Presynaptic muscarinic receptors inhibiting endogenous noradrenaline release in the portal vein of the freely moving rat.

1. In the portal vein of the freely moving unanaesthetized rat, the existence of presynaptically located inhibitory muscarinic receptors was investigated by use of the muscarinic agonist methacholine (MCh) 2. Infusion of MCh (0.3 micrograms min-1) did not significantly inhibit the endogenous noradrenaline (NA) overflow in portal plasma. However, after inducing high intra-synaptic concentrations of NA by blocking the presynaptic alpha 2-adrenoceptors with yohimbine (1 mg kg-1), MCh (0.3 microgram min-1) was able to reduce the yohimbine-induced enhanced NA overflow by 38%. 3. The MCh-induced inhibition was almost completely abolished after blockade of the presynaptic muscarinic receptors with atropine (0.6 mg kg-1). 4. During electrical stimulation of the portal vein nervous plexus the evoked NA overflow was strongly inhibited (95%) during MCh-infusion (0.3 microgram min-1). Again atropine (0.6 mg kg-1) was able to reverse this inhibition. 5. These results show the existence of presynaptic muscarinic receptors inhibiting endogenous NA overflow from the portal vein nervous plexus under conditions of enhanced sympathetic activity in the freely moving rat.     

Characterization of presynaptic beta-adrenoceptors facilitating endogenous noradrenaline release in the portal vein of permanently cannulated, freely moving rats

We investigated the nature of presynaptic beta-adrenoceptors and the possible heterogeneity of these receptors in the portal vein nervous plexus of freely moving unanesthetized rats using the differential blockade technique with CGP 20712A as a highly beta 1-selective antagonist, ICI 118,551 as a very beta 2-selective antagonist and fenoterol and endogenous NA as beta 2- and beta 1-selective agonists respectively. The fenoterol (0.25 mg/kg)-induced increase of the basal NA level (290%) was dose dependently decreased by 0.1, 0.3 and 1.0 mg/kg ICI 118,551, but was not affected by a high dose (3.0 mg/kg) of CGP 20712A. During electrical stimulation (2 Hz, 3 ms, 5 mA) of the portal vein nervous plexus, 0.25 mg/kg fenoterol induced a 2.1-fold increase in NA overflow compared to the control stimulation value. ICI 118,551 was also able to decrease the fenoterol-induced enhancement during stimulation. During stimulation in the presence of CGP 20712A and fenoterol, the control stimulation value was not significantly decreased. Pretreatment with yohimbine (0.5 mg/kg) was used to create a strong beta 1-stimulus by raising the intra-synaptic NA level through blockade of the inhibitory alpha 2-adrenoceptors. Under these conditions, CGP 20712A did not deminish the yohimbine-induced enhancement of the stimulus evoked NA overflow, clearly indicating the absence of the beta 1-adrenoceptor subtype. ICI 118,551 (0.1 mg/kg) was also unable to influence the evoked NA overflow under these conditions, implying that, even at high concentrations, NA is not able to facilitate its own release by stimulation of the presynaptic beta 2-adrenoceptor.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prejunctional histamine H3-receptors inhibit electrically evoked endogenous noradrenaline overflow in the portal vein of freely moving rats

The effects of intra-arterial injection of different doses of the selective histamine H₃-receptor agonist R-α-methylhistamine and the selective histamine H₃-receptor antagonist thioperamide on basal and electrically evoked noradrenaline overflow in the portal vein as well as on mean arterial pressure (MAP) and heart rate (HR) were investigated in permanently instrumented freely moving rats. R-α-Methylhistamine (0.01, 0.1 and 1 μmol/kg) inhibited the evoked noradrenaline overflow up to 43%, the ED₅₀ value being 0.013 μmol/kg. Thioperamide (0.1, 0.5 and 1.0 μmol/kg) antagonized the effect of 1.0 μmol/kg R-α-methylhistamine dose-dependently, evoked overflow returning to control values at 1.0 μmol/kg of the antagonist; thioperamide alone had no effect on electrically evoked noradrenaline overflow. Basal noradrenaline levels, blood pressure and heart rate were not at all influenced by R-α-methylhistamine and thioperamide, alone or in combination. The results clearly show the presence of prejunctional histamine H₃-receptors inhibiting the electrically evoked noradrenaline overflow from vascular sympathetic nerve terminals in the portal vein of freely moving rats. Received: 27 August 1996 / Accepted: 14 October 1996     

