Inhibitory Effect Of Noradrenaline Research Articles

Pharmacological characterization of the receptor mediating the adrenergic inhibition of responses to substance P in the cingulate cortex

The excitatory responses of neurones in the anterior cingulate cortex of the rat to iontophoretically applied substance P (SP) are reduced by noradrenaline (NA) applied iontophoretically or released from noradrenergic pathways. In order to determine the receptor involved in this inhibitory effect we have studied the effects of a number of receptor-specific adrenergic agonists and antagonists on responses of cingulate neurones to SP in rats anaesthetized with chloral hydrate. Low iontophoretic currents (0–15 nA) of NA, adrenaline and the β-agonist, clenbuterol, all strongly reduced responses to SP. Isoprenaline was also effective but less consistently so, although problems were experienced with its iontophoretic release from micropipettes. Theα 1-agonists, phenylephrine and methoxamine were also able to reduce responses to SP. However, this reduction required higher iontophoretic currents (15–60 nA) and was associated with depressant effects on baseline firing rate. Theα 2-agonist clonidine was only weakly active at high currents and this too was associated with depression of baseline firing. Similar weak effects were noted with dopamine. The inhibitory effects of NA on SP responses were convincingly blocked or reversed by the β-antagonist, practolol, but not by theα 1-antagonist, prazosin. The reduction of SP responses by phenylephrine was also blocked by practolol but unaffected by prazosin. Finally, reduction of SP excitations by activation of the coeruleocortical pathway was also blocked by practolol applied iontophoretically to the cortical cells. These results are consistent with the hypothesis that the effect of NA on SP responsiveness in the cingulate cortex is mediated by β-adrenoreceptors.

Effects of prostaglandin D2 on the activity of hypothalamic neurons in the rat.

The effects of electrophoretically applied prostaglandin D2 (PGD2) on neuronal activity in the rat lateral preoptic area (LPOA) and posterior hypothalamic area (PHA) were examined. In the LPOA, 20% of the tested neurons were excited, 26% inhibited, and 6% showed bidirectional response. The direct effects often showed desensitization after repeated applications. Neurons excited by PGD2 were significantly sensitive (excitation) to acetylcholine (ACh). The ACh excitatory effect was sometimes (38%) attenuated, blocked, or reversed by concurrent PGD2 application. Excitatory or inhibitory effect of noradrenaline (NA) was not related to the effects of PGD2; however, modulation of the NA responses by PGD2 was common (58%). Inhibition, the predominant NA response, was changed to no effect or to excitation during simultaneous PGD2 application. Changes of the NA responses from inhibition to excitation, or from excitation to inhibition-excitation sequences were observed after PGD2 infusion into the third cerebral ventricle at low concentrations. In 43% of the cells, neurotransmission in the LPOA following ventral noradrenergic bundle stimulation was modified by PGD2 application. PGD2 application tended to reduce the duration of inhibition and to extend that of excitation. The direct effects of PGD2 in the PHA were similar to those in the LPOA. Desensitization was also observed in the PHA, but no interrelations were observed among the effects of PGD2, ACh, and NA. Modulation of ACh and NA responses by PGD2 was rarely seen in the PHA. Possible contributions of PGD2 to sleep and thermoregulation are discussed.

Alpha 1-adrenergic receptor involvement in norepinephrine-ethanol inhibition of rat brain Na+ -K+ ATPase and in ethanol tolerance.

Norepinephrine (NE) sensitization of rat brain Na+ -K+ ATPase to ethanol (EtOH) inhibition appears to be mediated by alpha 1-adrenoreceptors, since it was reversed by prazosin and WB-4101 (alpha 1-receptor antagonists) in a concentration-dependent manner, but not by yohimbine and piperoxan (alpha 2-receptor antagonists). In addition, clonidine (alpha 2-agonist) and methoxamine (central receptor type uncertain) produced very little sensitization. Chronic EtOH administration to rats for 3 weeks produced tolerance to the hypothermic effect of test doses of EtOH (3 g/kg, i.p.) and a decreased inhibitory effect of NE + EtOH on the enzyme in vitro. This inhibition was still prevented by prazosin and WB-4101. However, the binding of tritiated WB-4101 and prazosin to brain membrane preparations from control and EtOH-tolerant rats revealed that the maximum number of binding sites (Bmax) and the dissociation constant (KD) of alpha 1-adrenoreceptors were decreased after tolerance development. These changes in numbers and binding properties of alpha 1-adrenoreceptors probably account for the decreased NE sensitization of the ATPase to EtOH inhibition in preparations from EtOH-tolerant rats.

