Reflex activation of renal nerves in humans: differential effects on noradrenaline, dopamine and renin overflow to renal venous plasma

Using a thermodilution technique for renal venous blood flow measurements, renal sympathetic nerve activity was evaluated in 10 healthy volunteers by measurements of noradrenaline (NA) and dopamine (DA) overflow to renal venous plasma. Renin release was measured simultaneously. At rest, arterial adrenaline (ADR) levels were 0.24 +/- 0.03 nmol-1 and NA and DA levels were higher in renal venous than in arterial plasma (1.24 vs. 0.98 and 0.14 vs. 0.09 nmol l-1, respectively, P less than 0.01 for both). The renal extraction of ADR from arterial plasma was 40 +/- 4%. ADR extractions were used to correct for the renal removal of NA or DA from arterial plasma when calculating the renal overflow of NA or DA to renal venous plasma. At rest, the thus corrected renal venous overflows of NA and DA were 228 +/- 34 and 29 +/- 3 pmol min-1, respectively. Isometric handgrip exercise (IHG) increased renal vascular resistance (RVR) by 20% and NA overflow by 123%, without altering renin release or DA overflow. Vasodilatation induced by dihydralazine (HYDR) increased NA overflow by 63% (P less than 0.05) and elevated DA overflow by 107 +/- 59%. The renal DA/NA overflow ratio was reduced from 0.15 to 0.06 (P less than 0.01) during IHG, but was not altered by HYDR. Renin release increased by 377% after HYDR (P less than 0.001) and was correlated to the reduction of mean arterial pressure but not changes in NA overflow. Thus, both IHG and HYDR increased renal sympathetic nerve activity, although differential effects on renin release and DA overflow were observed. The dissociation of renal NA and DA responses suggests that the human kidney may have a subset of dopaminergic nerves.     

Ischaemia-induced release of noradrenaline and creatine kinase in the isolated, working rat heart

In order to examine an early ischaemia-induced local release of myocardial noradrenaline (NA), the left coronary artery of the isolated working rat heart was ligated for periods varying between 7.5 min and 30 min, followed by reperfusion for 5 min. As perfusion substrate, glucose, lactate or both were used. In part of the experiments, hearts were pre-labelled with [3H]NA. Already after 7.5 min of ischaemia, an increased efflux of endogenous NA was observed in the perfusate at reperfusion, concomitant with a decrease in tissue NA content. This effect was most pronounced with lactate as substrate. Qualitatively similar effects were seen on [3H]NA efflux from labelled hearts. The combination of glucose and lactate as substrate markedly reduced (compared with lactate alone) the efflux of NA, whereas no such reduction was observed on the efflux of creatine kinase (CK). It is concluded that ischaemia is associated with an early local release of NA. Furthermore, ischaemia may induce different effects on the metabolic processes of the myocyte as compared with the adrenergic nerve ending.     

Influence of acetylcholine, peptides, and other vasodilators on endogenous noradrenaline overflow and vasoconstriction in canine blood perfused gracilis muscle

The effects of acetylcholine, substance P and vasoactive intestinal polypeptide (VIP) on the endogenous noradrenaline (NA) overflow were compared to those of two other vasodilators, nitroglycerin and felodipine, neither of which are thought to influence NA neurotransmission in blood perfused skeletal muscle. The lack of prejunctional effects of nitroglycerin was verified in vitro. The sympathetic nerve stimulation (SNS) evoked NA overflow was reduced by 37 +/- 9% by a dose of acetylcholine which reduced the perfusion pressure at rest by 44 +/- 6%. Conversely, atropine tended to enhance SNS evoked NA overflow. Acetylcholine reduced the vasoconstrictor responses to SNS when compared to the responses observed with an equipotent vasodilatory dose of, e.g. nitroglycerin. The SNS evoked NA overflow was not influenced by a moderate mechanical blood flow reduction or by pronounced reductions of vascular resistance induced by either substance P, VIP, nitroglycerin or felodipine, supporting the idea that the transport of NA from nerve terminal to blood is not importantly influenced by moderate decreases in blood flow or vascular tone. Prejunctional muscarinic inhibition of NA release in skeletal muscle was verified under in vivo conditions, but the other substances tested did not influence sympathetic neurotransmission. Endogenous NA overflow appears to mirror NA release in vivo also when diffusion is influenced by changes in blood flow or vascular tone in this experimental model.     

