Effects of nucleotides and nucleosides on smooth muscle tension and the release of previously stored [3H]-noradrenaline were studied in the mouse isolated vas deferens. The tissue was stimulated twice by 20 electrical field pulses delivered at 2 Hz (S1, S2). alpha,beta-Methylene-ATP, ATP gamma S, ATP and UTP elicited contraction, with potency decreasing in that order; there was no contractile response to adenosine (up to 100 mumol/l) and uridine (up to 1 mmol/l). The electrically evoked overflow of tritium was reduced by the drugs in the following order of potency: ATP gamma S greater than ATP = adenosine greater than UTP; alpha,beta-methylene-ATP (up to 10 mumol/l) and uridine (up to 1 mmol/l) did not significantly change the evoked overflow. 8-(p-Sulphophenyl)theophylline did not alter the contractile responses to the nucleotides; it prevented the overflow-inhibiting effect of adenosine and reduced that of UTP; the overflow-inhibiting effects of ATP and ATP gamma S were not significantly attenuated. After prolonged exposure to alpha,beta-methylene-ATP, all contractile nucleotide effects were abolished; in contrast, the depression by adenosine and the nucleotides of the evoked overflow of tritium persisted. None of the effects was changed by indometacin, yohimbine or reactive blue 2. It is concluded that ATP, ATP gamma S, alpha,beta-methylene-ATP and UTP produce contraction of the vas deferens by activation of P2x-receptors. Moreover, the nucleotides inhibit per se the release of [3H]-noradrenaline (and presumably the co-transmitter mixture of noradrenaline and ATP); the effect of ATP is not, or only to a small extent, due to breakdown to adenosine. The presynaptic site of action of the purine nucleotides is a P2-receptor which differs from the P2x-receptor and may be a reactive blue 2-resistant "P2y-like" receptor.
The aim of the study was to subclassify the soma-dendritic alpha2-autoreceptors in the locus coeruleus (LC) of the rat by means of antagonists. To this end, the frequency of spontaneous action potentials was recorded extracellularly from single LC neurones in brain slices. The neurones fired spontaneously at an average rate of 1 Hz. The selective alpha2-adrenoceptor agonist 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK 14,304) and noradrenaline decreased the action potential discharge with IC50 values of 5 and 510 nM, respectively. The concentration-inhibition curves of UK 14,304 and noradrenaline were shifted to the right by phentolamine (0.15 microM) and rauwolscine (0.15 microM) but not by prazosin (1 microM). Apparent Kd values of phentolamine were 17 nM (against UK 14,304) and 20 nM (against noradrenaline). Apparent Kd values of rauwolscine were 47 nM (against UK 14,304) and 70 nM (against noradrenaline). (+)-Oxaprotiline (1 microM) suppressed the firing of the neurones within 10 to 33 min. In the continued presence of oxaprotiline, phentolamine and rauwolscine restored firing with EC50 values of 120 and 250 nM, respectively. Prazosin (1 microM) again was ineffective. All three antagonist affinity estimates - against UK 14,304, exogenous noradrenaline and endogenous noradrenaline (that accumulates in the extracellular space in the presence of oxaprotiline) - yield an affinity order phentolamine > rauwolscine >> prazosin, prazosin being ineffective even at a concentration of 1 microM. These findings identify the soma-dendritic alpha2-autoreceptors of the LC as the rat variant of the alpha2A/D-adrenoceptor, i.e. alpha2D. Not only presynaptic but also soma-dendritic alpha2-autoreceptors may at least predominantly be alpha2A/D throughout the nervous system.
The postganglionic sympathetic nerves of rabbit isolated hearts were stimulated with pulses delivered at 5 Hz and train durations of 1-5 s. Ethylketocyclazocine 0.01-1 mumol/l and fentanyl 1 and 10 mumol/l but not morphine 1 and 10 mumol/l, Met-enkephalin 1 and 4 mumol/l or D-Ala2, D-Leu5-enkephalin 0.5 and 5 mumol/l diminished the stimulation-evoked increase in heart rate. The effect of ethylketocyclazocine 0.1 mumol/l was antagonized by naloxone 1 and 10 mumol/l. In contrast, the effect of fentanyl was not changed by naloxone 10 mumol/l. Ethylketocyclazocine 0.03 and 1 mumol/l did not reduce the tachycardia elicited by exogenous noradrenaline. The results suggest that, under in vitro conditions, only presynaptic opioid kappa- but not mu- or delta-receptors inhibit the release of noradrenaline from the sympathetic neurones innervating the sinus node.
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