Influence of the baroreceptor reflex on the modulation of noradrenaline overflow through prejunctional receptors in the portal vein of freely moving rats

1 The effects of alterations in mean arterial blood pressure (MAP), as induced by vasoactive drugs, on heart rate (HR), basal noradrenaline concentration and electrically evoked noradrenaline overflow and on blood flow in the portal vein of freely moving rats, were investigated. 2 By infusion of sodium nitroprusside or phenylephrine (0.5, 1.0 and 2.5 μg kg^?1 min^?1), MAP was altered over a range of 50 to 150 mmHg. The resulting changes in HR showed a sigmoidal relationship with MAP. Noradrenaline overflow increased linearly when MAP was decreased; when MAP was increased, however, noradrenaline levels only decreased to 70% and reached a plateau from 125 mmHg onwards. 3 Nitroprusside (2.5 μg kg^?1 min^?1) and fenoterol (0.25 mg kg^?1) decreased MAP to the same extent (– 46 mmHg). HR and basal noradrenaline concentration, however, were increased to a higher extent by fenoterol (+ 192 beats min^?1; + 373 pg ml^?1, respectively) than by nitroprusside (+ 78 beats min^?1; + 206 pg ml^?1, respectively). Electrically evoked overflow was not changed at all after nitroprusside, whereas fenoterol induced an increase to 206% of control. 4 Phenylephrine (2.5 μg kg^?1 min^?1) and angiotensin II (1 μg kg^?1 min^?1) increased MAP to the same extent (to 155 and 161 mmHg, respectively). Basal noradrenaline concentration decreased by 30% after phenylephrine, whereas angiotensin II increased noradrenaline levels to 226% of control. Evoked noradrenaline overflow was not changed after phenylephrine but was increased to 204% of control after angiotensin II. 5 Portal venous blood flow (15.3 ml min^?1) was not affected after brisk changes in MAP induced by nitroprusside (2.5 μg kg^?1 min^?1), fenoterol (0.25 mg kg^?1) or phenylephrine (2.5 μg kg^?1 min^?1). 6 The results showed that the electrically evoked overflow of endogenous noradrenaline in the portal vein of the freely moving rat is not influenced by baroreceptor reflex-induced changes in basal noradrenaline overflow. As a consequence, the prejunctional effects of drugs on the electrically evoked overflow are only of local origin. Portal venous blood flow is not changed by brisk changes in MAP or electrical stimulation, therefore no changes in noradrenaline spillover from nerve terminals are expected. However, the enhancement of basal noradrenaline overflow from numerous peripheral sympathetic junctions as seen with fenoterol and angiotensin II, is augmented or dampened, respectively, by baroreceptor reflexmediated changes of sympathetic activity.     

Increased noradrenaline release in rat portal vein during sympathetic nerve stimulation due to activation of presynaptic beta-adrenoceptors by noradrenaline and adrenaline.

With the aim of investigating whether exogenous noradrenaline (NA) and adrenaline (A) can modulate transmitter release via the stimulation of presynaptic beta-adrenoceptors, 3H-release from isolated portal veins was studied after pretreatment with 3H-1-NA, phenoxybenzamine, desipramine and normetanephrine. NA (10 muM) and A (0.05 muM) increased the fractional 3H-release elicited by sympathetic nerve stimulation by 30%. This effect could be blocked by d, 1-propranolol which per se reduced the release by 10%. It is concluded that NA can facilitate its own release via a presynaptic beta-adrenoceptor-mediated positive feed-back mechanism and that adrenaline can stimulate this beta-adrenoceptor-mediated mechanism.     

