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ABSTRACfFenoldopam mesylate (PM), a selective post-junctional dopaminergic (DA,) vasodilator, causes lesions of large caliber splanchnic arteries 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 (< 100 Jlm) 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 DA, 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 DA 1 receptors was confirmed in isolated perfused mesenteric arteries by standard pharmacologic techniques; stimulation by PM resulted in vasodilation which was inhibited by the DA) 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 PM 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 oflarge caliber arteries were increased, but PBZ prevented the formation of dopamine-induced fibrinoid lesions in arteries ofsmall 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 PM is caused by stimulation of, and interaction between, alpha-adrenoceptors and dopaminergic DA 1 receptors. Fibrinoid lesions of small arteries (alphaadrenoceptor-mediated) were repaired, as observed morphologically by 14 d after exposure to dopamine. Hemorrhagic lesions of large caliber arteries (DA) receptor-mediated) had undergone significant repair by 28 d after exposure to PM 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 ofpost-junctional dopaminergic DA, receptors may represent a model of polyarteritis nodosa.

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The postsynaptic alpha-adrenoceptors in the isolated rat aorta have been characterized according to the sensitivity of the tissue to selective alpha 1- and alpha 2-adrenoceptor agonists and antagonists. The potency (-log EC50) order of the non-selective alpha-agonist norepinephrine and relatively selective agonists was as follows: norepinephrine (alpha 1 = alpha 2; 7.30); clonidine (alpha 2 greater than alpha 1; 7.01); phenylephrine (alpha 1 greater than alpha 2; 6.99), SK & F 89748--A (alpha 1 greater than alpha 2; 6.65); BHT-920 (alpha 2 much greater than alpha 1; 5.56) and M-7 (alpha 2 greater than alpha 1; 4.66). The isolated rat aorta was 12-200-fold more sensitive to the alpha 1-adrenoceptor agonists phenylephrine and SK & F 89748-A, than to the alpha 2-agonists, BHT-920 and M-7. Prazosin is 245-1259-fold more potent than rauwolscine as an antagonist of contractions induced by various alpha 1- and alpha 2-agonists in the rat aorta. These data indicate that constriction of the smooth muscle of the rat aorta to alpha-adrenergic agonists is mediated through alpha 1- but not alpha 2-adrenoceptors.

THE ROLE of the sympathetic nervous system in human essential hypertension and in animal models of essential hypertension remains controversial despite intensive study for many years. A major ap-