Peripheral Dopaminergic Receptors: Proceedings of the Satellite Symposium of the 7th International Congress of Pharmacology, Strasbourg, 24-25 July 1978

SCHWARTZ

Introductory Lecture The Dopamine Vascular Receptor: Agonists and Antagonists

Leon I. Goldberg,     Committee on Clinical Pharmacology, Departments of Pharmacological and Physiological Sciences and Medicine, University of Chicago, 947 East 58th Street, Chicago, Illinois 60637, U.S.A.

ABSTRACT

This paper describes the research which led to the discovery of the renal vasodilating action of dopamine (DA) and the subsequent evidence indicating that the phenomenon was due to action on a specific vascular receptor. The structure activity relationship of agonists and lists of specific antagonists of this receptor will be presented and compared with agonists and antagonists reported to be active on other DA receptors. Physiological and clinical implications of these findings will be discussed.

Fifteen years has elapsed since my colleagues and I reported that dopamine (DA) dilated the renal vascular bed by an unusual mechanism (1–3). Since that time the peripheral actions of DA have become an extremely popular subject of research. Our initial findings have been confirmed (3) and other unusual actions of DA have been demonstrated (4). This meeting, the first to be concerned primarily with the peripheral actions of DA, represents an unusual opportunity for investigators from many countries to compare notes and discuss the many interesting problems which have arisen. The purpose of my paper is to set the stage for this meeting by reviewing what we have learned to date, and with this background, speculate about the future. My presentation will be concerned for the most part with personal experiences. Extensive reviews of literature have been presented elsewhere (1,4).

The fact that a meeting of this sort has been convened is most encouraging when I think back to the early days of DA research. When I first began studies of DA in 1959 at the National Heart Institute in Bethesda, Maryland, there was little evidence either in the brain or periphery that DA could serve any purpose except as a substrate for norepinephrine. Indeed, most studies indicated that DA was pharmacologically similar to norepinephrine with much less potency.

It is interesting to review the early history of cardiovascular studies of DA and, in particular, to note the results which suggested that DA may have unusual actions. The first reports of the synthesis of DA appeared in 1910 by Manich and Jacobsohn (5) and Barger and Ewins (6). In 1910 Barger and Dale (7) reported that DA exhibited a pressor potency in the spinal cat 1/50th that of d, 1-norepinephrine. In 1930 Tainter (8) reported that DA raised pressure in the spinal cat but that it was reversed by ergotoxine. In 1931 Hamet (9) reported that the pressor effect of DA in the anesthetized dog was reversed by yohimbine. These investigators, however, considered that these actions of DA were similar to those of epinephrine. The first clue that I could find of unusual actions of DA was in the studies of Gurd (10) reported in 1937. Gurd reported that the pressor effect of DA had a greater cardiac component than epinephrine. It was this difference that awakened my interest in DA more than 20 years later.

The most significant early studies demonstrating that DA was qualitatively different from other catecholamines was published in 1942 by Holtz and Credner (11). These investigators reported that DA differed from epinephrine in that DA decreased the blood pressure of the guinea pig and rabbit, whereas, epinephrine increased blood pressure in these species. Holtz and Credner postulated that the decrease in blood pressure was due to the formation of an aldehyde by action of monoamine oxidase. Subsequent investigations, however, demonstrated that inhibition of monoamine did not prevent the depressor effect. Later Holtz. and associates (12) suggested that the reduction in blood pressure was due to formation of a condensation product of DA, tetrahydropapaveroline. More recent studies, however, demonstrated that this material also was not responsible for the reduction in blood pressure.

In 1959 I began studying DA in the laboratories of Dr. Albert Sjoerdsma at the National Heart Institute. A major project of the laboratory was influence of monoamine oxidase inhibitors on metabolism of endogenous amines. I compared the effects of several endogenous amines in the anesthetized dog on contractility of the heart and blood pressure before and after administration of several monoamine oxidase inhibitors (13). DA was one of the amines studied. Figure 1 illustrates an experiment in which DA was compared to norepinephrine before and after administration of the monoamine oxidase inhibitor, R05-0700. As noted in the upper right panel, DA exerted a biphasic effect on blood pressure with a transient initial increase and then a more prolonged decrease in blood pressure. The effects of DA were potentiated by the monoamine oxidase inhibitor, whereas, the effects of norepinephrine were essentially unchanged. In 1960 Dr. David Horowitz, Dr. Sjoerdsma, and I (14) administered DA, apparently the first time to human beings, to determine whether similar potentiation would occur in patients treated for hypertension by monoamine oxidase inhibitors. Marked potentiation of the pressor effects of DA was observed in these patients.