L-dopa-like regulatory actions of L-threo-3,4-dihydroxyphenylserine on the release of endogenous noradrenaline via presynaptic receptors in rat hypothalamic slices.

Effects of L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS) on the spontaneous release and the stimulus(2 Hz)-evoked release of endogenous noradrenaline were studied in rat hypothalamic slices with functioning L-aromatic amino acid decarboxylase (AADC) and with AADC inhibition. In non-inhibited slices, spontaneous release was not modified by L-threo-DOPS at 1 pM-100 nM, tended to increase at 1-10 microM and increased at 100 microM. Noradrenaline tissue content slightly increased at 100 microM. Stimulated release was concentration-dependently facilitated at 1-1000 pM and tended to decrease gradually from a maximum at 10 nM-10 microM. Under AADC inhibition, spontaneous release concentration-dependently increased at 10-100 microM by 60% of the increase seen in slices without AADC inhibition. Increase in noradrenaline tissue content was abolished. L-threo-DOPS produced a triphasic pattern on stimulated release; concentration-dependent facilitation at 1-1000 pM similar to that seen in slices with functional AADC, no facilitation at 10-1000 nM, and a concentration-dependent increment at 10-100 microM. The facilitation at 1 nM was stereoselective and was antagonized by (-)-propranolol 10 nM, and no facilitation at 100 nM was restored to the maximum by yohimbine 10 nM, DG-5128 10 nM or S-sulpiride 1 nM. Furthermore, L-threo-DOPS (1-1000 pM)-induced facilitation was competitively antagonized by L-dopa methyl ester, a competitive antagonist for L-dopa, with a pA2 value of 13.6, whereas it was noncompetitively antagonized by (-)-propranolol.     

Characterization of the prejunctional muscarinic receptors mediating inhibition of evoked release of endogenous noradrenaline in rabbit isolated vas deferens

The aim of the present study was to characterize the prejunctional modulation of evoked release of endogenous noradrenaline in rabbit vas deferens by the use of muscarinic receptor agonists and subtype-prefering antagonists.Vasa deferentia of the rabbit were stimulated electrically by trains of 120 pulses delivered at 4 Hz or trains of 30 pulses at 1 Hz. The inhibition by muscarinic agonists of the stimulation-evoked overflow of endogenous noradrenaline in the absence and presence of antagonists was used to determine affinity constants for antagonists. These values were compared with those observed at putative M₁ receptors inhibiting neurogenic twitch contractions in the rabbit vas deferens and with affinity data obtained at M₁(m₁)-M₄(m₅) receptors in functional studies and binding experiments.The evoked overflow of noradrenaline from sympathetic nerves was enhanced by the Al receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), the P₂ purinoceptor antagonist pyridoxalphosphate-6-azophenyl-2,4-disulfonic acid (PPADS) and indomethacin, indicating a tonic inhibition by endogenous A₁ and P₂ purinoceptor agonists and prostanoids, respectively. The stimulation-evoked overflow at 4 Hz was not sensitive to inhibition by the muscarinic agonists methacholine or 4-(4-chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium iodide (4-Cl-McN-A-343). In contrast, at a stimulation frequency of 1 Hz the evoked noradrenaline release was decreased by muscarinic agonists (EC₅₀): arecaidine propargyl ester (0.062 M), 4-Cl-McN-A-343 (0.32 M), 4-(4-fluorophenylcarbamoyloxy)-2-butynylN-methyl-pyrrolidinium tosylate (4-F-PyMcN⁺; 0.48 M) and methacholine (0.86 M). The affinity constants of most of the muscarinic antagonists [atropine: pK_B = 9.47; (R)-trihexyphenidyl: pK_B = 9.18; pirenzepine: pA₂ = 7.68; methoctramine: pK_B = 6.90] are consistent with estimates of these antagonists at M₁(m₁) receptors determined in various functional and binding studies. The high antagonistic potency of pirenzepine and (R)-trihexyphenidyl and the agonistic activity of 4-F-PyMcN⁺ argue for the involvement of M₁, and against that of M₂ and M₃ receptors in the inhibition of evoked noradrenaline overflow. However, the high apparent pK_B of 8.30 for himbacine is not in accordance with an M₁ receptor; by contrast, it would be compatible with the presence of M₂ or M₄ receptors. The potencies of the tested muscarinic agonists and antagonists largely agree with those obtained for the inhibition of neurogenic twitch responses (0.05 Hz) in the rabbit vas deferens. In conclusion, the rabbit vas deferens is endowed with prejunctional muscarinic receptors mediating heteroinhibition of noradrenaline release that are probably of the same subtype as the putative M₁ receptors inhibiting neurogenic twitch contractions, and are not of the M₂, M₃ or m₅ subtype. Correspondence to: U. Grimm at the above address     

