Presynaptic alpha-autoreceptors.
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Adrenergic alpha-Agonists↗
Biomedical subjects
K Starke
Publications and source records attributed to K Starke.
Changed sensitivity of alpha 2-adrenoceptors mediating a decrease in protein kinase inhibitor activity in the brain of vasopressin-hypertensive rats.
Clonidine produced an increase of cGMP content and a decrease of the endogenous type II inhibitor of protein kinase in rat hypothalamic slices. When administered to rats, the effect of clonidine on type II inhibitor activity in the hypothalamus and brain-stem depended on the dose. Low doses (10-50 micrograms X kg-1 i.p.) produced an increase, probably by stimulating presynaptic alpha 2-adrenoceptors, whereas large doses (200-1000 micrograms X kg-1 i.p.) produced a decrease of type II inhibitor activity by stimulating postsynaptic receptors. The development of vasopressin hypertension was associated with a gradual reduction of the response of the type II inhibitor to low and high doses of clonidine. In vasopressin-hypertensive rats neither small nor large doses of clonidine were able to induce changes in type II inhibitor activity suggesting subsensitivity of pre- and postsynaptic alpha 2-adrenoceptors. However, clonidine appeared to be equally effective in blocking electrically stimulated [3H]noradrenaline release from hypothalamic slices of vasopressin-hypertensive and control, normotensive rats. Reduced reactivity of postsynaptic alpha 2-adrenoceptors seems to be of great importance since treatment of vasopressin-hypertensive rats with 6-hydroxydopamine resulted in a decrease of blood pressure and reappearance of the sensitivity of postsynaptic alpha 2-adrenoceptors to clonidine.
Animals↗
Blockade of alpha 2-adrenoceptors permits the operation of otherwise silent opioid kappa-receptors at the sympathetic axons of rabbit jejunal arteries.
We sought for presynaptic, release-inhibiting opioid receptors at the postganglionic sympathetic axons innervating the jejunal arteries of rabbits. Evoked excitatory junction potentials (e.j.p.s; trains of 15 pulses at 1 Hz) as well as evoked overflow of tritium after preincubation with [3H]-noradrenaline (trains of 120 pulses at 1 Hz) were used to estimate transmitter release. In otherwise untreated tissues ethylketocyclazocine reduced neither the e.j.p. amplitudes nor the evoked overflow of tritium; [Met5]-enkephalin depressed the evoked overflow of tritium. Ethylketocyclazocine reduced e.j.p. amplitudes, however, in tissues exposed to either yohimbine, tolazoline or phentolamine, but not in tissues exposed to prazosin. Ethylketocyclazocine also depressed the evoked overflow of tritium when yohimbine was present. The inhibition produced by ethylketocyclazocine in the presence of yohimbine was antagonized by (-)-3-furylmethyl)-alpha-noretazocine (MR 2266) but not by N,N-diallyl-Tyr-alpha-aminoisobutyric acid-alpha-aminoisobutyric acid-Phe-Leu-OH (ICI 174864). It is concluded that the sympathetic neurones of rabbit jejunal arteries possess presynaptic kappa-receptors in addition to the previously identified delta-receptors. The kappa-receptors become operative only when presynaptic alpha 2-adrenoceptors have been blocked.
Adrenergic alpha-Antagonists↗
Autoreceptors and alpha 2-adrenoceptors at the serotonergic axons of rabbit brain cortex.