Fig. 1 Norepinephrine and DA on arterial blood pressure (BP) and high contractile force (CF) in anesthetized dog. Note that the depressor effect of DA at a time when CF is increased (reprinted from reference 13 with permission of the publisher).

It was during the course of these studies that I began to consider the possibility that DA might be useful in the treatment of congestive heart failure. This concept was a direct result of my training as a graduate student with Professor Robert P. Walton at the Medical University of South Carolina. Professor Walton had postulated that if a sympathomimetic amine could be found which stimulates the heart without increasing heart rate or blood pressure, it would be useful in the treatment of heart failure. He carried out preliminary studies in this area but clinically useful drugs were not found (15). In subsequent investigations my colleagues and I investigated other sympathomimetic amines with similar lack of success (16).

In the initial investigations of DA at the National Heart Institute we found that DA could increase cardiac contractile force in animals (Fig. 2) (13) and pulse pressure in man (Fig. 3) (14) without significant effects on diastolic blood pressure or heart rate. On this basis Dr. Horowitz and I in collaboration with Dr. Samuel Fox conducted hemodynamic studies in normal subjects and in a few patients undergoing cardiac catheterization (17). We found that DA was able to increase cardiac output without significantly changing heart rate or diastolic arterial pressure when infused intravenously at a rate of 5-11 µg/kg/min.

Fig. 2 Effects of increasing intravenous doses of DA on cardiac contractile force, systolic and diastolic blood pressure, and heart rate in anesthetized dogs. Data obtained from reference 20.

Fig. 3 Effects of intravenous infusions of DA and norepinephrine on directly recorded arterial pressure of a normal subject. Note the difference in diastolic and pulse pressure produced by DA and norepinephrine. Reprinted from reference 17 with permission of the publisher.

When I went to Emory University in 1961 my colleagues and I simultaneously began studies to delineate the mechanism of the depressor effects of DA in the dog and to determine the effects of DA in patients with congestive heart failure. In our first abstract read at the meetings of the Federation of American Societies for Experimental Biology in 1962 (18), we reported that the depressor effects of DA were not blocked by beta-adrenergic blocking agents, atropine, or antihistamines. We also reported that phenoxybenzamine changed the pressor effect of a large dose of DA to depressor. Later that year at the Fall Pharmacology Meetings we described studies (19) with the perfused hindlimb of the dog. The full paper appeared in 1963 (20). When DA was injected directly into the perfusion circulation of the limb pressure increased (vasoconstriction). On the other hand, when DA was injected intravenously perfusion pressure decreased (vasodilation). Since section of the nerve trunks to the perfused limb greatly reduced or eliminated the vasodilation we concluded that the vasodilation was indirect and probably the result of a central nervous system or reflex mechanism. We concluded that the effect had to be mediated via the sympathetic nervous system since removal of the stellate ganglion prevented vasodilation of the limb. One problem during the study which disturbed us was that administration of the ganglionic blocking agent, hexamethonium, did not completely eliminate the depressor effect of DA, suggesting that another mechanism in addition to a neurogenic phenomenon was operating (Fig. 4). At that time, however, we had no indication that DA was a direct vasodilating drug. This early study should be viewed in the light of current knowledge of ganglionic (21) and pre-synaptic DA receptors (22). Later my colleagues and I came back to the problem in searching for the mechanism of the reduction in blood pressure produced by 1-dopa (23). We found that 1-dopa inhibited post-ganglionic sympathetic nerve activity and that this effect was blocked by a decarboxylase inhibitor, suggesting that the phenomenon was related to generation of DA. We did not, however, conclude that the effect was the result of action on a presynaptic receptor.