Differential changes in noradrenaline turnover in specific regions of rat brain produced by controllable and uncontrollable shocks

A series of three studies was performed to investigate the effects of the ability to avoid or escape shock (controllability) and the lack of ability to do so (uncontrollability) on noradrenergic neurons in various brain regions of male Wistar rats. The levels of noradrenaline (NA) and its major metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4), in the hypothalamus, amygdala, thalamus, midbrain, hippocampus, cerebral cortex, pons plus medulla oblongata, and basal ganglia were measured fluorometrically. These studies indicated that after 3 hr and 6 hr in a free operant avoidance-escape stress procedure, the experimental rats able to avoid or escape shock showed greater increases in NA turnover (lower NA levels and higher MHPG-SO4 levels) in specific brain regions (i.e., the hypothalamus, amygdala, and thalamus) than the yoked rats unable to control the same shock. After 21 hr of stress, in contrast to stress of either 3-hr or 6-hr duration, the yoked rats exhibited a more marked enhancement of NA turnover in these brain regions than did experimental rats. Once shock-controlling responses had been acquired and well established by experimental rats, the responses of NA neurons in these rats did not differ markedly from those in the nonshocked control rats. Yoked rats given the same repetitive sessions of uncontrollable shock displayed sustained increases in NA turnover preferentially in the hypothalamus and amygdala, compared with the experimental rats. These results suggest that NA release in specific brain regions in the experimental "coping" rats is increased before the rats have learned the effective coping response. However, once a coping response is firmly established, NA release is reduced.     

Plasma noradrenaline and dopamine in renin-mediated hypertension

Noradrenaline (NA) and dopamine (DA) have opposite effects on the kidney; NA causes vasoconstriction and increased sodium reabsorption while DA promotes vasodilation and natriuresis. In 15 patients investigated for renin-mediated hypertension measurements of plasma renin activity (PRA), NA and DA concentrations were made in arterial and renal venous blood from both kidneys before and after acute stimulation of renin release by i.v. dihydralazine. Nine patients had unilateral renin secretion and were classified as renin-positive, while the remaining six patients were renin-negative. Renin-positive patients had higher arterial and renal venous PRA, NA and DA levels than the negative ones. In the renin-positive group V-A differences for NA and DA were present on both sides despite unilateral secretion of renin. NA but not DA levels were higher in the renin-secreting kidney, which can partly be explained by the reduced plasma flow to the involved kidney. After dihydralazine the arterial NA and DA rose similarly in renin-positive and renin-negative patients, while PRA rose only in the renin-positive cases. In the renin-positive patients where stimulation of renin secretion caused a marked increase of the PRA gradient on the affected side only, renal gradients for NA and DA increased bilaterally. The increase in DA was more pronounced than that of NA yielding a rise in DA/NA ratio on the affected side. Arterial PRA was positively correlated to the plasma concentrations of NA and DA. V-A differences for PRA and NA or DA were positively correlated on the involved renin-secreting side. In summary, patients with renin-dependent hypertension have elevated plasma NA and DA concentrations. Stimulation of renin release by dihydralazine increases the DA/NA ratio in arterial and renal venous blood indicating release of 'precursor dopamine' from noradrenergic fibres and/or activation of dopaminergic nerves. There seems to be a relationship between renal nerve activity and renin release in renin-dependent hypertension.     