Slices of the rabbit occipito-parietal cortex were preincubated with 3H-serotonin and then superfused and stimulated electrically (2 min at 3 Hz). In the absence of drugs, the stimulation-evoked overflow of tritium was approximately 3% of the tritium content of the tissue. Unlabelled serotonin and 5-carboxamido-tryptamine, when administered in the presence of 6-nitroquipazine, reduced the evoked overflow of tritium. Their effects were antagonized by metitepin (apparent pA2 value 8.1) and (+/-)-cyanopindolol (apparent pA2 value 6.4). Metitepin, but not cyanopindolol, increased evoked tritium overflow; the effect of metitepin was greater in the presence than in the absence of nitroquipazine. The evoked overflow of tritium was also depressed by clonidine, an effect antagonized by idazoxan (apparent pA2 value 7.0) but not by prazosin. Phenylephrine caused a decrease only at high concentrations that simultaneously accelerated basal tritium efflux. Prazosin and idazoxan did not change evoked tritium overflow, and phentolamine increased it significantly only when administered in the presence of (+)-oxaprotiline. Rauwolscine produced an inhibition that was prevented by metitepin. It is concluded that the serotonergic axons of the rabbit occipitoparietal cortex possess presynaptic, release-inhibiting serotonin autoreceptors and alpha 2-adrenoceptors. The receptors appear to receive an input of endogenous serotonin and, to a lesser extent, noradrenaline, under the conditions of these in vitro experiments.
Adrenergic alpha-Agonists↗
Mutual interaction between presynaptic alpha 2-adrenoceptors and opioid kappa-receptors at the noradrenergic axons of rabbit brain cortex.
The interaction between presynaptic, release-inhibiting alpha 2-adrenoceptors and opioid receptors was studied in slices of the parieto-occipital cortex of rabbits. The slices were preincubated with 3H-noradrenaline and then superfused with 3H-noradrenaline-free medium and stimulated electrically (3 or 7 Hz, 2 or 5 V/cm voltage drop between the electrodes). Clonidine and ethylketocyclazocine (EK) depressed, whereas yohimbine increased the electrically evoked overflow of tritium. When clonidine was administered first and retained in the medium for the rest of the experiment, the overflow-inhibiting effect of EK was reduced. When yohimbine was administered first and kept for the rest of the experiment, the effect of EK was enhanced. When, finally, EK was administered first and clonidine as the second drug, the overflow-inhibiting effect of clonidine was attenuated. The changes in the effect of EK (by clonidine or yohimbine) and clonidine (by EK) were not due to the changes in release per se produced by the drugs that were given first. Naloxone shifted the concentration-response curve of EK to the right; the dissociation constant of the naloxone-receptor complex, calculated from the shift, was 13 nmol/l. It is concluded that there is an interaction between presynaptic alpha 2-adrenoceptors and opioid kappa-receptors, either at the level of the receptors themselves or of the post-receptor reaction chains. Activation of one kind of receptor blunts the inhibition of release produced by activation of the other kind of receptor.
Animals↗
Receptor protection experiments confirm the identity of presynaptic alpha 2-autoreceptors.
Receptor protection experiments were carried out in cerebrocortical slices from rabbits in order to study the sites at which drugs with alpha-adrenoceptor affinity modulate the release of noradrenaline. The slices were preincubated with 3H-noradrenaline. They were then superfused with 3H-noradrenaline-free medium and stimulated electrically (3 Hz) twice for 2 min each, after 60 and 250 min of superfusion (S1, S2). Phenoxybenzamine was added from 85 to 95 min of superfusion. Potential protecting drugs were present for 5 min before and during the exposure to phenoxybenzamine and then washed out together with the latter. Phenoxybenzamine 0.1 and 1 mumol/l increased the evoked overflow of tritium by 77 and 287%, respectively, as indicated by the S2/S1 overflow ratio. When cocaine was present throughout superfusion, phenoxybenzamine 0.1 and 1 mumol/l increased the evoked overflow by 97 and 353%, respectively. Clonidine 0.1-100 mumol/l, when added before and during the contact with phenoxybenzamine, reduced or even abolished the increase caused by the latter. This interaction was not changed when cocaine was included in the superfusion fluid. The increase caused by phenoxybenzamine was also reduced or abolished by noradrenaline 1-100 mumol/l (tested in the presence of cocaine), yohimbine 0.01-1 mumol/l and phentolamine 0.1-10 mumol/l. Only high concentrations of clonidine, noradrenaline, yohimbine and phentolamine changed the evoked overflow when given alone (and subsequently washed out). The effect of phenoxybenzamine was not modified by prazosin 1 mumol/l, morphine 1 mumol/l and naloxone 10 mumol/l.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Opioid peptides decrease noradrenaline release and blood pressure in the rabbit at peripheral receptors.