Clonidine and presynaptic adrenoceptor theory

The effects of clonidine, a presumed selective presynaptic alpha 2-adrenoceptor agonist or partial agonist, were examined in guinea-pig atria. Split left atrial preparations were stimulated transmurally at 2 Hz with 100 pulses of 0.5 ms duration and the efflux of 3H-transmitter determined. Clonidine inhibited efflux at 3 X 10(-8)M to 3 X 10(-7)M by about 30%. Yohimbine, at a concentration (10(-6)M) which caused a 3 fold increase in the release of 3H-transmitter during field stimulation, did not alter the ability of clonidine to inhibit transmitter efflux. At 10(-6)M clonidine alone had no significant effect on the stimulation-induced efflux of 3H-transmitter, but in the presence of yohimbine (10(-6)M), inhibited efflux by over 50%. The inhibitory effect of noradrenaline (10(-6)M) on 3H-transmitter efflux was antagonized by clonidine at 10(-6)M but not at 10(-8)M, although neither concentration of clonidine alone inhibited transmitter efflux. The present findings indicate that the effects of clonidine on the efflux of noradrenaline from sympathetic nerves cannot be accommodated within the currently held view that the compound is an agonist or partial agonist on presynaptic alpha 2-adrenoceptors. It appears that clonidine has multiple sites of action few of which are antagonized by a concentration of the prototypical presynaptic antagonist yohimbine, which enhances efflux 3 fold.

Presynaptic modulation of acetylcholine release from cardiac parasympathetic neurons.

Acetylcholine can be released from parasympathetic nerve endings in rat atria by 57 mM K+ depolarization or by electrical field stimulation. We have studied the presynaptic modulation of [3H]acetylcholine release from superfused rat atria prelabeled with [3H]choline. Exogenous acetylcholine and the specific muscarinic agonist oxotremorine inhibit the stimulation-induced overflow of [3H]acetylcholine into the superfusion medium. The half-maximal inhibitory concentration (IC50) of oxotremorine is 0.3 microM. The cholinesterase inhibitor neostigmine also decreases K+-stimulated [3H]acetylcholine overflow, whereas the muscarinic antagonist atropine enhances the overflow of [3H]acetylcholine. These data suggest that acetylcholine release in atria is modulated through negative feedback by the endogenous transmitter. The sympathetic adrenergic neurotransmitter norepinephrine and the neurohormone epinephrine also inhibit the overflow of [3H]acetylcholine by approximately 60%. The IC50 values for the inhibitory effects of these catecholamines are 6.3 and 2.2 microM, respectively. The inhibitory effect of norepinephrine is blocked by the alpha-adrenergic receptor antagonist yohimbine but not by the beta-adrenergic receptor antagonist propranolol. We suggest that presynaptic muscarinic and alpha-adrenergic receptors participate in the physiological and pharmacological control of cardiac parasympathetic activity.

Medial preoptic area involvement in norepinephrine-induced suppression of pulsatile luteinizing hormone release in ovariectomized rats.