Characterization of vascular histamine receptors in the rat.

1 In the rat the decrease in blood pressure caused by histamine involves activation of both H1- and H2-receptors. Since arterial pressure measurements alone do not permit the separation of responses into cardiac and vascular components, the following experiments were undertaken to study vascular histamine receptors. 2 Vascular responses were studied in the autoperfused hindquarters of anaesthetized rats. Intra-arterial histamine caused vasodilatation which was only partially attenuated by treatment with mepyramine, an H1-receptor antagonist. Treatment with metiamide, the H2-receptor antagonist, did not affect vasodilatation caused by histamine but did attenuate vasodilatation which persisted after mepyramine. 3 Intra-arterial 4-methylhistamine, an H2-receptor agonist, caused vasodilatation which was reduced by metiamide. The H1-receptor agonist, 2-(2-pyridyl)ethylamine also caused vasodilatation which was blocked by mepyramine. 4 It is concluded that in the rat, histamine causes vasodilatation mediated by both H1- and H2-receptors.     

Characterization of the functional muscarinic receptors in the rat urinary bladder.

1. Muscarinic receptors mediating contraction of the rat urinary bladder were characterized functionally in vitro by use of atropine, 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP methiodide), 4-diphenylacetoxy-N-(2-chloroethyl)-piperidine hydrochloride (4-DAMP mustard), hexahydro-sila-diphenidol hydrochloride (HHSiD), the p-fluoro analogue of hexahydro-sila-diphenidol hydrochloride (p-F-HHSiD), methoctramine, and pirenzepine. 2. (+)-cis-Dioxolane contracted bladder strips in a concentration-dependent manner with an EC50 of 0.169 +/- 0.018 microM and an Emax of 7.84 +/- 0.67 g. 3. Concentration-effect curves to (+)-cis-dioxolane were shifted to the right in the presence of the antagonists in a concentration-dependent manner. The rank order of antagonist affinities against the (+)-cis-dioxolane response was (pA2 values in the parentheses) atropine (9.28) > or = 4-DAMP methiodide (9.04) > HHSiD (8.01) > p-F-HHSiD (7.28) = pirenzepine (7.12) > or = methoctramine (6.77, 7.25). The profile resembles that associated with the M3 receptor subtype. 4. Atropine, 4-DAMP methiodide, pirenzepine, and methoctramine had no effects on the contractile response to 120 mM KCl. However, HHSiD and p-F-HHSiD decreased the response to KCl, and 4-DAMP mustard increased it. 5. Contractile responses to electrical field stimulation (1-32 Hz, 0.05 ms pulse duration) were biphasic in nature. The tonic response was suppressed more than the phasic response by all antagonists except methoctramine. The suppression was not always concentration-dependent, and did not seem to be related to antagonism of any one receptor subtype. 6. Our findings are consistent with the minority M3 receptors mediating the contractile response to muscarinic stimulation by (+)-cis-dioxolane in the rat bladder.     

Effects of cocaine and desipramine on the neurally evoked overflow of endogenous noradrenaline from the rat heart.