Effects of dynorphin-(1-13), Leu5-enkephalin, D-Ala2,D-Leu5-enkephalin (DADLE), and for comparison bremazocine, on plasma noradrenaline concentration and mean arterial pressure (MAP) were studied in pithed rabbits. In the first series of experiments, the sympathetic outflow was stimulated electrically via the pithing rod at 2 Hz twice for 3 min each (S1, S2). Drugs were administered before S2. Bremazocine 10 micrograms/kg + 2 micrograms/kg/h and 100 micrograms/kg + 20 micrograms/kg/h, dynorphin 1 and 3 micrograms/kg/min, Leu5-enkephalin 100 micrograms/kg/min and DADLE 10 and 30 micrograms/kg/min all diminished the electrically-evoked increase in plasma noradrenaline and MAP. The effects were antagonized by naloxone. In the second series, an infusion of noradrenaline (2 micrograms/kg/min) was given twice for 3 min each (N1, N2). Drugs were administered before N2. Bremazocine 100 micrograms/kg + 20 micrograms/kg/h slightly enhanced the pressor effect of exogenous noradrenaline, whereas dynorphin 3 micrograms/kg/min, Leu5-enkephalin 100 micrograms/kg/min and DADLE 30 micrograms/kg/min caused no significant change. In the third series, the sympathetic outflow was stimulated continuously at 2 Hz, and the interaction of dynorphin and DADLE was studied. Dynorphin 1 microgram/kg/min and DADLE 10 micrograms/kg/min initially decreased MAP to a similar extent. The effect of DADLE faded with time. When, during continuous infusion of DADLE 10 micrograms/kg/min, and after return of MAP to the pre-DADLE level, dynorphin 1 microgram/kg/min or DADLE 10 micrograms/kg/min was infused additionally, the effect of dynorphin was unchanged, whereas that of DADLE was almost abolished. We conclude that the opioid peptides as well as bremazocine decrease action potential-evoked release of noradrenaline and, secondarily, blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Release of previously incorporated gamma-[3H]aminobutyric acid in rabbit caudate nucleus slices.
The release of gamma-aminobutyric acid (GABA) was studied in slices of the head of the rabbit caudate nucleus. The slices were preincubated with [3H]GABA and then superfused. Aminooxyacetic acid was present throughout. Both the tritium in the slices and that in the superfusate consisted practically entirely of [3H]GABA. Stimulation for 2 min by electrical field pulses of 3 ms width and 9 V/cm voltage drop (36 mA current strength) at 5 or 20 Hz elicited an overflow of [3H]GABA that amounted to 0.23 or 0.47% of the tritium content of the tissue, respectively, and was diminished by 85% in the presence of tetrodotoxin. At higher current strength, less of the stimulation-evoked overflow was tetrodotoxin-sensitive. cis-1,3-Aminocyclohexane carboxylic acid diminished the uptake of [3H]GABA into the tissue but did not change the percentage released by electrical stimulation. Ca2+ withdrawal greatly accelerated basal [3H]GABA efflux and almost abolished the response to stimulation. Nipecotic acid 10-1,000 microM enhanced both the basal and (up to eightfold) the stimulation-evoked overflow. The method described allows us to elicit electrically a quasiphysiological, i.e., Ca2+-dependent and tetrodotoxin-sensitive, neuronal release of [3H]GABA. Nipecotic acid diverts released [3H]GABA from reuptake to overflow.