This study examined whether the medial preoptic area (MPOA) is a site which mediates the inhibitory effects of norepinephrine (NE) on pulsatile luteinizing hormone (LH) secretion in ovariectomized rats. Animals were bled continuously at a rate of 50 microliter whole blood/7 min for 2 h prior to push-pull perfusion in the MPOA, and during a 2-3 h period of perfusion of the MPOA (20 microliter/min) with artificial CSF, or 2 or 20 pg NE/min. In another group of rats LH levels were only determined during a 2-3 h period of MPOA perfusion with CSF. Pulsatile LH release was not affected by push-pull perfusion with CSF when a comparison was made to preperfusion LH values in the same rats. Moreover, LH levels obtained from rats only bled during MPOA perfusion with CSF were not different from LH values obtained during the preperfusion periods in the other groups. However, push-pull perfusion of the MPOA with 2 or 20 pg NE/min significantly suppressed mean LH levels by causing a 35-45% reduction in pulse frequency. No decrease occurred in LH pulse amplitude. Therefore, these studies demonstrate that NE acting at the level of the MPOA can suppress pulsatile LH release solely by decreasing LH pulse frequency.

Synthesis of phosphatidylcholines in rat hepatocytes. Possible regulation by norepinephrine via an alpha-adrenergic mechanism.

The effect of norepinephrine on phosphatidylcholine and phosphatidylethanolamine formation was investigated in short-term incubations with freshly isolated rat hepatocytes. In the presence of dl-propranolol, norepinephrine decreases the incorporation of [methyl-14C]choline into phosphatidylcholines in a dose-dependent manner. At a concentration of 50 microM, norepinephrine (plus 20 microM propranolol) inhibits the incorporation of [methyl-14C]choline over a wide range of choline concentrations (59% inhibition at 5 microM choline; 34% inhibition at 1 mM choline). Norepinephrine also decreases the incorporation rates of [1-14C]palmitic acid and [1-14C]oleic acid into phosphatidylcholines. The effect of norepinephrine is mediated through an alpha-adrenergic receptor. Norepinephrine (plus propranolol) does not decrease the uptake or phosphorylation rate of [methyl-14C]choline. Pulse-label and pulse-chase studies indicate that the conversion rate of phosphocholine to CDP-choline, catalyzed by CTP:phosphocholine cytidylyltransferase, is diminished by norepinephrine. In contrast with the inhibitory effect of norepinephrine on phosphatidylcholine synthesis, this hormone stimulates the formation of phosphatidylethanolamines from [1,2-14C]ethanolamine. This increased incorporation rate is apparent at ethanolamine concentrations above 25 microM. A combination of norepinephrine and propranolol decreases, however, the synthesis of phosphatidylcholines from [1,2-14C]ethanolamine. The results indicate that alpha-adrenergic regulation dissociates the synthesis of phosphatidylcholines from that of phosphatidylethanolamines.

An unlikely role for cyclic AMP in the mediation of the excitatory and inhibitory effects of noradrenaline on transmission in the olfactory cortex

Simultaneous measurements have been made of the actions of noradrenaline and other agonists, alone and in the presence of appropriate antagonists, on synaptic transmission and cyclic AMP levels in the rat olfactory cortex. The possible role of cyclic AMP as an obligatory mediator of the excitatory and inhibitory actions of noradrenaline is discussed.

Excitatory and inhibitory effects of noradrenaline on synaptic transmission in the rat olfactory cortex slice

An investigation has been made of the effects of noradrenaline on excitatory transmission at the lateral olfactory tract (LOT)-superficial pyramidal cell synapse of the rat olfactory cortex slice by measuring the effects of bath-applied noradrenaline on the amplitudes and latencies of the field potentials evoked on LOT stimulation. Low concentrations of noradrenaline (0.1–5 μM) facilitate transmission whereas higher doses (20–250 μM) depress transmission. Both these effects were completely blocked by non-selective α- and β-adrenoceptor antagonists, by 2-amino-5-phosphonovaleric acid (an antagonist of excitatory amino acid receptors of the N-methyl- d-aspartate type) and by the methylxanthine theophylline. The depressant effects of noradrenaline were mimicked by bath application of GABA or adenosine and specifically antagonized by bicuculline and picrotoxin. In parallel experiments, noradrenaline (100 μM) significantly increased the potassium-evoked release of endogenous aspartate, glutamate and GABA, proposed transmitters of the olfactory cortex, although the effect on GABA release was specifically antagonized by 2-amino-5-phosphonovaleric acid. Noradrenaline (100 μM) also significantly increased the potassium-evoked release of d-[ 3H]aspartate, an effect antagonized by a number of α- and β-adrenoceptor antagonists. It is concluded that at low concentrations, noradrenaline facilitates transmission at the LOT-superficial pyramidal cell synapse by increasing excitatory amino acid neurotransmitter release. This effect is mediated by both α- and β-adrenoceptors although the primary site of release is unknown. At higher concentrations of noradrenaline, the increased levels of excitatory transmitters release sufficient endogenous GABA (and possibly adenosine) to cause an overall depression of transmission. These conclusions are supported by the results of a series of experiments in which the effects of noradrenaline on stimulus input-evoked field potential output relationships were assessed. It is not possible to exclude additional direct effects of noradrenaline on membrane excitability.