Fig. 4 Effects of hexamethonium on the cardiovascular actions of tetramethylammonium (TMA) and DA in anesthetized dogs. Note that hexamethonium virtually blocked the effects of TMA on blood pressure, heart rate, and contractile force but did not affect the decrease in blood pressure produced by DA. From reference 20 with permission of the publisher.

The first evidence that DA might be acting as a vasodilator resulted from clinical studies reported in 1962 (2,3,24). We administered DA to patients with congestive heart failure and each patient had a marked sodium diuresis and, in addition, exhibited increases in renal plasma flow and glomerular filtration rate. We assumed that these effects were secondary to the increase in cardiac output produced by DA. In order to test this hypothesis we administered DA to normal subjects and found that they also exhibited an increase in sodium excretion, an increase in renal plasma flow, and a slight increase in glomerular filtration rate. Since the renal plasma flow increased with doses which did not change blood pressure, we reported in 1963 that DA was a most unusual sympathomimetic amine with a selective renal vasodilating action (25,26). In order to investigate the mechanism of this renal vasodilation my colleagues and I developed models in the anesthetized dog in which renal blood flow could be measured directly by an electromagnetic flow meter and indirectly by pH clearance. We found that intravenous or direct injection of DA into the renal artery caused vasodilation and increase in sodium excretion. This vasodilation was not attenuated by beta-adrenergic blocking agents, atropine, or antihistamines. We also observed that with a larger dose of DA initial vasoconstriction occurred which was blocked by phenoxybenzamine. On this basis we established the procedure of administering phenoxybenzamine in all experiments in order to obtain a complete dose-response curve without influencing vasoconstriction (27, 28). In the following year Eble (29) confirmed our findings that DA was an unusual renal vasodilator and also described similar vasodilation in the mesenteric vascular bed.

These initial studies suggested that DA was acting on a specific receptor. DA-induced renal vasodilation was not due to non-specific vasodilation such as produced by papaverine or nitroglycerin, since vasodilation did not occur in all vascular beds. The vasodilation was clearly not due to attenuation of sympathetic nerves since it took place in the denervated kidney (this data indicated that the putative receptor was post-synaptic) (25,26). The vasodilation was not related to release of catecholamines since the phenomenon occurred in the reserpine treated animal. The vasodilation could not be due to action of the known metabolites of DA since all of them are inactive (25,28).

To prove the existence of a new receptor, however, requires additional evidence. First, it is necessary to demonstrate with a series of analogs that the same order of potency exists in more than one area subserved by the receptor. Second, specific antagonism has to be demonstrated. Our initial studies of structure activity relationships, in search of a series of analogs, indicated that the structural requirements for DA-like renal vasodilation were entirely different from those required by alpha- and beta-adrenergic agonists (30). Indeed, their requirements were much more specific. Of 44 amines studied only one compound, N-methyl DA (epinine) produced DA-like effects. Unfortunately, epinine exhibited almost the identical potency as DA, preventing a potency series study. In the same investigation we reported that apomorphine was DA-like, but much less potent than DA or epinine. We had difficulty in constructing a full dose-response curve with this compound and we now know this is because it is a partial agonist (31). Fulfillment of the first criterion was finally attained in 1976 when we reported (32) a similar potency relationship in the renal and mesenteric vascular beds for DA, 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (A-6,7-DTN), 6-propylnorapomorphine, and apomorphine; 6-propylnorapomorphine, unlike apomorphine, is a full agonist.

Demonstration of a specific antagonism of the renal vasodilation was reported in 1968 (33) (Figure 5). Following up on the observation by Van Rossum (34) that haloperidol decreased the hypotensive actions of DA in the yohimbine treated cat, we performed a quantitative study which demonstrated that haloperidol, within a relatively narrow dose range, specifically antagonized DA-induced renal vasodilation without affecting renal vasodilation produced by bradykinin and isoproterenol. Similar antagonism of DA by haloperidol was observed in the mesenteric vascular bed. With the demonstration of a potency series and specific antagonism there seemed to be little doubt that DA was causing vasodilation by action on a specific receptor which is clearly different from receptors previously described.