Amino Acids↗
A search for receptors modulating the release of gamma-[3H]aminobutyric acid in rabbit caudate nucleus slices.
Various putative striatal transmitters and related compounds were studied for their effects on the release of gamma-aminobutyric acid (GABA) from slices of the head of the rabbit caudate nucleus. The slices were preincubated with [3H]GABA and then superfused and stimulated electrically at 5 or 20 Hz. Aminooxyacetic acid was present throughout. The main changes observed were the following. The basal and, less consistently, the electrically evoked overflow of [3H]GABA were enhanced by 3,4-dihydroxyphenylethylamine (dopamine), an effect not blocked by cis-flupentixol or domperidone and not mimicked by apomorphine and D1-selective agonists. The electrically evoked overflow was diminished by 5-hydroxytryptamine (serotonin); the inhibition was prevented by methiothepin. The basal but not the electrically evoked overflow was enhanced by carbachol; acetylcholine and nicotine also accelerated the basal outflow whereas oxotremorine caused no consistent change; the effect of carbachol and acetylcholine were blocked by hexamethonium but not by atropine or by tetrodotoxin. These findings indicate that the GABA neurons in the caudate nucleus may be stimulated by dopamine, although the receptor type involved remains unclear; inhibited by serotonin; and stimulated by acetylcholine acting via a nicotine receptor. However, all drug effects observed were relatively small. No evidence was obtained for autoreceptors, alpha 2-adrenoceptors or receptors for opioids, adenosine or substance P at the GABA neurons.
Acetylcholine↗
Presynaptic opioid delta-receptors in the rabbit mesenteric artery.
Excitatory junction potentials (e.j.p.s) evoked by nerve stimulation were recorded from muscle cells of the rabbit isolated mesenteric artery. At 0.03 Hz the e.j.p. amplitudes were stable. When a train of fifteen pulses was applied at 0.25 Hz or at higher frequencies (0.5, 1 and 2 Hz), e.j.p.s showed an initial facilitation followed by depression. [Met5]enkephalin 0.1 and 1 mumol/l, [D-Ala2,D-Leu5]enkephalin 0.1 and 1, but not 0.01 mumol/l, and [D-Pen2, L-Pen5]enkephalin 3 mumol/l all depressed the e.j.p.s evoked by trains of fifteen pulses at 1 Hz. When more than one concentration was used ([Met5]enkephalin, [D-Ala2,D-Leu5]enkephalin), the inhibition was concentration dependent. It was always greater for the first few e.j.p.s than for the later ones in a train. [Met5]enkephalin 1 mumol/l reduced the first e.j.p. at 1 Hz and the e.j.p.s evoked by 0.03 Hz to a similar extent. The inhibitory effect of [Met5]enkephalin 1 mumol/l on e.j.p.s persisted in the presence of yohimbine 0.3 mumol/l. Naloxone 1 mumol/l did not interfere with the effect of [Met5]enkephalin 1 mumol/l. Naloxone 10 mumol/l depressed some e.j.p.s and prevented the inhibition by [Met5]enkephalin 1 mumol/l. Neither ICI 154129 10 mumol/l nor ICI 174864 0.3 mumol/l had any effect of their own and both compounds antagonized the action of [Met5]enkephalin 1 mumol/l. Normorphine 10 mumol/l, fentanyl 1 mumol/l, ethylketocyclazocine 0.1 mumol/l, and dynorphin A(1-13) 1 mumol/l were all ineffective. Ethylketocyclazocine 1 mumol/l did not change the e.j.p.s either, but antagonized [Met5]enkephalin 1 mumol/l. [Met5]enkephalin 1 mumol/l failed to influence both the resting membrane potential of the muscle cells and the depolarizing effect of noradrenaline 3 and 30 mumol/l. We suggest that the axon terminals of post-ganglionic sympathetic neurones in the rabbit mesenteric artery possess opioid delta-, but not mu- or kappa-receptors. The activation of presynaptic delta-receptors inhibits the release of the neuroeffector transmitter. There is no evidence for any effect of co-released endogenous opioid peptides under our experimental conditions.