Adrenergic transmission in the dog mesenteric vein and its modulation by alpha-adrenoceptor antagonists.

Adrenergic transmission was investigated in the dog mesenteric vein by recording electrical responses of single smooth muscle cells to perivascular nerve stimulation. Perivascular nerve stimulation generated an excitatory junction potential (e.j.p.) and a slow depolarization of the membrane. The amplitude of the e.j.p. was increased by increasing the stimulus intensity, and at high intensity, a spike potential was generated. Repetitive stimulation of the nerves showed facilitation of e.j.ps and enhanced the amplitude of slow depolarization. A linear relationship was observed between the amplitude of the e.j.p. and of slow depolarization. The slow depolarization was inhibited by application of yohimbine or phentolamine, but not by prazosin. The amplitude of e.j.p. was increased by prazosin and was decreased by yohimbine. Both e.j.p. and slow depolarization were inhibited by guanethidine or tetrodotoxin. Exogenously applied noradrenaline depolarized the muscle membrane and, in high concentrations (greater than 10(-7)M), generated slow waves. These effects of noradrenaline were blocked by yohimbine. High concentrations of prazosin (greater than 10(-6)M) showed weak inhibitory effects on the noradrenaline actions. The amplitude of e.j.p. was decreased by exogenously applied noradrenaline in a dose-dependent manner. The inhibitory effect of noradrenaline on the e.j.p. was suppressed by yohimbine, but not by prazosin or phentolamine. Phentolamine, but not prazosin, enhanced the facilitation process of e.j.ps. This effect was not suppressed by exogenously applied noradrenaline. Application of neostigmine but not of atropine, reduced the e.j.p. amplitude without affecting the slow depolarization. It was concluded that, in the dog mesenteric vein, perivascular nerve stimulation produced three types of electrical responses of the smooth muscle membrane, i.e., e.j.p., slow depolarization and spike potential. The slow depolarization was generated by activation of alpha 2-adrenoceptors. Exogenously applied noradrenaline reduced the e.j.p. amplitude through activation of prejunctional alpha 2-adrenoceptors, but the reduction may not involve alpha-autoinhibitory mechanisms.

Functional characterization of the alpha adrenergic receptor modulating the hydroosmotic effect of vasopressin on the rabbit cortical collecting tubule.