Fig. 5 Mean increments in renal blood flow produced by i.a. injections of several doses of bradykinin (B), isoproterenol (I) and dopamine (D) alone and in combination with haloperidol (1.4×10−7 mol). Results were obtained from eight experiments in anesthetized dogs. Solid lines and closed symbols represent data obtained with the vasodilators alone; broken lines and open symbols represent data obtained when the vasodilators were injected at the same time as haloperidol. Values for P were obtained by the paired t-test. Vertical lines indicate the standard error. From reference 33 with permission of the publisher.

Sufficient structure activity relationship studies have now been carried out to provide considerable detail concerning the structural requirements and confirmation required for a DA vascular analog (4,35). These studies have also permitted us to expand the potency series. The following requirements have been determined: First, in the catecholamine series 2 hydroxy groups on the 3 and 4 positions are essential; compounds with substitutions on the alpha and beta carbon have, thus far, been inactive; single substitutions on the amino group greater than methyl results in inactivity; disubstituted compounds with one or both substitutions being propyl are active, but 30 to 60 times less active than DA (36,37).

Studies of the conformational requirements for DA were made possible by the availability of two rotamers of DA, A-6,7-DTN, which was initially suggested as a DA agonist by Woodruff and synthesized by Pinder; and the alpha-rotameric compound, A-5,6-DTN, synthesized by Dr. Joseph Cannon. Studies with these two analogs demonstrated conclusively that the beta-rotameric trans conformation of DA as held in A-6,7-DTN is the active form, whereas, the A-5,6-DTN derivative is inactive (38). Interestingly, the A-5,6-DTN derivatives are active on beta-adrenergic receptors. Further structural studies with ADTN derivatives demonstrated that the same requirements for the open chain catecholamine nucleus holds for the semi-rigid analogs. N-methyl A-6,7-DTN is active, but additions on the nitrogen greater than one methyl are inactive unless the disubstituted compound is produced with one propyl group (38,39).

The other series of compounds studied were the apomorphine derivatives. As stated earlier, apomorphine appears to be a partial agonist, whereas, 6-propylnorapomorphine is a full agonist. Derivatives with one hydroxy group are inactive.

The list of DA antagonists has also been increased. The initial antagonist, haloperidol, and the phenothiazines were specific but exhibited a relatively narrow range of specificity. It is possible to antagonize the effects of DA with these drugs without affecting the vasodilation produced by bradykinin or isoproterenol. However, if the dose is increased sufficiently to completely antagonize DA, the effects of the other vasodilators are also attenuated. We recently reported that sulpiride was a much more potent and specific antagonist than haloperidol (4,40). With this antagonist it is possible to completely block the vasodilating effects of DA without affecting bradykinin or isoproterenol. A list of antagonists, their relative potencies, and ranges of specificity are shown in Table 1.

TABLE 1

DA Vascular Antagonists

aDose to produce 3- to 4-fold shift in DA dose-response curves.

b(minimal dose attenuating vasodilating responses of bradykinin or isoproterenol)/minimal dose attenuating vasodilating responses of DA

Finally, although the studies in the intact dog satisfy all the criteria required for designating the existence of a specific DA vascular receptor, evidence in the isolated system is desirable. Accordingly, in 1975 I went to Kyoto University to work with Professor Noboru Toda who had extensive experience in the study of isolated blood vessels. After many months of research Dr. Toda and I developed a system in which DA-induced relaxation could be repeatedly exhibited in isolated canine renal, mesenteric, cerebral, and coronary arteries less than 1 mm outside diameter (41–43). When the vessels were contracted with prostaglandin F2α after being treated for one hour with phenoxybenzamine, 10−5M, DA and epinine caused dose-related relaxation which was not antagonized by propranolol. In the initial studies we were unable to demonstrate unequivocal antagonism of relaxation by haloperidol or several phenothiazines. At this meeting Professor Toda and his associates and Drs. Kohli and Takeda from our laboratory will present papers demonstrating specific antagonism. Thus, the long chapter to prove the DA vascular receptor appears to be concluded.