1 Stimulation of postganglionic cardiac sympathetic nerves produced a stimulation frequency-dependent overflow of endogenous noradrenaline from the otherwise isolated rat heart. 2 Such nerve stimulation also produced increases in heart rate. There was significant correlation between heart rate increases and corresponding noradrenaline concentrations in the coronary venous effluent. 3 Cocaine (3 X 10(-5)M) caused a significant reduction in both the noradrenaline overflow and the heart rate increase, produced by nerve stimulation for 1 min at 4 Hz. 4 Desipramine (10(-6)M) caused a significant increase in the noradrenaline overflow produced by stimulation for 1 min (4 Hz) with a mean increase of approximately 60%. There was no significant effect on the heart rate increase produced by such stimulation. 5 The opposite effects of cocaine (3 X 10(-5)M) and desipramine (10(-6)M) on noradrenaline overflow are attributed to differences in the local anaesthetic properties of these agents.     

Autoradiographic localization of muscarinic acetylcholine receptors in the rat pulmonary vascular tree.

The pharmacological characteristics and the anatomical localization of muscarinic receptors in the pulmonary vascular tree were investigated in lung sections of Wister-Kyoto (WKY) and spontaneously hypertensive rats (SHR). [3H]Quinuclidinyl benzylate [( 3H]QNB) was bound by sections of rat lung in a manner consistent with the labeling of muscarinic acetylcholine receptors, with a dissociation constant value (Kd) of 0.41 +/- 0.3 nM in WKY rats and of 0.37 +/- 0.2 nM in SHR. The density of muscarinic acetylcholine receptors was higher in sections of lung of WKY rats than of SHR. In the pulmonary vasculature these sites were associated with the smooth muscle of the medial layer of different size branches of the pulmonary artery and vein. No [3H]QNB binding sites were found within the endothelium in the blood vessels of either WKY rats or SHR. The density of [3H]QNB binding sites was significantly lower in the smooth muscle of pulmonary vein and its branches in SHR. There were no significant hypertension-dependent changes in the density and pattern of muscarinic receptors of pulmonary artery smooth muscle.     

Inhibition of noradrenaline release in the rat brain cortex via presynaptic H3 receptors

Summary The effects of histamine and related drugs on the evoked tritium overflow from superfused rat brain cortex slices preincubated with³H-noradrenaline were determined. Tritium overflow was stimulated electrically (3 Hz; slices superfused with normal physiological salt solution) or by introduction of CaCl₂ 1.3 mmol/l (slices superfused with Ca²⁺-free medium containing K⁺ 20 mmol/l).Histamine slightly decreased the electrically evoked^H overflow in slices superfused in the presence of desipramine. The degree of inhibition obtained with histamine was doubled when both desipramine and phentolamine were present in the superfusion medium (pIC₁₅ 6.46). Under the latter condition, the evoked overflow was inhibited by the H₃ receptor agonist R-(–)--methylhistamine and its S-(+) enantiomer (pIC₁₅ 7.36 and 5.09, respectively), but was not affected by the H₂ receptor agonist dimaprit and the H₁ receptoragonist 2-thiazolylethylamine (both at up to 32 µmol/l). The concentration-response curve of histamine was shifted to the right by the H3 receptor antagonists thioperamide, impromidine and burimamide (apparent pA₂ 8.37, 6.86 and 7.05, respectively), by the H₂ receptor antagonist ranitidine (apparent pA₂ 4.27) and was not affected by the H₁ receptor antagonist dimetindene (32 µmol/l). The inhibitory effect of R-(–)--methylhistamine on the evoked overflow was also counteracted by thioperamide. Given alone, none of the five histamine receptor antagonists affected the evoked overflow. In the absence of desipramine plus phentolamine, impromidine and burimamide facilitated the electrically evoked³H overflow whereas thioperamide had no effect. The facilitatory effects of impromidine and burimamide were abolished by phentolamine, but not affected by desipramine. The concentration-response curve of noradrenaline for its inhibitory effect on the evoked overflow was shifted to the right by impromidine and burimamide, but not influenced by thioperamide (apparent pA₂ 5.24, 5.04 and <6.5, respectively; experiments carried out in the presence of desipramine). In slices superfused with Ca²⁺-free K⁺-rich medium containing tetrodotoxin, desipramine plus phentolamine, the tritium overflow evoked by introduction of Ca²⁺ was inhibited by histamine; the concentration-response curve of histamine was shifted to the right by thioperamide.The present study shows that the inhibitory effect of histamine on noradrenaline release in the rat brain cortex involves presynaptic H₃ receptors and that the degree of inhibition is increased in the presence of phentolamine. The H₃ receptor antagonists impromidine and burimamide are weak ₂-adrenoceptor antagonists. Send offprint requests to E. Schlicker at the above address     