Action Potentials↗
Dopamine1 receptor agonist and alpha-2 adrenoceptor antagonist effects of fenoldopam in rabbits.
Neurochemical and circulatory effects of fenoldopam were studied in pithed rabbits with electrically stimulated sympathetic outflow and in strips of the rabbit pulmonary artery. In pithed rabbits, fenoldopam (1-30 micrograms/kg/min) decreased the arterial blood pressure. Fenoldopam (3-30 microgram/kg/min) also increased the norepinephrine spillover rate (the rate at which endogenous norepinephrine enters into the plasma after having been released from postganglionic sympathetic nerves) and decreased the [3H]norepinephrine plasma clearance. The selective dopamine (DA)1 antagonist SCH 23390 (bolus injection of 10 micrograms/kg followed by infusion of 2 micrograms/kg/hr) antagonized markedly and the DA2-selective antagonist domperidone (bolus injection of 200 micrograms/kg followed by infusion of 50 micrograms/kg/hr) antagonized slightly the hypotensive effect. The increase in the norepinephrine spillover rate was enhanced after treatment with desipramine. Clonidine (0.3 microgram/kg/min) reduced the spillover of norepinephrine, and this effect was abolished by fenoldopam (30 micrograms/kg/min). In pulmonary artery strips preincubated with [3H]norepinephrine, fenoldopam (10(-7) and 10(-6) M) increased the electrically evoked overflow of tritium. The effect of fenoldopam (10(-6) M) was prevented in the presence of a supramaximal concentration of clonidine (10(-5) M). The results suggest that fenoldopam lowers blood pressure mainly by activation of vascular smooth muscle DA1 receptors. In addition, however, it blocks prejunctional alpha-2 autoreceptors at postganglionic sympathetic axons.
Adrenergic alpha-Antagonists↗
Prejunctional opioid receptors in the pulmonary artery of the rabbit.
The possible existence of prejunctional opioid receptors at postganglionic sympathetic vasoconstrictor axons was studied in superfused spiral strips of the main pulmonary artery of the rabbit. Ethylketocyclazocine 0.1 and 1 mumol/l and dynorphin-(1-13) 0.1 mumol/l but not morphine 0.01-1 mumol/l, (D-Ala2, NMePhe4, Gly-ol5)-enkephalin 0.001-1 mumol/l, Leu5-enkephalin 0.1-5 mumol/l and (D-Pen2, L-Pen5)-enkephalin 0.01-1 mumol/l reduced contractions of the artery strips elicited by electrical field stimulation at 0.5 or 1 Hz. The effect of ethylketocyclazocine was antagonized by naloxone. Ethylketocyclazocine 1 mumol/l did not change contractions elicited by exogenous noradrenaline (5-10 nmol/l). In artery strips preincubated with 3H-noradrenaline, ethylketocyclazocine 1 mumol/l diminished both the overflow of tritium and the contraction evoked by field stimulation at 1 Hz. All inhibitory effects were small, amounting maximally to about 20%. The results indicate that the postganglionic sympathetic axons of the artery possess prejunctional opioid receptors, activation of which leads to inhibition of the release of noradrenaline and, in consequence, inhibition of neurogenic vasoconstriction. It seems likely that the receptors are, at least predominantly, of the kappa-type.
Animals↗
Presynaptic inhibitory opioid delta- and kappa-receptors in a branch of the rabbit ileocolic artery.