What are the possibilities for future research with the background now available? First, the expanded series of agonists and antagonists active on the DA vascular receptor should make it possible to determine the identity of DA receptors with different responses and in different areas. We have recently extensively reviewed this area with the relatively limited data available and conclude that the post-synaptic DA vascular receptor is clearly different from the pre-synaptic or neurogenic receptor (4). Of particular significance, A-5,6-DTN derivatives and N-N-dimethyl DA derivatives which are active agonists on the pre-synaptic receptor are totally inactive on the post-synaptic DA vascular receptor. Relatively good correlation exists between DA-induced renal vasodilation and the increase in DA sensitive adenylate cyclase in preparations from the rat caudate. The most striking difference between studies of adenylate cyclase in the rat caudate and studies of the DA vascular receptor is that sulpiride is apparently ineffective in blocking DA-induced increases in adenylate cyclase (44,45). We are continuing studies begun at Emory (46) to determine whether the DA sensitive adenylate cyclase in the brain is different than DA sensitive adenylate cyclase in the renal vasculature. Comparison of the DA vascular receptor with various binding assays and behavioral models show almost zero correlation (4). Studies should be continued to determine whether this poor correlation is due to different receptors or due to problems in technique which do not permit differentiation of direct effects on DA post-synaptic receptors or from effects on other receptors or indirect mechanisms.

Secondly, availability of information concerning requirements for the DA vascular receptor suggests that it should be possible to synthesize DA vascular agonists with different spectra of activity. Although DA has clinical efficacy in the treatment of shock, its action on beta1-adrenergic receptors and on alpha-adrenergic receptors limits its clinical usefulness. We have recently reported that dipropyl DA acts on the DA vascular receptor but does not act on beta-adrenergic receptors and exhibits a weaker alpha-adrenergic action (36). This agent also appears to have greater action than DA on pre-synaptic receptors and decreases arterial blood pressure (48). These results suggest that it should be possible to synthesize a DA vascular agonist acting only on DA receptors.

Thirdly, the demonstration that A-6,7-DTN is the preferred rotamer for activation of the DA vascular receptor has provided information of the conformation of the receptor itself. Additional studies, however, are needed to define the precise relationship of the agonist-receptor interaction since A-6,7-DTN is not a totally rigid molecule and exists in the plus (+) and minus (−) forms. We have presented preliminary evidence that (+)-ADTN is more potent than (−)-ADTN (49).

Fourthly, an area in which we need much more information is the question of a physiological role of DA in the periphery. Several studies have suggested that DA may have a physiological role in the kidney. Bell and Lang reported studies in 1973 which suggested that the renal vasculature is innervated by nerves which release DA as a transmitter (50). They demonstrated that an increase in renal blood flow occurred after midbrain stimulation in dogs pretreated with quanethidine and that this increase in renal blood flow was attenuated by haloperidol. Recently Dinerstein et al (51) found catecholamine histofluorescence associated with the arterial supply to the glomerular poles of the dog kidney. By microspectrofluorometry the catecholamine fluorphore associated with the glomerular vascular pole was identified as DA. The origin of the fluorescent fibers was found to be outside the kidneys and surgical denervation abolished all fluorescence. These DA containing fibers were distinguished from other fluorescent nerves which contained large amounts of norepinephrine. Confirmation of these interesting studies in other species is required.

The question may then be asked as to what function DA exerts in the kidney. Considerable evidence suggests that DA may be involved in the regulation of the renal excretion of sodium (52–56). Many opportunities exist for research in the peripheral actions of DA. I feel that the future will be even more exciting than the past.

ACKNOWLEDGMENTS

I wish to acknowledge and thank many collaborators who participated in the research described. I also want to thank the chemists who so kindly supplied innovative substances for these investigations. This research was supported in part by NIH grants PHS GM-22220 and NS-12324.

REFERENCES

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4. Goldberg, L. I., Volkman, P. H., Kohli, J. D. A comparison of the vascular dopamine receptor with other dopamine receptors. Ann. Rev. Pharmacol. and Toxicol. 1978; 18:57–79.

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31. Goldberg, L. I., The vascular dopamine receptor as a model for other dopamine receptorsRoberts, P.J., et al, eds. Adv. in Biochem. Psychopharmacol, 19. New York: Raven Press, 1978.

32. Crumly, H. J., Jr., Pinder, R. M., Hinshaw, W. B., Goldberg, L. I. Dopamine-like renal and mesenteric vasodilation caused by apomorphine, 6-propylnorapomorphine, and 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene. Nature. 1976;