Finding
The 20 year period over which the meetings have occurred has seen interesting changes in the status of peripheral DA.
Paper
THE MOVING FINGER WRITES … 20 YEARS OF PERIPHERAL DOPAMINE RESEARCH
Citations: 2
Full textAbstract
Although dopamine (DA; 3,4-dihydroxyphenylethylamine, 3-hydroxytyramine) was first synthesized in 1910, it was only with the discovery of the enzyme dihydroxyphenylacetic acid (DOPA) decarboxylase in 1938 that the essential role of DA in catecholamine biosynthesis began to be recognized. Even after that time, the weak sympathomimetic activity of DA prevented any consideration that it may subserve any biological role other than that of acting as a precursor for the production of noradrenaline (NA) and adrenaline. This situation changed dramatically in the late 1950s, when development of sensitive fluorometric assays and the formaldehydecondensation technique for monoamine visualization, together with introduction of new psychotropic drugs, such as reserpine, led to the realization that DA was an independent neurotransmitter in some areas of the brain. Shortly after this time, studies in dogs and humans began to suggest that DA may also exert biological effects in the periphery. While many groups had been firmly locked into the thinking that DA was merely acting as a precursor to NA here also, Blaschko speculated in 1957 that ‘... although DA may be acting as a true intermediary compound in the tissues where it was found in minute quantities, in tissues with levels of the amine comparable to those of NA, DA may in fact be regulating functions of its own’. In some vascular beds, in particular the renal and mesenteric circulations, infusion of DA produced vasodilator responses that were unaffected by atropine, antihistamines or adrenoreceptor antagonists but were sensitive to blockade by agents known to antagonize dopaminergic neurotransmission in the brain. The accumulating evidence pointed to the involvement of specific receptors for DA in the periphery. The existence of these DA receptors led, logically, to suggestions that they may be activated physiologically and the first report of renal vasodilation mediated by endogenous DA was published in 1973. Simultaneously, clinical observations on the urinary output of DA during salt loading indicated a probable role of this catecholamine in sodium balance and opened up the prospect that abnormalities of renal DA may be a factor in a variety of cardiorenal disease states. Goldberg decided to adopt a separate nomenclature for the peripheral dopaminergic receptors, namely DA1 and DA2, to distinguish them from their central nervous system counterparts D1 and D2, while still retaining an overall similar classification terminology. Thus, under this scheme, the DA1 receptor was the post-synaptic receptor involved in mediating renal, mesenteric and coronary vasodilation, while the DA2 was the presynaptic peripheral receptor. Subsequently, the DA1 and DA2 receptor populations were also identified at other sites in peripheral tissues, including the renal, endocrine and gastrointestinal systems. This pharmacological classification has been superseded by molecular characterization through the use of recombinant DNA cloning techniques that has revealed an extensive heterogeneity within the DA receptor system. The tissue distribution for these DA receptors has been determined by northern blot analysis, in situ hybridization histochemistry and immunohistochemistry. At first, many of these studies were conducted within the brain, although, in more recent years, such studies have been extended to peripheral tissue sites. The first International Meeting to address the significance of peripheral DA was organized by Jean Schwartz and Jean-Louis Imbs and was held in Strasbourg in 1979. Subsequent meetings have been held at frequent intervals since that time; in 1986 (Ghent), 1987 (Melbourne), 1989 (Essen), 1990 (Charlottesville), 1992 (Porto), 1994 (Kyoto) and 1996 (Camerino). At some time during this sequence, the meetings began to be numbered but, for unknown reasons, this process has never taken account of every occasion, so this year’s meeting, denoted by convention as the seventh, was in fact the ninth! The 20 year period over which the meetings have occurred has seen interesting changes in the status of peripheral DA. Early indications of its role in normal natriuretic responses have been confirmed, but it remains uncertain to what extent deficits in this process can be linked to the important clinical entities of hypertension and renal failure. Substantial efforts by the pharmaceutical industry during the 1980s resulted in two DA analogues with potential for use in renal and cardiac failure; fenoldopam and dopexamine. Subsequent clinical use, however, indicated that neither agent was as widely useful as had been predicted. Nevertheless, the dominant theme at meetings has remained the cardiorenal aspects of DA. Recent research work has now, in contrast, begun to demonstrate putative roles for endogenous DA in the modulation of immune responses, gastrointestinal function and ovarian cycling, as well as within other areas of peripheral organ physiology. This year’s meeting allowed an opportunity to review progress in these new directions. It also acted as a forum for the re-introduction of fenoldopam and dopexamine, both of which have now been acquired by new companies and are being marketed with more specific patient groups in view than had been the case originally. The 1998 meeting, held at Trinity College, Dublin, was sponsored by a broad spectrum of industry and we wish to express our gratitude to all companies that were involved: Ipsen, Neurex, Servier, THE MOVING FINGER WRITES ... 20 YEARS OF PERIPHERAL DOPAMINE RESEARCH
Authors
C. Bell, D. P. O'connell
Journal
Clinical and Experimental Pharmacology and Physiology