The largest rami caecales of the ileocolic artery (a branch of the mesenteric artery) were perfused at a constant rate of flow. Either vasoconstriction or the release of previously incorporated [3H]noradrenaline was measured. The following opioid agonists inhibited the vasoconstriction elicited by electrical field pulses (5 pulses at 10 Hz; EC50 values in brackets): [Leu5]enkephalin (596 nmol/l), [D-Ala2,D-Leu5]enkephalin (69 nmol/l), dynorphin-(1-13) (366 nmol/l) and ethylketocyclazocine (668 nmol/l). Fentanyl (up to 30 mumol/l) and normorphine (up to 100 mumol/l) caused at best minimal inhibition. The effects of [Leu5]enkephalin and dynorphin-(1-13) were antagonized by naloxone. Only the effect of [Leu5]enkephalin but not that of dynorphin-(1-13) was antagonized by the delta-selective antagonist ICI 154129. [Leu5]Enkephalin and dynorphin-(1-13) did not decrease the vasoconstrictor response to exogenous noradrenaline or ATP. In arteries preincubated with [3H]noradrenaline, electrical stimulation (50 pulses at 1 Hz) increased the outflow of tritium. The stimulation-evoked overflow was reduced by [Leu5]enkephalin and dynorphin-(1-13), and the effect of [Leu5]enkephalin was antagonized by naloxone. It is concluded that the postganglionic sympathetic neurons of the ramus caecalis possess presynaptic opioid receptors which, when activated, inhibited transmitter release. The receptors appear to be of the delta- and kappa- but not the mu-type.
Animals↗
Inhibition of neuroeffector transmission in the rabbit mesenteric artery by [Met5]enkephalin.
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Animals↗
The sympathetic axons innervating the sinus node of the rabbit possess presynaptic opioid kappa- but not mu- or delta-receptors.
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.
Animals↗
Noradrenaline and adenosine triphosphate as co-transmitters of neurogenic vasoconstriction in rabbit mesenteric artery.
The largest rami caecales of the ileocolic artery, which is a branch of the mesenteric artery, were perfused at a constant rate of flow. Either vasoconstriction (as an increase in perfusion pressure) or the release of previously incorporated [3H]-noradrenaline was measured. Noradrenaline and ATP, but not carbachol, serotonin, adenosine, Arg-vasopressin and neuropeptide Y, caused marked vasoconstriction. When the sympathetic vasoconstrictor axons in the arterial wall were stimulated by electrical field pulses (either 5 pulses at 10 Hz or 100 pulses at 5 Hz; 0.3 ms pulse width, 200 mA current strength), the ensuing vasoconstriction was at best slightly reduced by phentolamine, prazosin and phenoxybenzamine. The response to 100 pulses, 5 Hz was even enhanced by phentolamine and yohimbine. All antagonists except yohimbine blocked the effect of exogenous noradrenaline. Prazosin did not change the effect of exogenous ATP. alpha,beta-Methylene-ATP (3-15 mumol/l) elicited transient vasoconstriction. Subsequently, responses to ATP as well as to electrical stimulation were reduced and recovered slowly. The response to noradrenaline was not changed. That part of the electrically induced vasoconstriction that remained after alpha,beta-methylene-ATP was almost abolished by phentolamine or prazosin. Pre-treatment of the animals with reserpine decreased but did not prevent the electrically evoked contraction of their arteries. The reserpine-resistant response was not changed by prazosin but was abolished by alpha,beta-methylene-ATP. The vasoconstriction elicited by electrical pulses was not affected by atropine or methysergide but was entirely blocked by tetrodotoxin, guanethidine or exposure to 6-hydroxydopamine. In arteries pre-incubated with [3H]-noradrenaline, electrical stimulation (100 pulses at 5 Hz) increased the outflow of tritium. The evoked overflow was blocked by tetrodotoxin, not changed by alpha,beta-methylene-ATP (9 mumol/l) or prazosin, and enhanced by phentolamine, phenoxybenzamine and yohimbine. We conclude that, in the branch of the mesenteric artery examined, both noradrenaline and ATP or a closely related compound transmit information from sympathetic neurones to smooth muscle. An alpha-adrenoceptor antagonist can reduce neurogenic vasoconstriction by blockade of post-junctional alpha-(probably alpha 1) receptors, reserpine by selective depletion of noradrenaline, and alpha,beta-methylene-ATP by desensitization of the post-junctional ATP (probably P2) receptor mechanism. Noradrenaline and ATP appear to be released from the same neurone. In addition, prejunctional alpha 2-adrenergic autoinhibition of transmitter release operates in the artery. alp
Adenosine Triphosphate↗
Inhibition by diltiazem of norepinephrine release from sympathetic nerves in the rabbit pulmonary artery.
