Journal of the autonomic nervous system最新文献

Effects of 6-[(4,6,8-trisulfo-1-naphthyl)iminocarbonyl-1,3-(4-methylphenylene)iminocarbonyl-1,3-phenylene-azo]-pyridoxal-5′-phosphate (SB9), a heterodimeric bivalent ligand consisting of pyridoxal-5′-phosphate and the suramin monomer, were studied on contractions of the rat vas deferens elicited by αβ-methylene ATP (αβmeATP; mediated by P2X₁-like receptors), contractions of the guinea-pig ileal longitudinal smooth muscle elicited by adenosine 5′-O-(2-thiodiphosphate) (ADPβS; mediated by P2Y₁-like receptors), and the degradation of ATP by ecto-nucleotidases in folliculated Xenopus laevis oocytes. SB9 (0.1–10 μM) antagonized contractile responses produced by αβmeATP or ADPβS in a concentration-dependent manner. Schild analysis yielded linear regression lines of unit slope, indicating competitive antagonism. From the rightward shifts of the agonist concentration–response curves pA₂ values of 6.05±0.13 (vas deferens) and 6.98±0.07 (ileum) were derived. In both preparations, SB9 behaved as a slow onset, slow offset antagonist. Incubation of three oocytes in the presence of ATP produced an increase in inorganic phosphate (P_i) over a 30-min period, which amounted to 35.1±1.9 μM P_i from 100 μM ATP. SB9 (10–1000 μM) reduced this degradation (pIC₅₀=4.33±0.10). The results illustrate that SB9 is a high-affinity P2Y₁ receptor antagonist with a remarkable selectivity for P2Y₁ vs. P2X₁ receptors (about 10-fold) and ecto-nucleotidases (447-fold). These properties make it unique among the pyridoxal-5′-phosphate and suramin derivatives reported to date.

Arterial pressure depends on the level of activity of sympathetic vasoconstrictor outflow to blood vessels. This activity is generated in the central nervous system, and involves inputs from a variety of brain regions projecting to sympathetic preganglionic neurones. Of especial interest are a group of neurones in the rostral ventrolateral medulla (RVLM), as they have been demonstrated to have a fundamental role in reflex regulation of the cardiovascular system, and in generation of tonic drive to sympathetic outflow. Sympathetic outflow to blood vessels is additionally modulated at sympathetic ganglia, and at the peripheral terminals of sympathetic nerves. This review considers the role of P2 purine receptors in this neural pathway. Ionotropic P2X receptors are expressed in the RVLM, in sympathetic ganglia, and at the sympathetic neuromuscular junction, and mediate fast excitatory neurotransmission, indicating a general role for ATP as a regulator of sympathetic vasomotor tone. P2Y receptors couple to G proteins and mediate slower signalling to ATP; they have been reported to inhibit prejunctionally neurotransmission at the peripheral terminals of sympathetic nerves, but little is known about their possible role in the central nervous system and in sympathetic ganglia.

This paper, written for the symposium in honour of more than 40 years’ contribution to autonomic research by Professor Geoffrey Burnstock, highlights the progress made in understanding the organisation of the enteric nervous system over this time. Forty years ago, the prevailing view was that the neurons within the gut wall were post-ganglionic neurons of parasympathetic pathways. This view was replaced as evidence accrued that the neurons are part of the enteric nervous system and are involved in reflex and integrative activities that can occur even in the absence of neuronal influence from extrinsic sources. Work in Burnstock’s laboratory led to the discovery of intrinsic inhibitory neurons with then novel pharmacology of transmission, and precipitated investigation of neuron types in the enteric nervous system. All the types of neurons in the enteric nervous system of the small intestine of the guinea-pig have now been identified in terms of their morphologies, projections, primary neurotransmitters and physiological identification. In this region there are 14 functionally defined neuron types, each with a characteristic combination of morphological, neurochemical and biophysical properties. The nerve circuits underlying effects on motility, blood flow and secretion that are mediated through the enteric nervous system are constructed from these neurons. The circuits for simple motility reflexes are now known, and progress has been made in analysing those involved in local control of blood flow and transmucosal fluid movement in the small intestine.