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Dopamine (3,4-dihydroxyphenylethylamine) is considered to be the immediate metabolic precursor of norepinephrine (1), from which it differs by the absence of a P-OH group. Despite this chemical similarity, previous studies of the action of dopamine (2-9) have demonstrated that many of the circulatory and metabolic effects of this catecholamine are different from those produced by norepinephrine. Horwitz, Fox, and Goldberg (6) observed that intravenous administration of dopamine to normal subjects produced consistent increases in cardiac output and either decreased or did not change peripheral resistance. Norepinephrine, on the other hand, decreases or does not change cardiac output and increases peripheral resistance in normal subjects (10). The circulatory effects of dopamine are potentiated by monoamine oxidase inhibitors to a much greater extent than are those of norepinephrine (9). Dopamine also contrasts with norepinephrine in its failure to increase circulating free fatty acids (7,8). These differences suggest that the effects of

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A. Human StudiesInhalation is the major route of occupational exposure to carbon disulfide. Investigations in volunteers and occupationally exposed workers suggest that equilibrium between inhaled and exhaled CS2 is generally attained during the first 2 hr of Initially, the fraction of inhaled CS2 absorbed was relatively constant over a wide range of exposure concentrations, with approximately 70 to 80% of the inhaled carbon disulfide a b s~r b e d .~' .~~~~~~~ At equilibrium, retention of inhaled CS2 declined to approximately 15 to 45% of the inhaled vapor.61,2239289 It is interesting to note a report that described retention of inhaled CS2 in individuals not previously exposed to this agent that was greater than in those who were chronically exposed to CS2.289 Although the mechanism of the decreased retention with chronic exposure is not known, this observation does suggest caution in extrapolation of acute human exposure data to the chronic exposure situation.Percutaneous absorption is a second potential source of occupational exposure to CS2. Dutkiewicz and Baranowska" evaluated skin absorption by immersion of the hand in aqueous CS2 solutions (0.33 to 1.67 g/Q) for 1 hr. Absorption of CS2 was quantitated by two methods: indirectly by determining CS;? elimination by the lung; and by measurement of the CS2 concentration in the aqueous solutions before and after immersion of the hand. Absorption rates determined by solution analysis were found to range from 0.232 to 0.789 mg/cm2/ hr and were approximately 10 times higher than rates calculated from lung excretion of CS2. Further calculations indicated that only 3% of cutaneously absorbed CS2 was eliminated by the lung. Using the solution data, these investigators also calculated that immersion of a hand for 1 hr in a viscose rayon washing bath containing 0.1 mg/g CS2 would result in a total dose of 17.5 mg. One potential difficulty with this study, however, was that no precautions were described to prevent loss of CS2 from the solutions due to volatilization. Failure to adequately control for this variable would result in an overestimate of percutaneous absorption.Following inhalation exposure the primary route of excretion for unmetabolized CS2 is exhalation from the lung. In 1943, McKee et a1.'56 estimated that 6 to 10% of exposure. 148,156,250,254,296 Volume 11, Issue 3 CRC Critical Reviews in Toxicologyidentification of metabolite(s) responsible for the hepatotoxic effects of high-dose exposure to CS2, particularly in phenobarbital pretreated rats. The formation of the toxic metabolite(s) is thought to involve activation of CS2 by the microsomal mixed function oxidase system. Formation of Water-Soluble MetabolitesAn early study by Strittmatter et a1.226 characterized the overall disposition of the radiolabel in guinea pigs after inhalation of 35S-carbon disulfide. A small fraction (8 to 17%) of the total radioactivity recovered during the 48 hr after various inhalation exposures (13.6 ppm for 8 hr; 20.6 ppm for 16 hr, 25.7 ppm for 40 hr) was exhaled as CS2. ...

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• We have recently demonstrated that intravenous administration of the naturally occurring catecholamine, dopamine, increases effective renal plasma flow, glomerular filtration rate, and sodium excretion in normal human subjects.1 Since renal plasma flow increased in the absence of an alteration in mean arterial pressure, it was concluded that renal vascular resistance was decreased by dopamine. Comparable effects were observed in the dog. The present study was undertaken to characterize these findings more fully. The effects of intravenous dopamine infusion on directly measured renal blood flow and blood pressure were compared with those of isoproterenol and norepinephrine, chosen as catecholamines with strong vasodilator and vasoconstrictor effects, respectively. In addition, renal blood flow responses to direct renal arterial injections of these three agents were studied. To determine whether the renal vascular responses to dopamine were typical of other vascular beds, comparable experiments studying femoral blood flow responses to intraarterial injections of dopamine, isoproterenol, From the Department of Pharmacology and the Department of Medicine (Section of Clinical Pharmacology), Emory University School of Medicine, Atlanta, Georgia.Supported by Grants H-649I and HE-5582 from the U. S. Public Health Service and grants from the American Heart Association, Georgia Heart Associations, the Heart Associations of Palm Beach and Martin Counties, Florida.A portion of the material in this paper has previously appeared in abstract form in Clinical Research 11: 248, 1963 and The Pharmacologist 5: 269, 1963.Accepted for publication November 19, 1964. and norepinephrine were also performed. We found that dopamine is unique among vasoactive agents, since it produces renal vasodilatation and femoral vasoconstriction.Methods Mongrel dogs ranging in weight from 11 to 20 kg were anesthetized by the intravenous injection of either pentobarbital, 25 mg/kg, or a combination of pentobarbital, 15 mg/kg, and barbital, 220 mg/kg. Supplemental maintenance doses were administered as needed.Blood flow in the left femoral or left renal artery was measured continuously by means of an electromagnetic flowmeter.* The kidney itself was not manipulated, and adjacent structures were disturbed minimally. Renal nerves were left intact except in four experiments in which all visible nerve structures entering the kidney were divided prior to drug administration. In experiments in which femoral artery blood flow was studied, the hind limb was acutely denervated by the division of the femoral and sciatic nerves, and circulation through the paw was occluded using a crushing device applied at the level of the lower tibia. The zero-flow base line and phase adjustments of the flowmeter were performed immediately after application of the flow probe and at intervals throughout each experiment by mechanical occlusion of the artery distal to the flow probe. Two or three separate calibrations of each flow probe were performed during the series of ex...