Characterization of noradrenaline release in the locus coeruleus of freely moving awake rats by in vivo microdialysis

Rationale The origin and regulation of noradrenaline (NA) in the locus coeruleus (LC) is unknown.Objectives The neurochemical features of NA overflow (nerve impulse dependence, neurotransmitter synthesis, vesicle storage, reuptake, ₂-adrenoceptor-mediated regulation) were characterized in the LC.Methods Brain microdialysis was performed in awake rats. Dialysates were analyzed for NA.Results NA in the LC decreased via local infusion of Ca²⁺-free medium (–42±5%) or the sodium channel blocker tetrodotoxine (TTX) (–47±8%) but increased (333±40%) via KCl-induced depolarization. The tyrosine hydroxylase (TH) inhibitor -methyl-p-tyrosine (250 mg kg^–1, i.p.) and the vesicle depletory drug reserpine (5 mg kg^–1, i.p.) decreased NA. Therefore, extracellular NA in the LC satisfies the criteria for an impulse flow-dependent vesicular exocytosis of neuronal origin. Local perfusion of the ₂-adrenoceptor agonist clonidine (0.1–100 M) decreased NA (E_max=–79±5%) in the LC, whereas the opposite effect (E_max=268±53%) was observed with the _2A-adrenoceptor antagonist BRL44408 (0.1–100 M). This suggests a tonic modulation of NA release through local _2A-adrenoceptors. The selective NA reuptake inhibitor desipramine (DMI) (0.1–100 M) administered into the LC increased NA in the LC (E_max=223±40%) and simultaneously decreased NA in the cingulate cortex, confirming the modulation exerted by NA in the LC on firing activity of noradrenergic cells and on the subsequent NA release in noradrenergic terminals.Conclusion Synaptic processes underlying NA release in the LC are similar to those in noradrenergic terminal areas. NA in the LC could represent local somatodendritic release, but also the presence of neurotransmitter release from collateral axon terminals.     

Calcium channels involved in the inhibition of acetylcholine release by presynaptic muscarinic receptors in rat striatum.

1. The mechanism of the inhibitory action of presynaptic muscarinic receptors on the release of acetylcholine from striatal cholinergic neurons is not known. We investigated how the electrically stimulated release of [3H]-acetylcholine from superfused rat striatal slices and its inhibition by carbachol are affected by specific inhibitors of voltage-operated calcium channels of the L-type (nifedipine), N-type (omega-conotoxin GVIA) and P/Q-type (omega-agatoxin IVA). 2. The evoked release of [3H]-acetylcholine was not diminished by nifedipine but was lowered by omega-conotoxin GVIA and by omega-agatoxin IVA, indicating that both the N- and the P/Q-type (but not the L-type) channels are involved in the release. The N-type channels were responsible for approximately two thirds of the release. The release was >97% blocked when both omega-toxins acted together. 3. The inhibition of [3H]-acetylcholine release by carbachol was not substantially affected by the blockade of the L- or P/Q-type channels. It was diminished but not eliminated by the blockade of the N-type channels. 4. In experiments on slices in which cholinesterases had been inhibited by paraoxon, inhibition of [3H]-acetylcholine release by endogenous acetylcholine accumulating in the tissue could be demonstrated by the enhancement of the release after the addition of atropine. The inhibition was higher in slices with functional N-type than with functional P/Q-type channels. 5.We conclude that both the N- and the P/Q-type calcium channels contribute to the stimulation-evoked release of acetylcholine in rat striatum, that the quantitative contribution of the N-type channels is higher, and that the inhibitory muscarinic receptors are more closely coupled with the N-type than with the P/Q-type calcium channels.     

