M. Midol-Monnet

Presynaptic β-adrenoceptors in rat atria: evidence for the presence of stereoselective β1-adrenoceptors

1 Presynaptic β‐adrenoceptor activity was studied in rat isolated atria, previously loaded with [3H]‐noradrenaline. The stimulation‐induced release of 3H transmitter was measured in the presence of cocaine, and adrenaline was used as a facilitatory β‐adrenoceptor agonist. 2 Adrenaline (0.1 and 2 nM) increased, by about 50%, the evoked efflux of tritium. With phenoxybenzamine present, the same activity was shown with 10 nM adrenaline. 3 The β2‐selective adrenoceptor blocking drugs: IPS 339 and ICI 118 551 caused a concentration‐dependent decrease in the activity of adrenaline. Cardioselective β‐blocking drugs: acebutolol, betaxolol, nebivolol and its isomers (R 67 138 and R 67 145) also reduced dose‐dependently the agonistic action of adrenaline. The order of potency for nebivolol and its isomers was R 67 138 > nebivolol > R 67 145. The activity of pindolol was not concentration‐dependent. The inhibitory effect of acebutolol was also observed in the presence of blockade of α‐adrenoceptors. 4 The postsynaptic β‐adrenoceptor blocking activity of nebivolol and its isomers was studied in pithed rats. They reduced isoprenaline‐induced tachycardia without altering hypotensive responses. The order of potency was: R 67 138 > nebivolol > R 67 145. 5 It is concluded that in rat isolated atria, presynaptic β2‐ and β1‐adrenoceptors coexist and that facilitatory β1 ‐adrenoceptors are stereospecific.

Biochemical characterization of the mechanisms involved in the 5-hydroxytryptamine-induced increase in rat atrial rate

Several possible mechanisms for 5-hydroxytryptamine (5-HT)-induced tachycardia in rat have been suggested: an activation of 5-HT1C or 5-HT2 receptors, an indirect sympathomimetic effect or a mechanism independent of 5-HT2 receptor stimulation. The aim of this study was to investigate the involvement of these mechanisms in the 5-HT-induced increase in rat atrial rate using biochemical methods. Indeed, the 5-HT1C and 5-HT2 receptors are linked to phosphoinositide hydrolysis and the noradrenaline (NA) released by 5-HT can stimulate the beta 1-adrenergic receptors linked to adenylate cyclase stimulation. The effect of varying concentrations of 5-HT on inositol phospholipid hydrolysis and adenylate cyclase activity of the rat isolated atria were measured. 5-HT (2 microM) did not modify total inositol phosphate (IP) production, while 5-HT 10 and 50 microM increased it 2-fold. The 5-HT2 antagonist ketanserin (1 microM) abolished IP accumulation induced by 5-HT microM), which indicates that this accumulation is 5-HT2 and not 5-HT1C receptor-mediated. Moreover, cyclic AMP (cAMP) formation was enhanced by 5-HT (5, 10, 20 and 50 microM). When atria were incubated 10 min with the beta-adrenergic receptor antagonist nadolol (1 microM), the increase in the cAMP level induced by 5-HT, whatever its concentration (10, 20 or 50 microM), was inhibited. Treating rats with reserpine (2.5 mg/kg, i.p., 48 and 24 hr before experimentation), which caused NA depletion in the heart, seemed to reduce the stimulating effect of 5-HT 10 and 50 microM on adenylate cyclase activity. Thus, the 5-HT-induced increase in cAMP is indirectly due to the activation of the beta-adrenergic receptors by the NA released by 5-HT. It is concluded that 5-HT stimulates both phosphoinositide turnover and adenylate cyclase activity in the rat isolated atria by activation of 5-HT2 receptors and by an indirect sympathomimetic effect.