In order to determine if the calcium blocker diltiazem could alter excitation-secretion coupling in vascular sympathetic nerves, superfused rabbit pulmonary arterial strips were preincubated with 3H-norepinephrine and stimulated electrically (2-8 Hz) and by KCl (60 mM). Diltiazem significantly inhibited tension development with 4 Hz (1.5 X 10(-5) M) and 8 Hz (1.5 X 10(-6), 1.5 X 10(-5) M) stimuli, but only at 1.5 X 10(-5) M did diltiazem inhibit the 3H overflow evoked by an 8-Hz stimulus. No inhibition of 3H overflow was noted with the 2 and 4 Hz stimuli. With an 8-Hz stimulus the inhibition of tension development (45.4%) by diltiazem (1.5 X 10(-5) M) was significantly greater than the inhibition of 3H overflow (33.8%). A similar relationship was noted with 60 mM KCl stimulation. These data suggest that excitation-secretion coupling in vascular sympathetic nerves can be inhibited by diltiazem.
Animals↗
Alpha-adrenoceptor antagonists and the release of noradrenaline in rabbit cerebral cortex slices: support for the alpha-autoreceptor hypothesis.
Slices of rabbit cerebral cortex were preincubated with [3H]-noradrenaline and then superfused and stimulated electrically twice for 2 min each (S1, S2) at various frequencies (0.2-3 Hz). The stimulation-evoked overflow of tritium (S1) increased with increasing frequency and was higher when cocaine (10 microM) was present. In the absence of cocaine, tetraethylammonium (TEA; 100 and 300 microM), added before S2, increased the stimulation-evoked overflow of tritium to about the same extent, irrespective of the frequency. In contrast, rauwolscine (0.1 and 1 microM) and idazoxan (0.1-10 microM) increased the evoked overflow much more, the higher the frequency of stimulation. Phentolamine (0.1 and 1 microM) reduced the overflow elicited at 0.3 and 1 Hz, and (1 microM) caused an increase only at 3 Hz. In slices superfused throughout with cocaine 10 microM, rauwolscine (1 microM) and idazoxan (1 and 10 microM) again increased the evoked overflow of tritium more, the higher the frequency of stimulation. For a given frequency, rauwolscine and idazoxan enhanced the evoked overflow to a greater extent in the presence than in the absence of cocaine. Idazoxan (1 and 10 microM) and rauwolscine (1 microM) counteracted the inhibition that phentolamine (0.1 microM) produced at low frequency. The increases caused by rauwolscine (1 microM) and TEA (300 microM) were approximately additive, but those caused by rauwolscine (1 microM) and idazoxan (10 microM) were not. The effects of rauwolscine, idazoxan and phentolamine depend on the experimental conditions (frequency, cocaine) in a manner compatible with the operation of a presynaptic alpha 2-adrenoceptor-mediated autoinhibition of noradrenaline release. When given at sufficient concentrations, these antagonists enhance the release of noradrenaline more, the higher the biophase concentration of the transmitter and the stronger, hence, the autoinhibition. In the case of the partial alpha 2-adrenoceptor agonist phentolamine, a low perineuronal noradrenaline concentration even reverses facilitation to inhibition. This pattern differs markedly from the pattern of effects of TEA which increases the release of noradrenaline by a mechanism other than alpha-adrenoceptor blockade.
Adrenergic alpha-Antagonists↗