Role of dopaminergic and adrenergic receptors in the pathogenesis of arterial lesions induced by fenoldopam mesylate and dopamine in the rat

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.