n(6)-cyclopentyladenosine and 5--adenylyl-(beta-gamma-methylene)diphosphonate

1. We looked for P2-purinoceptors modulating noradrenaline release in rat heart atria. Segments of the atria were preincubated with [3H]-noradrenaline and then superfused with medium containing desipramine (1 microM) and yohimbine (1 microM) and stimulated electrically, by 30 pulses/1 Hz unless stated otherwise. 2. The adenosine A1-receptor agonist, N6-cyclopentyl-adenosine (CPA; EC50 9.7 nM) and the nucleotides, ATP (EC50 6.6 microM) and adenosine-5'-O-(3-thiotriphosphate) (ATP gamma S; EC50 4.8 microM), decreased the evoked overflow of tritium. The adenosine A2a-agonist, 2-p-(2-carbonylethyl)-phenethylamino-5'-N-ethylcarboxamido-a denosine (CGS-21680; 0.03-0.3 microM) and the P2x-purinoceptor agonist beta, gamma-methylene-L-ATP (30 microM) caused no change. 3. The concentration-response curve of CPA was shifted to the right by the adenosine A1-receptor antagonist, 8-cyclopentyl-1,3-dipropyl-xanthine (DPCPX; 3 nM; apparent pKB value 9.7) but hardly affected by the P2-purinoceptor antagonist, cibacron blue 3GA (30 microM). In contrast, the concentration-response curves of ATP and ATP gamma S were shifted to the right by DPCPX (3 nM; apparent pKB values 9.3 and 9.4, respectively) as well as by cibacron blue 3GA (30 microM; apparent pKB values 5.0 and 5.1, respectively). Combined administration of DPCPX and cibacron blue 3GA caused a much greater shift of the concentration-response curve of ATP than either antagonist alone. The concentration-response curve of ATP was not changed by indomethacin, atropine or the 5'-nucleotidase blocker alpha, beta-methylene-ADP. 4. Cibacron blue 3GA (30 microM) increased the evoked overflow of tritium by about 70%. The increase was smaller when the slices were stimulated by 9 pulses/O00 Hz instead of 30 pulses/I Hz.5. The results indicate that the postganglionic sympathetic axons in rat atria possess P2-purinoceptors in addition to the known adenosine Al-receptor. Both mediate inhibition of noradrenaline release. Some adenine nucleotides such as ATP and ATP gamma S act at both receptors. The presynaptic P2-purinoceptor seems to be activated by an endogenous ligand, presumably ATP, under the condition of these experiments. This is the first evidence for presynaptic P2-purinoceptors at cardiac postganglionic sympathetic axons.

Topics: Adenosine; Adenosine Diphosphate; Adenosine Triphosphate; Animals; Antihypertensive Agents; Atropine; Desipramine; Dose-Response Relationship, Drug; Electric Stimulation; Heart Atria; Indomethacin; Male; Norepinephrine; Phenethylamines; Protein Synthesis Inhibitors; Purinergic P1 Receptor Antagonists; Purinergic P2 Receptor Antagonists; Rats; Rats, Wistar; Receptors, Purinergic P1; Receptors, Purinergic P2; Suramin; Triazines; Xanthines; Yohimbine

The aim was to determine the capacity of nodose ganglion afferent neurones with epicardial sensory endings to respond to mechanical and chemical stimuli, in particular to purinergic compounds.. Alterations in spontaneous activity generated by epicardial afferent neurones in nodose ganglia in situ of 17 anaesthetised dogs were identified using extracellular recording techniques when mechanical and chemical stimuli were applied to their receptor fields, as well as during brief periods of coronary artery occlusion.. 92 cardiac afferent neurones were identified. Localised epicardial distortion modified the activity generated by 34 neurones [0.19(SEM 0.02) to 1.2(0.4) impulses.s-1]. Application of bradykinin, substance P, N6-cyclopentyladenosine or beta, gamma-methylene adenosine 5'-triphosphate to localised epicardial fields altered the activity of 69 neurones. Thus the majority of identified epicardial neurones responded to chemical stimuli alone (63%) as opposed to mechanical stimuli alone (25%), 12% responding to both types of stimuli. Activity was enhanced overall by chemical stimuli from a mean range of 0.1-0.4 to 11.6-13.2 impulses.s-1. Following termination of short lasting chemical as opposed to mechanical stimuli, activity remained increased for up to 45 min. Activity generated by 16 chemosensitive neurones was modified by brief periods of coronary artery occlusion [0.26(0.12)-1.66(0.61) impulses.s-1]; activity increasing further [2.51(0.47) impulses.s-1] during reperfusion periods.. (1) Chemical stimuli induce an order magnitude greater enhancement of activity generated by nodose ganglion cardiac afferent neurones than do mechanical stimuli, such enhancement persisting long after removal of chemical as opposed to mechanical stimuli. Thus qualitative and quantitative differences exists between central neuronal inputs derived from nodose ganglion epicardial afferent neurones sensitive to chemical as opposed to mechanical stimuli. (2) Adenosine and ATP can activate nodose ganglion cardiac afferent neurones.

Topics: Adenosine; Adenosine Triphosphate; Animals; Bradykinin; Constriction; Coronary Vessels; Dogs; Female; Male; Mechanoreceptors; Neural Pathways; Neurons, Afferent; Nodose Ganglion; Pericardium; Substance P