To characterize the type of alpha adrenergic receptor, the effects of specific alpha adrenergic agonists and antagonists on antidiuretic hormone [( Arg8]-vasopressin [AVP])-induced water absorption were evaluated in cortical collecting tubules isolated from the rabbit kidney and perfused in vitro. In the presence of AVP (100 microU/ml), net fluid volume absorption (Jv, nanoliters per minute per millimeter) was 1.39 +/- 0.09 and osmotic water permeability coefficient (Pf, X 10(-4) centimeters per second) was 150.2 +/- 15.0. The addition of 10(-6) M phenylephrine (PE), an alpha adrenergic agonist, resulted in a significant decrease in Jv and Pf to 0.72 +/- 0.11 (P less than 0.005) and 69.9 +/- 10.9 (P less than 0.005). The addition of 10(-4) M prazosin (PZ), an alpha adrenergic antagonist, did not cause any significant change in Jv and Pf, which were 0.71 +/- 0.09 (P = NS vs. AVP + PE) and 67.8 +/- 9.5 (P = NS vs. AVP + PE), respectively. In a separate group of tubules, in the presence of AVP (100 microU/ml) and PE (10(-6) M), Jv and Pf were 0.78 +/- 0.17 and 76.1 +/- 18.0, respectively. The addition of 10(-6) M yohimbine (Y), an alpha 2 adrenergic antagonist, resulted in a significant increase in Jv to 1.46 +/- 0.14 (P less than 0.01) and Pf to 157.5 +/- 22.3 (P less than 0.005). Y (10(-4) M) or PZ (10(-4) M) alone did not significantly affect Jv and Pf in the presence of AVP )100 microU/ml). The effect of the natural endogenous catecholamine norepinephrine (NE) on Jv and Pf in the presence of AVP and propranolol (PR) was next examined. Jv and Pf were 1.53 +/- 0.07 and 176.3 +/- 5.2, respectively, in the presence of AVP (100 microU/ml) and PR (10(-4) M). The addition of NE (10(-8) M) resulted in a significant decrease in Jv to 1.19 +/- 0.11 (P less than 0.05) and Pf to 127.0 +/- 11.3 (P less than 0.02). Increasing the concentration of NE to 10(-6) M resulted in a further decrease in Jv and Pf to 0.70 +/- 0.10 (P less than 0.01 vs. NE 10(-8) M) and 68.5 +/- 10.6 (P less than 0.01 vs. NE 10(-8) M), respectively. The inhibitory effect of NE on AVP-induced water absorption was blocked by Y, but not by PZ. The effect of the alpha 2 adrenergic agonist clonidine (CD) on Jv and Pf was also examined. In the presence of AVP (10 microU/ml) Jv and Pf were 1.65 +/- 0.04 and 175.1 +/- 13.1, respectively. The addition of CD (10(-6) M) resulted in a significant decrease in Jv to 1.08 +/- 0.12 (P < 0.01) and Pf to 108.1 +/- 15.4 (P < 0.01). Increasing the concentration of CD to 10(-4) M resulted in a further significant decrease in Jv and Pf to 0.57 +/- 0.13 (P < 0.02 vs. CD 10(-6) M) and 54.7 +/- 13.8 (P < 0.01 vs. CD 10(-6) M), respectively. Similar results were obtained in the presence of AVP (100 microU/ml). The inhibitory effect of CD on AVP-induced water absorption was blocked by Y. CD did not significantly affect Jv and Pf in the presence of 8-bromo adenosine 3',5'-cyclic monophosphate. These studies indicate that alpha adrenergic agonists directly inhibit AVP-mediated water absorption at the level of renal tubule, an effect that can be blocked by specific alpha2 adrenergic antagonists, but not by specific alpha1 adrenergic antagonists. Alpha2 adrenergic stimulation directly inhibits AVP-mediate water absorption at the level of the tubule, an effect that can be blocked by a specific alpha2 adrenergic antagonist. This effect appears to be exerted at the level of activation of adenylate cyclase, since it is absent in the present of cyclic AMP.

Further studies on norepinephrine-induced suppression of pulsatile luteinizing hormone release in ovariectomized rats.

