ可防止多巴胺诱导的小口径动脉纤维蛋白样病变的形成。选择性DA1多巴胺能受体拮抗剂SK&F 83566-C可防止FM和多巴胺诱导的大口径动脉出血性病变。同时暴露于多巴胺、酚苄明和SK&F 83566-C的大鼠未出现所有动脉病变。所测试的其他受体拮抗剂均不能预防动脉损伤。因此，多巴胺和FM在大鼠中诱导内脏动脉病变是由α肾上腺素能受体和多巴胺能DA1受体的刺激及相互作用引起的。节后多巴胺能（DA1）受体的激活与大鼠大口径内脏动脉新型出血性病变的诱导存在因果关系。
