Pathogenesis of arterial lesions induced by dopaminergic compounds in the rat.
Fenoldopam mesylate (FM), a selective post-junctional dopaminergic (DA1) vasodilator, causes lesions of large caliber splanchnic arteries (100-800 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 is an alpha- and beta-adrenoceptor and a dopaminergic receptor agonist. Because these arterial lesions are thought to result from the pharmacologic activity of these 2 compounds, we sought to ascertain the presence of DA1 receptors in mesenteric arteries of the rat and to determine the role of these or other vascular receptor subtypes in lesion induction. We also studied the process of repair after arterial injury caused by FM or dopamine. The presence of DA1 receptors was confirmed in isolated perfused mesenteric arteries by standard pharmacologic techniques; stimulation by FM resulted in vasodilation which was inhibited by the DA1 receptor antagonist SK&F 83566-C. Likewise, SK&F 83566-C prevented the induction of hemorrhagic lesions of large caliber arteries in rats upon infusion of FM or dopamine. In rats co-exposed 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, but PBZ prevented the formation of dopamine-induced fibrinoid lesions in arteries of small caliber. Rats exposed concurrently to dopamine, phenoxybenzamine, and SK&F 83566-C were free of all arterial lesions. 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. Fibrinoid lesions of small arteries (alpha-adrenoceptor-mediated) were repaired, as observed morphologically by 14 d after exposure to dopamine. Hemorrhagic lesions of large caliber arteries (DA1 receptor-mediated) had undergone significant repair by 28 d after exposure to FM but these arteries possessed a thicker media surrounded by adventitial fibrosis. Thus, morphologically distinct receptor-mediated splanchnic arterial lesions induced by dopaminergic and alpha-adrenoceptor agonists follow a markedly different course of repair. Arterial lesions induced by FM or dopamine by activation of post-junctional dopaminergic DA1 receptors may represent a model of polyarteritis nodosa.
Kerns
W D
WD
Department of Experimental Pathology, Smith Kline & French Laboratories, King of Prussia, Pennsylvania 19406.
Arena
E
E
Macia
R A
RA
Bugelski
P J
PJ
Matthews
W D
WD
Morgan
D G
DG
D000818:Animals; D001158:Arteries / Q000473:pathology / Q000503:physiopathology; D001552:Benzazepines / Q000633:toxicity; D004298:Dopamine / Q000633:toxicity; D015259:Dopamine Agents / Q000633:toxicity*; D018492:Dopamine Antagonists; D018818:Fenoldopam; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects; D013152:Splanchnic Circulation / Q000187:drug effects; D014652:Vascular Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology
D001552:Benzazepines; D015259:Dopamine Agents; D018492:Dopamine Antagonists; D011954:Receptors, Dopamine; D018818:Fenoldopam; D004298:Dopamine