The present study examined three aspects of the inhibitory effects of continuous intraventricular infusion of norepinephrine (NE) on pulsatile luteinizing hormone (LH) release in ovariectomized, nonsteroid-primed rats: whether the inhibitory effects of NE infusion were exerted on LH pulse frequency and/or amplitude; whether central nervous system desensitization occurred in response to the inhibitory effects of continuous NE infusion on pulsatile LH secretion, and whether dopamine of serotonin were involved as possible interneuronal transmitter mediators of NE-induced suppression of pulsatile LH release. Unanesthetized rats with external jugular cannulae were bled continuously at a rate of 50 microliters whole blood/7 min for 2 h prior to infusion and for 2-3 h during continuous intraventricular infusion of artificial cerebrospinal fluid or NE. Infusion of cerebrospinal fluid had no effect on pulsatile LH release, while continuous infusion of 0.3 or 1.8 micrograms NE/h for 2-3 h produced suppression of pulsatile LH secretion. Although desensitization to the stimulatory effects of NE on LH release in ovariectomized, steroid-primed rats had been observed to occur rapidly within 90 min after the onset of infusion, desensitization to the inhibitory effect of NE on pulsatile LH release did not occur even after continuous infusion of NE for periods up to 20 h. Mean blood LH levels were as low in rats bled 17-20 h after the onset of NE infusion as in those bled at 0-3 h. The suppressive effect of NE on pulsatile LH release was not prevented by prior blockade of dopamine or serotonin receptors with pimozide or metergoline, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in sensitivity to the inhibitory effects of adrenergic agonists on intestinal motor activity after chronic sympathetic denervation.

The concentration-effect relationships of adrenergic agonists in inhibiting muscular tone, carbachol-induced contraction of circular muscle strips and nerve-mediated motor activity during the peristaltic reflex have been studied in intact and sympathetically denervated preparations of isolated guinea-pig colon. The order of potencies of adrenergic agonists was different for muscular and nerve-mediated effects, being clonidine greater than noradrenaline greater than methoxamine greater than isoprenaline for the inhibition of peristalsis and isoprenaline greater than noradrenaline greater than methoxamine greater than clonidine for the relaxation of circular muscle. Denervation supersensitivity was specific for the adrenergic agonists and developed both to the muscular and nerve-mediated effects, involving both alpha and beta receptors. The degree of potentiation was similar for noradrenaline and isoprenaline when measured for the muscular effects but was significantly higher for noradrenaline than for isoprenaline or methoxamine when measured for peristalsis inhibition. No potentiation could be observed for papaverine and for the muscular effects of methoxamine and phenylephrine. The increase in potency of noradrenaline ranged from a 26-fold increase for the inhibition of propulsion velocity to a 2.5-fold increase for the inhibition of carbachol-induced contraction. A much narrower range was observed for isoprenaline. Potentiation could also be observed for the inhibitory effect of noradrenaline on acetylcholine release. Clonidine was the most potent agonist against peristaltic reflex and the weakest agonist in relaxing circular muscle. Denervated preparations became subsensitive to the inhibitory effect of clonidine on peristaltic reflex. The potency of clonidine relative to noradrenaline was 488 in intact preparations and only 3.1 in denervated organs.(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of uptake2 on the inhibition by unlabelled noradrenaline of the stimulation-evoked overflow of 3H-noradrenaline in rabbit aorta with regard to surface of amine entry.

The release by electrical field stimulation of 3H-noradrenaline from the adrenergic nerve endings in the rabbit aorta was studied in a special double-chambered organ bath. Independently of the frequency (1-10 Hz) and the number of pulses used (300-3,000 pulses), only 10-20% of the stimulation-evoked overflow of tritium (total evoked overflow) left the aortic wall via the intimal surface (intimal evoked overflow). The corresponding percentage value for the basal efflux was twice that for the evoked overflow, thus indicating that part of the radioactivity in the basal efflux originated from an extraneuronal compartment. The radioactivity in the total evoked overflow (in response to stimulation at 10 Hz) originated from at least two compartments (compartment I and II) with half times for efflux of about 2 and 6 min, respectively. In the intimal evoked overflow, compartment II (but not compartment I) was involved. When uptake1 was inhibited, 70% of the radioactivity in the intimal evoked overflow (stimulation at 1 Hz) consisted of metabolites, while unchanged amine prevailed by far in the total and adventitial evoked overflow, respectively. Additional inhibition of uptake2 thus had a striking effect only on the composition of the radioactivity in the intimal evoked overflow. The intimal surface was exposed to unlabelled noradrenaline in order to inhibit the evoked overflow of tritium (stimulation at 1 Hz; uptake1 inhibited). When uptake2 was inhibited additionally, the dose-response curve for the inhibitory effect of noradrenaline was shifted to the left by a factor of 4.(ABSTRACT TRUNCATED AT 250 WORDS)