Effect of hypoxia on nerve-stimulation-induced release of noradrenaline from the rabbit heart

The present study addressed the hypothesis that cardiac production of adenosine (ADO) and/or prostacyclin (PGI2) during hypoxia is augmented to a level sufficient to affect nerve-stimulation-induced release of noradrenaline (NA). Innervated rabbit hearts were perfused at high (95% O2) or low (8% O2) oxygen pressure. The effluxes of NA and purines from the heart were determined by HPLC and that of the PGI2 metabolite by radioimmunoassay. Five minutes of hypoxia elevated effluent purines (sum of ADO, inosine, and hypoxanthine) from 1.1 microM to 6.2 microM, but did not affect the outflow of NA. The ADO receptor antagonists THEO (100-200 microM) and 8PSOT (100 microM) given during hypoxia increased the evoked outflow of NA by 77% (P less than 0.01) and 37% (P less than 0.05), respectively. Indomethacin (30 microM, a prostaglandin synthesis inhibitor) reduced the efflux of PGI2 metabolite by 93% but did not per se affect NA outflow during simultaneous administration of THEO, either under normoxia or hypoxia. It is concluded that ADO, but not PGI2, plays a role in reducing transmitter release during hypoxia. In addition, hypoxia leads to an enhancement of transmitter release, probably unrelated to ADO or purines. The lack of effect of hypoxia alone on evoked outflow of transmitter seems to be the result of a combination of these two processes.     

Myocardial interstitial choline and glutamate levels during acute myocardial ischaemia and local ouabain administration

AIM: Noradrenaline (NA) uptake transporters are known to reverse their action during acute myocardial ischaemia and to contribute to ischaemia-induced myocardial interstitial NA release. By contrast, functional roles of choline and glutamate transporters during acute myocardial ischaemia remain to be investigated. Because both transporters are driven by the normal Na+ gradient across the plasma membrane in a similar manner to NA transporters, the loss of Na+ gradient would affect the transporter function, which would in turn alter myocardial interstitial choline and glutamate levels. The aim of the present study was to examine the effects of acute myocardial ischaemia and the inhibition of Na+,K+-ATPase on myocardial interstitial glutamate and choline levels. METHODS: In anaesthetized cats, we measured myocardial interstitial glutamate and choline levels while inducing acute myocardial ischaemia or inhibiting Na+,K+-ATPase by local administration of ouabain. RESULTS: The choline level was not changed significantly by ischaemia (from 0.93 +/- 0.06 to 0.82 +/- 0.13 microm, mean +/- SE, n = 6) and was decreased slightly by ouabain (from 1.30 +/- 0.06 to 1.05 +/- 0.07 microm, P < 0.05, n = 6). The glutamate level was significantly increased from 9.5 +/- 1.9 to 34.7 +/- 6.1 microm by ischaemia (P < 0.01, n = 6) and from 8.9 +/- 1.0 to 15.9 +/- 2.3 microm by ouabain (P < 0.05, n = 6). Inhibition of glutamate transport by trans-L-pyrrolidine-2,4-dicarboxylate (t-PDC) suppressed ischaemia- and ouabain-induced glutamate release. CONCLUSION: Myocardial interstitial choline level was not increased by acute myocardial ischaemia or by Na+,K+-ATPase inhibition. By contrast, myocardial interstitial glutamate level was increased by both interventions. The glutamate transporter contributed to glutamate release via retrograde transport.     

Possible involvement of neuropeptide Y in sympathetic vascular control of canine skeletal muscle

Sympathetic nerve stimulation (2 min, 2 and 10 Hz) increased perfusion pressure in the blood perfused canine gracilis muscle in situ after pretreatment with atropine, desipramine and beta-adrenoceptor antagonists. This vasoconstriction was accompanied by clear-cut increases in the overflow of endogenous noradrenaline (NA) at both frequencies and, at 10 Hz but not at 2 Hz, also of neuropeptide Y-like immunoreactivity (NPY-LI). The irreversible alpha-adrenoceptor antagonist phenoxybenzamine enhanced the nerve stimulation induced overflows of NA and NPY-LI five- to eightfold and threefold, respectively. The fractional overflows of NA and NPY-LI per nerve impulse were similar in response to the high-frequency stimulation, indicating equimolar release in relation to the tissue contents of the respective neurotransmitter. The maximal vasoconstrictor response elicited by 10 Hz was reduced by about 50% following a dose of phenoxybenzamine which abolished the effect of exogenous NA and the remaining response was more long-lasting. Local i.a. infusion of NPY evoked long-lasting vasoconstriction in the presence of phenoxybenzamine, while the stable adenosine 5(1)-triphosphate (ATP) analogue alpha-beta-methylene ATP was without vascular effects. Locally infused NPY reduced the nerve stimulation evoked NA overflow by 31% (P less than 0.01) at 1 microM in arterial plasma, suggesting prejunctional inhibition of NA release. In conclusion, NPY-LI is released from the canine gracilis muscle upon sympathetic nerve stimulation at high frequencies. There is nerve stimulation evoked vasoconstriction, which is resistant to alpha-adrenoceptor blockade. This may in part be mediated by NPY released together with NA from the sympathetic vascular nerves.     

