1 Adenosine-induced dilatation of rat aorta was present in aorta taken from 4 week-old rats, attenuated with increase in age of rats to 8 weeks, and was virtually absent in the aorta from 12 week-old rats. 2 Removal of the endothelium by mechanical rubbing attenuated adenosine-induced dilatation. 3 Haemoglobin and methylene blue partly reversed the adenosine-induced endothelium-dependent dilatation. 4 The order of potency of adenosine derivatives was 5'-(N-ethylcarboxamido)indicating that adenosine receptors mediating the dilatation are of the A2 subtype. 5 [3H]-NECA bound to preparations of membranes from rats of 4 weeks old; it was displaced more effectively by NECA and the A2 ligand CV-1808 than by the A1 ligands CHA and S-PIA. ligands CHA and S-PIA. 6 The number but not affinity of specific binding sites for NECA decreased considerably with increase in age of rats to 8 weeks, and binding sites for [3H]-NECA were hardly detected in membrane preparations from rats of 20 weeks old. 7 Adenosine caused a marked increase in cyclic GMP production, but did not induce an increase in the cyclic AMP level. 8 This increase in cyclic GMP production induced by adenosine was abolished by methylene blue or 8-phenyltheophylline, or by removal of the endothelium. 9 The age-associated decrease in adenosine-induced dilatation was found to be associated with a reduction in the formation of cyclic GMP, but not of cyclic AMP. 10 These results suggest that adenosine causes dilatation via A2 receptors by inducing production of an endothelium-derived relaxing factor (EDRF), which in turn stimulates soluble guanylate cyclase, and so increases production of cyclic GMP. It is also suggested that the main reason for the age-associated decrease in adenosine-induced dilatation is a decrease in the number of A2-receptors or the ability of the endothelium to produce EDRF, leading to decreased production of cyclic GMP.

1 The effects of aging on histamine-induced vasodilatation and cyclic GMP production in rat thoracic aorta were investigated. 2 This histamine-induced dilatation of the aorta was mediated by H1-receptors and was dependent on the endothelium. 3 Histamine induced the greatest dilatation of arteries of 3-4 week old rats, progressively less of those of rats of 8 to 56 weeks old, and scarcely detectable dilatation of those of 100 week old rats. 4 Histamine induced cyclic GMP production in aorta from rats of 4 weeks old, with no change in the cyclic AMP level. This increase in the cyclic GMP level induced by histamine also decreased with age, being about 70% as great at 8 weeks, 50% as great at 50-60 weeks, and 10% as great at 130 weeks of age. 5 Removal of the endothelium completely abolished the histamine-induced increase in cyclic GMP. 6 The dilator effect of nitroprusside, which enhances cyclic GMP production by stimulating guanylate cyclase directly (not indirectly via the endothelium derived relaxing factor, EDRF), also showed age-related attenuation. 7 The dilator effect of 8-bromo cyclic GMP, which stimulates cyclic GMP-dependent protein kinase, also decreased during aging. 8 These results suggest that aging reduces the ability of the endothelium to produce EDRF, which stimulates guanylate cyclase, and so decreases cyclic GMP production. Thus the decreased dilator response of the arteries to histamine during aging is probably due to both loss of endothelial function and reduction of guanylate cyclase activity. Alteration of cyclic GMP-dependent protein kinase activity may also participate in the age-related changes.

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New Findings r What is the central question of this study?It has been widely assumed that C fibres innervating the bladder are mainly excited in overactive bladder syndrome. However, it remains unclear whether Aδ fibres are also activated in pathological conditions. r What is the main finding and its importance?We found that a certain population of Aδ fibres, which become active specifically at a bladder pressure of more than 15 cmH 2 O in normal conditions, showed increased excitability in conditions of prostaglandin E 2 -induced overactive bladder. This result suggests that a certain population of Aδ fibres, together with C fibres, triggers pathophysiological activity.In overactive bladder syndrome, afferent C fibres innervating the bladder show an increased activity level. However, it remains unclear whether all C fibres are highly activated and whether Aδ fibres, the other type of bladder afferent fibre, are also involved in pathological conditions. To address these questions, we analysed the relationship between bladder pressure and single-unit firing patterns of afferent nerves in the left L6 dorsal roots in living rats. The recorded fibres were classified as Aδ fibres or C fibres based on the response to 0.3 μm tetrodotoxin. Certain populations of both Aδ fibres and C fibres were activated at bladder pressures below 15 cmH 2 O (classified as low-threshold fibres), indicating their potential contribution to detection of normal bladder filling. Intravesical administration of prostaglandin E 2 (PGE 2 ) induced hyperexcitation in approximately half of such C fibres, whereas the activity patterns of low-threshold Aδ fibres were unchanged. All fibres, regardless of type, which were almost silent in control conditions (classified as high-threshold fibres), were activated by application of PGE 2 . Notably, the firing patterns of Aδ fibres, rather than C fibres, were highly time locked to PGE 2 -induced micro-oscillation of bladder pressure. These modulatory effects of PGE 2 on Aδ fibres and C fibres might trigger pathophysiological activity together in overactive bladder syndrome.

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