Central noradrenergic-cholinergic interaction in regulation of gastric acid secretion in rats

Possible roles of noradrenaline (NA) and acetylcholine (ACh) within the lateral hypothalamic area (LHA) in regulation of gastric acid secretion were examined in urethane anesthetized rats. When NA 30 nmoles was given into the LHA, the gastric acid output decreased and this inhibitory effect of NA was potentiated in rats pretreated with reserpine (2 mg/kg, i.p., 20 hr). Even in a dose of 3 nmoles which was without effect in non-treated control animals, there was a remarkable decrease in acid output. In these reserpinized animals, ACh in a dose of 30 nmoles induced a remarkable increase in acid output, while in the controls this ACh-induced increase was observed only with a 10 times higher dose. In the rats not given reserpine, the cholinergic muscarinic agonist bethanechol (10 nmoles) increased the gastric acid output while nicotine (30 nmoles) was without effect. Therefore, in rats, the central noradrenergic inhibitory mechanisms related to regulation of gastric function may be present at the level of LHA as well as the ala cinerea (area of the dorsal motor nucleus of vagi and the nucleus tractus solitarius). In addition, in the LHA, a cholinergic muscarinic mechanism which elevates gastric acid secretion may be antagonized by a noradrenergic inhibitory mechanism.

Inhibition of the activity of sympathetic preganglionic neurones and neurones activated by visceral afferents, by alpha-methylnoradrenaline and endogenous catecholamines

The responses of electrophysiologically identified sympathetic preganglionic neurones (SPGN) and neurones activated by visceral afferents (VA) to iontophoretic application of: (1) the intraneuronal metabolites of α-methyl-DOPA (α-MD): α-methylnoradrenaline (α-MNA) and α-methyldopamine (α-MDA); (2) noradrenaline (NA) and adrenaline (Ad); and (3) N-methyl-β-hydroxy-phenylethylamine (NMPEA), were tested in the upper and lower segments of the thoracic spinal cord of the cat. α-Methylnoradrenaline, NA and Ad had an inhibitory action on the majority of spontaneously firing neurones. Inhibition of the activity of preganglionic neurones and neurones activated by visceral afferents induced by α-MNA was usually equal to the effect of NA, but in some neurones α-MNA was more potent. The transport numbers of both amines are similar. The alpha adrenoceptor antagonists, thymoxamine, piperoxan and yohimbine, antagonized the inhibitory effects of α-MNA in spontaneously-active preganglionic neurones and neurones activated by visceral afferents. Piperoxan antagonized also the inhibitory effects of NA. The inhibitory effect of α-MDA was weaker and that of NMPEA was much weaker than that of α-MNA and NA. The inhibitory effects of α-MNA and NA in the cerveau isolé preparation resembled those observed in anaesthetized animals. In reserpinized cats, with catecholamine levels in brain stem and spinal cord reduced by 98–99%, the inhibitory effects of α-MNA were preserved. It is postulated that α-MNA modulates the activity of preganglionic neurones and that this action, leading to a decrease in sympathetic output and mediated by α 1 and α 2 adrenoceptors, could be the most important factor in the antihypertensive effect of α-MD. The inhibition of the activity of neurones activated by visceral afferents by α-MNA indicates that α-MD may also attenuate the response of the central nervous system to the input from the heart and other organs.

Effect of neurotensin on mechanical and intracellular electrical activity of the canine stomach.

