Decreased Noradrenaline Release Research Articles

Aerobic exercise training increases neuronal nitric oxide release and bioavailability and decreases noradrenaline release in mesenteric artery from spontaneously hypertensive rats

To study the effect of aerobic exercise training on sympathetic, nitrergic and sensory innervation function in superior mesenteric artery from spontaneously hypertensive rats (SHRs). De-endothelized vascular rings from sedentary and trained SHRs (treadmill 12 weeks) were used. Vasomotor responses to electrical field stimulation (EFS), noradrenaline, nitric oxide donor DEA-NO and calcitonin gene-related peptide (CGRP) were studied. Neuronal nitric oxide synthase (nNOS) expression and nitric oxide, superoxide anions (O(2.-)), noradrenaline and CGRP levels were also determined. Aerobic exercise training decreased vasoconstrictor response to EFS but increased noradrenaline response. Phentolamine decreased while N(ω)-nitro-(L)-arginine methyl ester ((L)-NAME) increased the response to EFS; the effect of both drugs was greater in trained animals. Training also decreased noradrenaline release and O(2.-) production and increased nNOS expression, nitric oxide release and the vasodilator response to DEA-NO. The O(2.-) scavenger tempol increased DEA-NO-induced vasodilation only in sedentary rats. The EFS-induced contraction was increased to a similar extent in both experimental groups by preincubation with CGRP (8-37). CGRP release and vasodilator response were not modified by training. Aerobic exercise training decreases contractile response to EFS in mesenteric artery from SHRs. This effect is the net result of decreased noradrenaline release, increased sensitivity to the vasoconstrictive effects of noradrenaline and increased neuronal nitric oxide release and bioavailability. These modifications might contribute to the beneficial effects of aerobic exercise training on blood pressure.

Effect of short- and long-term portal hypertension on adrenergic, nitrergic and sensory functioning in rat mesenteric artery

In the present study, we analysed possible alterations in adrenergic, nitrergic and sensory functioning in mesenteric arteries from rats at 1 and 21 months after partial portal vein ligation, and the mechanisms involved in these alterations, if any. For this purpose, we analysed the vasoconstrictor response to EFS (electrical field stimulation) and the effect of the α-antagonist phentolamine, the NOS (nitric oxide synthase) inhibitor L-NAME (N(G)-nitro-L-arginine methyl ester) and the CGRP (calcitonin gene-related peptide) receptor antagonist CGRP-(8-37) in mesenteric segments from ST (short-term; 1 month) and LT (long-term; 21 months) SO (sham-operated) and pre-hepatic PH (portal hypertensive) rats. The vasomotor responses to NA (noradrenaline), the NO donor DEA-NO (diethylamine NONOate) and CGRP were analysed. NA, NO and CGRP releases were measured. Phospho-nNOS (neuronal NOS) expression was studied. The vasoconstrictor response to EFS was decreased in STPH animals. Phentolamine decreased this vasoconstrictor response more strongly in SO animals. Both L-NAME and CGRP-(8-37) increased vasoconstrictor response to EFS more strongly in PH than SO segments. PH did not modify vasomotor responses to NA, DEA-NO or CGRP, but it decreased NA release while increasing those of NO and CGRP. Phospho-nNOS expression was increased by PH. In LTPH, no differences were observed in vasoconstrictor response to EFS, vasomotor responses or neurotransmitter release when compared with age-matched SO animals. In conclusion, the mesenteric innervation may participate in the development of the characteristic hyperdynamic circulation observed in STPH through the joint action of decreased adrenergic influence, and increased nitrergic and sensory innervations influences. The participation of each innervation normalizes under conditions of LTPH.

Effects of sedatives on noradrenaline release from the medial prefrontal cortex in rats

N-Methyl-d-aspartate (NMDA) receptor antagonism and GABA(A) receptor activation are believed to be critical targets for general anesthetic action. However, as NMDA antagonism of intravenous anesthetic agents causes post-anesthetic emergence reactions such as hallucination and agitation, while the GABA(A)-mimetic intravenous anesthetic agents do not, these two classes of intravenous anesthetic agents produce differential clinical profiles. We have investigated the differential effects of the GABA(A) agonists propofol and midazolam and the NMDA antagonist ketamine on noradrenaline release from the medial prefrontal cortex of the rat using microdialysis, as noradrenergic neurons have a role to play in anesthesia and are known to be important in the control of sleep, attention and learning. Twenty-one male Wistar rats (200-270 g) were randomly allocated into three groups: ketamine 100 mg x kg(-1) (n = 6), propofol 60 mg x kg(-1) (n = 8) and midazolam 5 mg x kg(-1) (n = 7) IP. A unilateral guide cannula was implanted stereotaxically into the medial prefrontal cortex under pentobarbital anesthesia (50 mg x kg(-1) IP). Forty-eight hours later, a dialysis probe was inserted through the guide cannula, and perfused with an artificial cerebrospinal fluid solution containing 1 mM pargyline. Following an equilibration period, samples of dialysate were collected every 10 min. Noradrenaline content was measured by high-performance liquid chromatography using an electrochemical detector. Anesthesia times, defined as the duration between the loss of righting reflex and recovery, were 24.7+/-5.6 (SEM), 20.5+/-1.9 and 25.2+/-1.5 min for propofol, midazolam and ketamine, respectively (no significant between-group differences). Both GABA(A )agonists, propofol and midazolam, significantly decreased noradrenaline release (75% and 71% of basal release, respectively). The NMDA antagonist ketamine markedly increased noradrenaline release (413% of basal). These data suggest that different clinical profiles observed with these two classes of sedatives may result from changes in noradrenaline release from the medial prefrontal cortex.

