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1 Histamine (0.02-0.1 mug/ml) contracted the chicken rectum preparation. This effect was antagonized by mepyramine (0.01 mug/ml) but not by hyoscine (0.02 mug/ml).2 5-Hydroxytryptamine (0.05-0.25 mug/ml) relaxed the rectum preparation and at higher concentration produced a biphasic response. These responses were not antagonized by methysergide (0.01 mug/ml), and the relaxation was not antagonized by tetrodotoxin (0.1 mug/ml) or a combination of propranolol (0.05 mug/ml) and phentolamine (0.1 mug/ml).3 Neither mepyramine (0.1 mug/ml) nor methysergide (0.01 mug/ml) antagonized the contractions produced by nerve stimulation in vagus nerve/oesophagus and Remak nerve/rectum preparations.4 5-Hydroxytryptamine (2 mug/ml) in the presence of methysergide (0.01 mug/ml), inhibited the contractions produced by nerve stimulation in Remak nerve/rectum and vagus nerve/oesophagus preparations.5 Adenosine, adenosine 5'-phosphate (AMP), adenosine 5'-diphosphate (ADP) and adenosine 5'-triphosphate (ATP), in order of decreasing potency, produced slow contractions in most oesophagus preparations. The action of ATP in this preparation was antagonized by tetrodotoxin (0.1 mug/ml), hyoscine (0.1 mug/ml) and strychnine (5 mug/ml).6 Desensitization of the vagus nerve/oesophagus preparation to ATP did not produce any antagonism of the contractions to nerve stimulation.7 Adenosine and AMP produced relaxations and ADP and ATP contractions in the rectum preparation. ATP was about 100 times as potent as ADP in producing fast contractions which were not antagonized by tetrodotoxin, hyoscine or strychnine.8 Desensitization of the Remak nerve/rectum preparation to ATP resulted in the contractions to nerve stimulation and acetylcholine being inhibited to the same extent.9 Prostaglandin E(2) produced slow contractions in the oesophagus and rectum preparations which were not antagonized by tetrodotoxin (0.1 mug/ml). Polyphloretin phosphate (10 mug/ml) antagonized spontaneous movements and responses to prostaglandin E(2) in the rectum but not the oesophagus.10 Neither polyphloretin phosphate (60 mug/ml) nor indomethacin (20-100 mug/ml) antagonized the contractions produced by nerve stimulation in vagus nerve/oesophagus (with hyoscine in the bathing solution) and Remak nerve/rectum preparations.11 These experiments seem to exclude histamine, 5-hydroxytryptamine, adenosine and its nucleotides and prostaglandin E(2) as possible motor transmitters in synapses and neuromuscular junctions in the chicken vagus nerve/oesophagus and Remak nerve/rectum preparations.

Vasopressin and related peptides (10(-9) to 10(-6) molar) induced bursting pacemaker potential activity and altered the current-voltage relations of the membrane in a specific molluscan neurosecretory cell. These effects long outlasted the period of application of the peptides. Sensitivity of the cell to these peptides was primarily localized on the axon hillock region. The observed effects do not resemble conductance changes evoked by conventional neurotransmitters, but rather suggest a membrane regulatory role for these peptides, and thus may be indicative of a new form of information transfer in the nervous system.

The effect of acetylcholine, norepinephrine, serotonin, GABA and histone preparations on nervous tissue acid ribonuclease activity has been studied. Acetylcholine and serotonin in vitro were found to reduce the leakage of this enzyme out of lysosomes, whereas norepinephrine and histones enhanced it. These agents did not change free acid ribonuclease activity. It is assumed that these neurotransmitters and histones can take part in the regulation of intracellular RNA metabolism in brain tissue by changing the amount of the free acid ribonuclease fraction through affecting lysosome membranes rather than the activity of the free enzyme. GABA changes neither enzyme leakage out of lysosomes nor its activity.

The influence of autonomic neurohormones on the immunologic release of beta-glucuronidase (EC 3.2.1.31) from, and the cyclic nucleotide levels in, human neutrophils was determined. Interaction of neutrophils with rheumatoid arthritic, serum-treated zymosan particles in a neutral balanced salt solution at 37 degrees resulted in the extracellular discharge of beta-glucuronidase without any loss of cell viability, as indicated by the failure of incubated cells to take up eosin Y or to release cytoplasmic lactate dehydrogenase (EC 1.1.1.27). Epinephrine reduced the release of beta-glucuronidase from neutrophils in the presence of zymosan during 2-30 min of incubation and elicited a concomitant elevation of adenosine 3':5'-monophosphate levels. Propranolol, a beta-adrenergic receptor antagonist, but not phentolamine, an alpha-adrenergic receptor antagonist, blocked both actions of epinephrine. Acetylcholine stimulated the release of beta-glucuronidase, but not lactate dehydrogenase, and provoked a concomitant elevation of guanosine 3':5'-monophosphate levels. Atropine, a muscarinic receptor antagonist, but not hexamethonium, a ganglionic blocker, inhibited both actions of acetylcholine. Interaction of neutrophils and zymosan particles resulted in an elevation of guanosine 3':5'-monophosphate levels within 2 min. These data suggest that intracellular guanosine 3':5'-monophosphate may be involved in mediating the immunologic release of lysosomal enzymes from human neutrophils whereas adenosine 3':5'-monophosphate may inhibit enzyme release. Moreover, autonomic neurohormones appear to be capable of modulating lysosomal enzyme release by virtue of their capacity to elevate neutrophil cyclic nucleotide levels.

The hypothesis that physiological and developmental regulatory mechanisms are similar has been presented. Well-known developmental systems chosen illustrate the capability of the model to suggest a simple mechanism underlying the effects on development of a diverse group of chemicals. This hypothesis might be applied to other systems including the induction of the lens, limb regeneration, and the induction of the head of hydra (124). I have proposed this hypothesis not only because it permits consideration of a complex and varied array of experimental observations as reflections of a simple basic biochemical mechanism, but because recent technical advances in instrumentation and methods allow it to be directly tested. The fluorescent antibody method for the cytochemical measurement of cyclic nucleotides provides a means for investigating changes in the concentrations of cyclic nucleotides in developing cells and could also be used to detect neurotransmitters in developing cells. Similarly, the scanning electron microscope in the emitted x-ray mode provides a method for measuring changes in the content and distribution of cations within developing cells. The hypothesis presented here suggests pleasing asceticism on the part of eukaryotes. It suggests that simple derivatives of metabolites, including neurotransmitters and cyclic nucleotides, are linked together as regulatory molecules throughout the eukaryotes. The neurotransmitters are suggested to have a more general role in information transmission in eukaryotes than is generally accepted. They are hypothesized to have progressed during evolution from being intracellular messengers to a role as intercellular messengers for the relatively slow communication of developmental informatbn; and, finally, this process has culminated with their participation in the rapid intercellular communication mediated by nerves. The thought that the complex pictures of physiological regulation and of the construction of a complex multicellular organism like man might be painted with so few colors is quite satisfying.