5-Hydroxytryptamine and β-adrenoceptors in rat isolated atria

Abstract. The positive chronotropic effect of a high concentration of 5-hydroxytryptamine (5-HT) in rat isolated atria results mainly from a tyramine-like mechanism and is linked to an increase in cAMP production by an indirect stimulation of β-adrenoceptors. Using this preparation, we have compared the action of tyramine and 5-HT. The tyramine (0.15 μM)-induced increase in atrial rate was suppressed by atenolol (a β1 -blocking drug) and by nadolol (a β1 β2 -blocker), while the positive chronotropic effect of 5-HT was reduced by atenolol and suppressed by nadolol. The 5-HT-induced elevation in cAMP was unchanged in the presence of atenolol and abolished by nadolol. The involvement of β2 -adrenoceptors in the effects of 5-HT could result from competition between 5-HT and noradrenaline at the β1 -adrenoceptors that results in a fixation of noradrenaline on β2 -adrenoceptors.

Modulation of noradrenergic transmission in the rat isolated portal vein: Role of prejunctional α2-adrenoceptors and β-adrenoceptors

1. The effect of several adrenoceptor agonists and antagonists on the spontaneous and stimulus-evoked release of [3H]noradrenaline was studied in rat isolated portal vein. 2. Yohimbine (10(-6)M) increased the stimulus-evoked [3H]noradrenaline efflux. Adrenaline alone (3 x 10(-6)M) was without effect, while it increased the resting efflux when added together with yohimbine. 3. Propranolol alone was without effect on the release of [3H]noradrenaline. When added (2 x 10(-6)M) at the same time as yohimbine, it reduced the stimulation-induced 3H efflux. When added before adrenaline and yohimbine, propranolol (10(-5)M) reduced both spontaneous and stimulus-evoked release of [3H]noradrenaline. 4. The effect of several beta-blocking drugs was measured on the enhancing effect of yohimbine on the stimulation-evoked 3H efflux. The beta 1-adrenoceptor blocking drugs: atenolol (5 x 10(-6) and 10(-5) M), metoprolol (5 x 10(-6) and 10(-5) M), like the more selective bisoprolol (2 x 10(-6) and 4 x 10(-6) M) inhibited yohimbine activity. Likewise, propranolol (2 x 10(-6) and 5 x 10(-6)M) and the beta 2-adrenoceptor blocker ICI 118551 exhibited an antagonistic effect. 5. These results indicate the possibility for noradrenaline to activate presynaptic beta-adrenoceptors in rat portal vein. They show an interaction between the presynpatic alpha 2- and beta-adrenoceptor mediated systems in the release of noradrenaline. They suggest the presence and the activity of facilitatory beta 1-adrenoceptors.

In vivo Presynaptic Interaction Between 5-HT and Adrenergic Antagonists on Noradrenergic Neurotransmission

ABSTRACT Functional modulatory mechanism of NA release by HT1-receptors and α2 and β2-adrenoceptors has been observed in vivo. The relative potencies of these inhibitory and facilitatory mechanisms can be modified using selective antagonists, which evidence possibility of reciprocal counterbalance.

Study on the mechanism of 5-HT-induced tachycardia in the pithed rat

1. Intravenous infusion of serotonin (5-HT) (2.5, 5, 10 and 20 micrograms/kg/min) in pithed rats induced a dose-dependent sustained tachycardia. 2. Pretreatment by phentolamine or diltiazem did not modify the chronotropic response to 5-HT. In contrast, atenolol antagonized this tachycardia and the 5-HT antagonists methysergide, ketanserin and MDL 72222 reduced it. 3. The 5-HT-induced tachycardia was abolished by desipramine and was not affected by fluvoxamine, a specific 5-HT uptake inhibitor. Surrenalectomy did not change the response to 5-HT but catecholamine depletion by reserpine markedly inhibited it. 4. Infusion of 5-HT increased the ratio of noradrenaline (NA) in the heart to NA in plasma, from 1.70 in control group to 2.76 in treated group (P less than 0.05). Desipramine inhibited this effect. 5. It was concluded that the tachycardia induced by an infusion of 5-HT in pithed rat results from a complex mechanism involving mainly the release of NA from the cardiac sympathetic nerves and a less important direct 5-HT2 mechanism.