Sustained prejunctional facilitation of noradrenergic neurotransmission by adrenaline as a co-transmitter in the portal vein of freely moving rats.

1. The duration of the facilitatory effect of adrenaline on the electrically evoked overflow of noradrenaline was studied in the portal vein of permanently adreno-demedullated freely moving rats. 2. Rats were infused with adrenaline (20 or 100 ng min-1) for 2 h. After an interval of 1 h, when plasma adrenaline had returned to undetectable levels, electrical stimulation resulted in an enhanced catecholamine overflow amounting to 219% (noradrenaline) and 241% (noradrenaline plus adrenaline) of control (saline infusion), respectively. 3. When stimulation was applied again, in the same animal, at 24, 48 and 72 h after the first stimulation episode, the evoked noradrenaline overflow was 150, 111 and 102% (after 20 ng ml-1 adrenaline) and 158, 134 and 105% (after 100 ng min-1 adrenaline) of control. 4. The beta 2-adrenoceptor antagonist, ICI 118,551 (0.3 mg kg-1), blocked the facilitatory effect obtained after the 100 ng min-1 adrenaline infusion on all days. 5. The results show that adrenaline, after being taken up by and released from sympathetic nerve terminals, is able to facilitate the evoked noradrenaline overflow through activation of prejunctional beta 2-adrenoceptors for at least 48 h after administration.     

Characterization of prejunctional purinoceptors inhibiting noradrenaline release in rat mesenteric arteries

The effects of purinoceptor agonists on noradrenaline NA release by electrical stimulation in rat mesenteric arteries were examined to clarify the pharmacological properties of prejunctional purinoceptors on adrenergic nerves. Adenosine and the other P1-receptor agonists, 5'-(N-ethylcarboxamido) adenosine and 2-chloroadenosine, significantly inhibited the release of NA. Also beta,gamma-methylene ATP and 2-methylthio ATP, P2-receptor agonists, significantly inhibited NA releases. The inhibitory effect of adenosine was significantly reduced by adenosine deaminase, but those of beta,gamma-methylene ATP and 2-methylthio ATP were not affected. This suggests that the inhibitory effects of P2-receptor agonists are not due to conversion into adenosine. 1,3-Dipropyl-8-cyclopentylxanthine (DPCPX), a P1 (A1)-receptor antagonist, significantly reduced the inhibitory effects of not only the P1- but also P2-receptor agonists. Therefore, DPCPX appears to act on both prejunctional P1- and P2-receptor as an antagonist. Pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), a P2-receptor antagonist, significantly reduced the inhibitory effects of the P2-receptor agonists, but not those of the P1-receptor agonists. From these findings in the rat mesenteric artery, the P1-receptor agonist-induced inhibition of NA-release appears to be mediated via a well-known prejunctional P1-receptor of the A1-subtype, but the P2-receptor agonist-induced inhibition appears to be mediated via an unidentified purinoceptor that is blocked not only by P2-receptor antagonists but also by P1-receptor antagonists.     

清醒自由活动大鼠下丘脑后部内源性γ－氨基丁酸的释放

清醒自由活动大鼠下丘脑后部内源性γ－氨基丁酸的释放郭莲军（武汉同济医科大学基础医学部药理教研室，武汉４３００３０）γ－氨基丁酸（γ－ａｍｉｎｏｂｕｔｙｒｉｃａｃｉｄ，ＧＡＢＡ）作为一种抑制性神经递质广泛分布于中枢神经系统，下丘脑后部含有大量的ＧＡＢＡ...     

Effects of presynaptic alpha-adrenoceptors and neuronal reuptake on noradrenaline overflow and cardiac response.