Intracellular microelectrode and standard organ bath techniques were used to study in vitro the effects of neurotensin on the electrical and mechanical activities of canine antral circular smooth muscle. Neurotensin reduced or abolished spontaneous contractions. Muscarinic and adrenergic antagonists and tetrodotoxin did not block the effects of neurotensin, suggesting that the action of neurotensin was due to a direct action on the smooth muscle cell. Although the inhibitory effect of norepinephrine and neurotensin was similar, the effect of neurotensin did not appear to occur by an adrenergic mechanism because alpha- and beta-receptor blockade had no effect. Neurotensin also reduced or abolished contractions stimulated by pentagastrin and acetylcholine. The inhibitory effect of neurotensin on spontaneous acetylcholine- and pentagastrin-stimulated contractions was associated with a decrease in the amplitude and duration of the plateau potential of the gastric action potential. The data suggest that modulation of antral contractions by neurotensin occurs through a voltage-dependent mechanism that operates during the plateau potential.

Negative control of norepinephrine on the thyroid cyclic AMP system

Negative control on the thyroid cyclic AMP system has been studied. The increase of cyclic AMP levels induced by TSH in dog thyroid slices and its consequent secretion were inhibited by norepinephrine. This effect was different from the previously described activation of cyclic AMP disposal by acetylcholine: it was not calcium-dependent, was observed in the presence of isobutyl methylxanthine and was not inhibited by atropine. The inhibitory action of norepinephrine was abolished by phentolamine but not by l-propranolol. Clonidine and epinephrine also markedly inhibited the elevation of cyclic AMP levels, but phenylephrine did not. The inhibitory effect of norepinephrine and clonidine was abolished by yohimbine but not by prazosin. These results suggest that the effect of adrenergic agents on dog thyroid follicular cells is mediated by α 2-receptors. Similar results were obtained on dog thyroid adenylate cyclase activity: norepinephrine diminished the activation of adenylate cyclase induced by TSH, in a sodium-dependent process. This inhibition was abolished by phentolamine and yohimbine, but not by l-propranolol and prazosin. This shows that the negative α 2-adrenergic effect bears directly on adenylate cyclase.

Differential inhibitory effects of noradrenaline upon insulin secretion by the isolated perfused pancreas of the rat.

Responses of basal and glucose-induced secretion phases of the isolated perfused pancreas of the rat to graded doses of noradrenaline (NA) are described. Maximal inhibition of basal secretion was achieved at [NA]=40, ng/100 ml; at [NA]=80 ng/100 ml, the 1st phase of glucose induced secretion was abolished; at [NA]=100 ng/100 ml the 2nd phase was abolished. At [NA]≤40 ng/100 ml basal secretion was less sensitive to NA inhibition than glucose induced output.

Involvement of α1-adrenergic receptors in stimulation of phosphatidylinositol metabolism by catecholamines in mouse thyroids

The effects of α-adrenergic agonists and thyroid stimulating hormone on the incorporation of radioactive phosphate into phosphatidylinositol were investigated in mouse thyroids in vitro. The incorporation of 32P orthophosphate into phosphatidylinositol was stimulated by thyroid stimulating hormone, norepinephrine (a mixed α 1-and α 2-adrenergic agonist), methoxamine and phenylephrine ( α 1-agonists) and slightly by clonidine and oxymetazoline ( α 2-agonists) but not by isoproterenol (β-agonist). Prazosin ( α 1-antagonist) inhibited the stimulation by norepinephrine of 32P incorporation into phosphatidylinositol, but yohimbine ( α 2-antagonist) was less effective. Although norepinephrine inhibits the thyroid stimulating hormone-induced release by activating α-, especially α 1-adrenoceptors in mouse thyroids [M.L. Maayan et al., Metabolism 26, 473 (1977); M.L. Maayan et al., Endocrinology 101, 284 (1977); T. Muraki et al., Endocrinology 110, 51 (1982)] α 1-agonists did not decrease the stimulation of turnover elicited by thyroid stimulating hormone and did not have additive action with it. These results suggest that (1) the stimulation of phosphatidylinositol turnover of mouse thyroids elicited by adrenergic agonists is mediated by activation of α 1-adrenoceptors and (2) the inhibitory effect of norepinephrine on the thyroid stimulating hormone-induced release of thyroxine is not mediated by norepinephrine-inhibition of phosphatidylinositol-turnover stimulated by thyroid stimulating hormone.