Elevation of intracellular cyclic AMP concentration fails to inhibit adrenaline-induced hyperpolarization in amphibian sympathetic neurones (original) (raw)
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British Journal of Pharmacology, 1977
I The /i-adrenoceptor agonist isoprenaline normally causes only a small and inconsistent increase in the membrane potential of cells in guinea-pig liver slices, in contrast to the large hyperpolarizations seen with a-agonists. However, after a selective a-adrenoceptor agonist has been applied, the response to isoprenaline becomes greatly enhanced. 2 Simultaneous application of small doses of an a-and a P-agonist produce hyperpolarizations larger than the sum of the responses to each agent alone. 3 These interactions occur with a range of sympathomimetic amines, including some which are not substrates for various processes for the uptake and inactivation of catecholamines. 4 Hyperpolarizations caused by externally applied cyclic adenosine-3',5'-monophosphate (cyclic AMP) also become larger after application of an a-agonist. 5 The adenine nucleotides adenosine 5'-diphosphate (ADP) and adenosine 5'-triphosphate (ATP) hyperpolarize guinea-pig liver cells in the dose range 0.1-1.0 mM. This response is not increased after an a-agonist. However, ADP and ATP are themselves able to enhance the response to f-agonists. 6 These interactions between a-agonists, P-agonists and adenine nucleotides seem to involve steps subsequent to receptor activation. Changes in the intracellular actions of cyclic AMP may be concerned.
A reassessment of the modulatory role of cyclic AMP in catecholamine secretion by chromaffin cells
British Journal of Pharmacology, 1995
The role of adenosine 3':5'-cyclic monophosphate (cyclic AMP) in the regulation of catecholamine (CA) secretion in chromaffin cells remains equivocal from previous studies. 2 In the present study the effect of this cyclic nucleotide on basal CA secretion, as well as on intracellular calcium and membrane potential has been examined. 3 Forskolin and the permeable cyclic AMP analogue, 8-(4-chlorphenylthio)-adenosine-3'-5' monophosphate cyclic (pClpcAMP), increased basal CA secretion in a dose-dependent manner. The ECss were 0.43 ± 0.10lM for forskolin and 39 ± 9gM for pClpcAMP. Other agonists with adenylate cyclase activity such as stimulants of adenosine receptors, P-adrenoceptors, GABAB receptors and intestinal vasoactive peptide (VIP), also increased basal CA secretion in a highly significant manner. However, when they were added together with forskolin, CA secretion was not affected although an additive increase in cyclic AMP levels was produced. 4 Statistical analysis of the correlation between cyclic AMP levels and CA secretion evoked by these cyclic AMP increasing compounds showed that a significant direct correlation between both parameters existed only when low levels of cyclic AMP were produced by secretagogue stimulation. When the increase in intracellular cyclic AMP concentrations exceeded approximately 8 times the basal cyclic AMP levels the correlation was not significant. These results indicate a dual dose-dependent effect of cyclic AMP on basal CA secretion. 5 The stimulatory effect of low cyclic AMP on basal CA secretion was accompanied by an increase in membrane potential and in intracellular calcium concentrations ([Ca2+]j), the latter mainly being due to an increase in intracellular Ca2" entry through L-type voltage-dependent Ca2" channels. 6 The possible mechanisms involved in these cyclic AMP effects are discussed.
European Journal of Neuroscience, 1990
Using primary neuronal or astrocyte cultures from the striatum of the embryonic mouse, we have observed that the p-adrenergic agonist isoprenaline astrocytes than in neurons. In both cell types, the a-adrenergic selective agonist methoxamine which alone did not affect the production of CAMP, potentiated the isoprenaline-evoked response. In support of these observations, when associated a2-noradrenergic and D1-dopaminergic responses were prevented, the mixed a l -and p-adrenergic agonist noradrenaline M) induced a production of cAMP which was totally blocked by propranolol made in the presence of 3-isobutyl-1-methylxanthine (1 mM), the observed effects on cAMP accumulation were not related to a modulation of phosphodiesterase activities. In addition, both in astrocytes and in neurons, the potentiation by al-adrenergic agonists of the p-adrenergic-evoked response required external calcium. Using INDO 1 as a fluorescent probe, methoxamine (25 kM) was shown to induce in astrocytes an increase in cytosolic calcium concentration which was prolonged by isoprenaline (1 0-5 M) only in the presence of external calcium. These results suggest that the prolonged increase in cytosolic calcium concentration linked to the activation of a l -and p-adrenergic receptors is responsible for the potentiation of the p-adrenergicinduced production of CAMP, which is partially dependent on external calcium. M) induced a more pronounced accumulation of cAMP in M), M) and partially abolished by prazosin M). Since experiments were
British Journal of Pharmacology, 2000
Constitutive activity of the b 2-adrenoceptor, which is sensitive to inhibition by an inverse agonist such as ICI 118551, has been readily demonstrated in recombinant systems expressing constitutivelyactive mutant receptors or over-expressing the wild-type b 2-adrenoceptor. Here we demonstrate the presence of constitutive b 2-adrenoceptor activity in BC3H1 cells which endogenously express this receptor. 2 In BC3H1 cells, only ICI 118551 behaved as an inverse agonist at b 2-adrenoceptors, while propranolol, ICI 118551, atenolol and, to a lesser extent, alprenolol exhibited inverse agonism in CHO-b 2 4 cells transfected with cDNA for the human b 2-adrenoceptor (310 fmol.mg protein 71). The level of expression of b 2-adrenoceptors in BC3H1 cells was not high (78 fmol.mg protein 71) and the eciency of receptor ± eector coupling in this cell line was much lower than in the recombinant CHO-b 2 4 cells (as judged by the partial agonist nature of both salbutamol and clenbuterol). 3 ICI 118551 (log K D 79.73+0.07) and propranolol (log K D 79.25+0.12) both behaved as conventional competitive antagonists of isoprenaline-stimulated cyclic AMP accumulation in high expressing CHO-b 2 4 cells. In contrast, ICI 118551 appeared to act as a non-competitive antagonist in BC3H1 cells and in low expressing CHO-b 2 6 cells (50 fmol.mg protein 71). 4 This non-competitive eect of ICI 118551 in BC3H1 cells was also observed when either salbutamol was used as agonist, or the incubation period with isoprenaline was extended to 30 min. 5 The possibility that these eects of ICI 118551 are due to an interaction with dierent anity states (R, R* and R') of the receptor is discussed.
Dissociation of Cardiac Inotropic and Adenylate Cyclase Activating Adrenoceptors
British Journal of Pharmacology, 1974
At higher temperatures, near the physiological range for mammals and nonhibernating frogs, the adrenoceptors for both inotropic responses to adrenaline and noradrenaline and for cyclic 3',5'-adenosine monophosphate (cyclic AMP) production in rat and frog isolated heart preparations, had typical ,B characteristics. Phenoxybenzamine potentiated the inotropic response and the accumulation of cyclic AMP; conversely, propranolol inhibited the two responses. 2 When the ambient temperature was reduced, the adrenoceptors mediating cyclic AMP production changed very little; they were blocked as effectively as at the higher temperature by propranolol and were not blocked by phenoxybenzamine. However, the adrenoceptors mediating the inotropic response were markedly changed by the decrease in temperature; phenoxybenzamine now inhibited this response and the inhibitory activity of propranolol was reduced about tenfold. 3 These results indicate that the adrenoceptors that mediate cardiac inotropic responses at physiological temperatures are distinct from those that mediate the production of cyclic AMP, and that the activation of adenylate cyclase and the accumulation of cyclic AMP are probably not intermediate steps in cardiac inotropic responses to catecholamines.