Using an in situ perfused, innervated rat heart model, we studied the effects of presynaptic alpha-adrenergic and neuronal reuptake inhibition on evoked noradrenaline (NA) overflow and the postsynaptic response by sympathetic ganglion stimulation. NA overflow was significantly increased by neuronal reuptake inhibitors (desipramine and (+)-oxaprotiline) or by alpha-adrenoceptor antagonists (phentolamine and yohimbine), but the inotropic response was augmented only by alpha-antagonists. In the presence of desipramine, nerve stimulation induced a frequency-dependent increase in NA overflow and postsynaptic response, both were enhanced by yohimbine. In the absence of desipramine, however, postsynaptic response was potentiated by yohimbine despite an unchanged (at 2 and 5 Hz) or even reduced NA overflow (at 10 Hz). Thus, this study suggests that NA release and cardiac response are modulated by presynaptic alpha-adrenoceptors, and that the neuronal reuptake modifies the amount of NA overflow but has little effect on the postsynaptic response.     

Increase of noradrenaline release in the hypothalamus of freely moving rat by postsynaptic 5-hydroxytryptamine1A receptor activation.

1. 5-Hydroxytryptamine (5-HT) plays a role in the regulation of noradrenergic neurones in the brain, but the precise mechanism of regulation of noradrenaline (NA) release by 5-HT1A receptors has not been defined. The present study describes the effect of a highly potent and selective 5-HT1A receptor agonist, 5-(3-[[(2S)-1,4-benzodioxan-2-ylmethyl)]amino]propoxy)-1,3-b enzodioxole HC1 (MKC-242), on NA release in the hypothalamus using microdialysis in the freely moving rat. 2. Subcutaneous injection of MKC-242 (0.5 mg kg-1) increased extracellular levels of NA and its metabolite, 3-methoxy-4-hydroxyphenylglycol, in the hypothalamus and hippocampus. 3. The 5-HT1A receptor agonists, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) (0.2 mg kg-1) and buspirone (3 mg kg-1) mimicked the effect of MKC-242 in increasing NA release in the hypothalamus. 4. The effects of MKC-242 and 8-OH-DPAT in the hypothalamus were antagonized by pretreatment with WAY100135 (10 mg kg-1), a silent 5-HT1A receptor antagonist. 5. Local administration of 8-OH-DPAT (10-100 microM), citalopram (1 microM), a 5-HT reuptake inhibitor, and MDL72222 (10 microM), a 5-HT3 receptor antagonist, into the hypothalamus, had no effect on NA release. 6. Intracerebroventricular injection with 5,7-dihydroxytryptamine caused a marked reduction in brain 5-HT content, but the treatment affected neither basal NA levels nor the MKC-242-induced increase in NA release. 7. The effect of MKC-242 in increasing NA release was not attenuated by repeated treatment with the drug (0.5 mg kg-1, once a day for 2 weeks).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of alpha- and beta-adrenoceptor blockade on the neurally evoked overflow of endogenous noradrenaline from the rat isolated heart.

beta-Adrenoceptor blockade by propranolol (4 X 10(-6)M) was without effect on the overflow of endogenous noradrenaline from the isolated heart of the rat induced by stimulation of sympathetic nerves for 1 min at 1 and at 4 Hz. The increase in heart rate in response to such stimulation was abolished by propranolol treatment. alpha 2-Adrenoceptor blockade by yohimbine (10(-6)M) induced approximately a two fold increase in the overflow of endogenous noradrenaline induced by stimulation of sympathetic nerves for 1 min at 1 and at 4 Hz. A combination of yohimbine (10(-6)M) and desipramine (10(-7)M) induced a more than 3 fold increase in the overflow of endogenous noradrenaline produced by sympathetic nerve stimulation at 1 and at 4 Hz. Heart rate increases produced by such stimulation were intensified. These results provide no evidence for the feedback stimulation of presynaptic beta-adrenoceptors in this preparation. The action of alpha-2-blockade was equipotent at stimulation frequencies of 1 and 4 Hz.