α 2A- But not α 2B/C-adrenoceptors modulate noradrenaline release in rat locus coeruleus: voltammetric data

In this study, we used subtype-selective antagonists to determine the subtype of α 2-adrenoceptor controlling noradrenaline release in rat locus coeruleus. Noradrenaline release was measured in locus coeruleus slices using fast cyclic voltammetry at carbon fibre microelectrodes. On long stimulation trains (40 pulses, 20 Hz), the α 2A-adrenoceptor selective antagonist BRL 44408 (2-[2 H-(1-methyl-1,3-dihydroisoindole) methyl]-4,5-dihydroimidazole) at 100 nM and 1 μM significantly increased stimulated noradrenaline release, whereas the α 2B/C-selective antagonist ARC 239 (2-[2[4-( o-methoxyphenyl)piperazin-1-yl] ethyl]-4,4dimethyl-1,3-(2 H,4 H)-isoquinolinedione) at 50 and 500 nM had no effect. On short stimuli (20 pulses, 200 Hz), the non-specific α 2-adrenoceptor agonist dexmedetomidine (10 nM) significantly decreased noradrenaline release, an effect reversed by BRL 44408 (1μM) but not by ARC 239 (500 nM). These data demonstrate that autoreceptor control of noradrenaline release in the locus coeruleus is mediated by α 2A but not α 2B/C-adrenoceptors.

Evidence that 5-HT2 receptor activation decreases noradrenaline release in rat hippocampus in vivo.

1. Recent electrophysiological studies have shown that 5-HT2/5-HT1C receptor agonists inhibit the electrical activity of noradrenergic neurones in the rat locus coeruleus. Here we examine the effect of various agonists and antagonists of 5-HT2/5-HT1C receptors on noradrenaline release in hippocampus of anaesthetized rats using microdialysis. 2. Subcutaneous administration of the 5-HT2/5-HT1C receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI: 0.2 and 0.5 mg kg-1), caused a marked decrease (50% of pre-drug levels 60 min after injection) of noradrenaline in hippocampal dialysates which was long-lasting (greater than 120 min). Noradrenaline output also decreased in response to administration of the structural analogue of DOI, 1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane (DOB: 1 mg kg-1, s.c.). 3. The effect of DOI on noradrenaline output was prevented by pretreatment with the 5-HT2/5-HT1C receptor antagonist, ritanserin (0.4 mg kg-1, s.c.). Spiperone (0.2 and 1 mg kg-1, s.c.), a 5-HT2/dopamine D2 receptor antagonist which has low affinity for 5-HT1C receptors, also antagonized the effect of DOI (0.5 mg kg-1, s.c.). Sulpiride (50 mg kg-1, s.c.), a dopamine D2 receptor antagonist did not alter the response to DOI (0.5 mg kg-1, s.c.). 4. Both the non-selective 5-HT receptor agonist, quipazine (1 mg kg-1, s.c.), and the 5-HT-releasing agent, p-chloroamphetamine (2 mg kg-1, s.c.), decreased noradrenaline release in hippocampus and these effects were antagonized by pretreatment with ritanserin (0.4 mg kg-1, s.c.).5. Our data suggest that in vivo, noradrenaline release in hippocampus is inhibited by 5-HT2 receptor activation. This effect is probably associated with a decrease in noradrenergic neuronal activity.

Modulation of noradrenaline release in the pithed rabbit: a role for angiotensin II.

This study in the pithed rabbit with electrically stimulated sympathetic outflow (spinal region, T-8; 3 Hz) was conducted to determine the contribution of the renin-angiotensin system to noradrenaline release in vivo. The rate of noradrenaline release (spillover) into the plasma was determined from the endogenous plasma noradrenaline level and the simultaneously determined noradrenaline plasma clearance. In the pithed rabbit, infusion of angiotensin II (0.1 microgram/kg/min i.v.) failed to increase the noradrenaline release rate and only slightly increased blood pressure. On the other hand, the angiotensin-converting enzyme inhibitor captopril (1 mg/kg i.v.) decreased both blood pressure and the noradrenaline release rate. Bilateral nephrectomy was performed to reduce endogenous angiotensin II formation; and in this case, infusion of angiotensin II markedly increased the noradrenaline release rate and blood pressure, whereas captopril had no effect on either parameter. These results suggest that angiotensin II modulates noradrenaline release in vivo through activation of facilitatory prejunctional angiotensin II receptors, and that in the pithed rabbit these receptors are probably maximally activated by endogenously synthesized angiotensin II. The actions of angiotensin II on noradrenaline release open the possibility that increases in blood pressure in the pithed rabbit--by decreasing renin release via intrarenal baroreceptors and hence decreasing angiotensin II formation--may lead to decreased noradrenaline release. This was investigated using phenylephrine (6 micrograms/kg/min i.v.), a selective alpha 1-adrenoceptor agonist, and adrenaline (1 microgram/kg/min i.v.), and alpha 1/alpha 2-agonist. Both drugs increased blood pressure and decreased the noradrenaline release rate. After bilateral nephrectomy, the inhibitory effect of phenylephrine on noradrenaline release was abolished, whereas that of adrenaline was maintained.(ABSTRACT TRUNCATED AT 250 WORDS)