Effect of 4-aminopyridine on release of noradrenaline from the perfused cat spleen by nerve stimulation.

1. 4-aminopyridine (4-AP, 1 mM) increased noradrenaline (NA) output from the perfused cat spleen at 5 Hz by about fivefold. Enhancement of NA release by 4-AP was reversible. Output of NA induced by potassium was not affected. 2. NA output was doubled at low concentrations (0.1--0.3 mM) of 4-AP, but maximal effect was obtained at 1--3 mM. At 10 mM, it induced spontaneous release of NA which was insensitive to calcium. 3. Insignificant outputs obtained at 5 Hz in 0.1 and 0.3 mM calcium-Krebs solution were markedly enhanced by 4-AP. 4-AP enhanced release at all calcium concentrations up to 5 mM, but maximum output was obtained at 2.5 mM. 4. 4-AP at pH 8.5 was more effective in enhancing NA release than at pH 7.4. 5. 4-AP increased the recovery of intra-arterially infused NA from the control 26 to 47%. 6. 4-AP did not affect release of catecholamines (CA) from the perfused cat adrenal gland by acetylcholine (ACh). 7. It is suggested that 4-AP inactivates potassium current in sympathetic nerves and prolongs the duration of the action potential, thereby allowing a greater influx of calcium ions into the neurone to enhance release of NA.     

Effects of noradrenaline on neuronal NOS2 expression and viability

The authors previously showed that conditioned media (CM) from activated microglia increased inducible nitric oxide synthase (NOS2) in cortical neurons. Here they examined the ability of noradrenaline (NA) to reduce neuronal NOS2 or cell death. Primary mouse cortical neurons were activated using CM from microglia incubated with lipopolysaccharide (LPS). Neuronal NOS2 was assessed by increases in nitrite accumulation, and increases in NOS2 mRNA levels and fluorescence of the NO-sensitive probe DAF-2 DA. NOS2 induction was associated with an increase in neuronal LDH release. When NA was added during microglial activation, neuronal NOS2 was significantly reduced (by approximately 70%); in contrast if NA was added to the neurons along with CM, there was less reduction (about 35% decrease) in NOS2 expression. NA added to either microglia or to neurons reduced neuronal LDH release comparably. Pretreatment of CM with blocking antibody to TNFalpha, alone or with IL1-receptor antagonist, partially reduced neuronal cell death and NOS2. Incubation of neurons with NA increased IkBalpha, which could reduce NOS2. These results demonstrate that NA modulates neuronal NOS2 expression and damage, and that these effects are primarily due to inhibition of microglia released factors. Perturbations of NA could exacerbate neuronal damage by allowing for increased inflammatory responses.     

Nature of anthopleurin-B-induced release of norepinephrine from adrenergic nerves

Anthopleurin-B (AP-B), a new polypeptide from sea anemone (Anthopleura xanthogrammica), markedly increased the amount of norepinephrine (NA) released from the guinea pig isolated vas deferens. The AP-B-induced release of NA was inhibited or abolished by pretreatment with reserpine and by guanethidine or procaine but remained almost unaffected by mecamylamine. D 600, nifedipine, diltiazem, Mn2+, and Mg2+ markedly inhibited the NA releasing action of AP-B. The AP-B-induced release of NA increased in a linear fashion with increasing Na+ concentrations (85-150 mM). Also the NA release by AP-B increased with an increase in the concentration of external Ca2+ from 0 to 0.8 mM but decreased with an increase in the Ca2+ concentration from 0.8 to 2.0 mM. These results suggest that AP-B increases the permeability across the nerve cell membrane to both Na+ and Ca2+ and that this plays an important role in the NA release from the adrenergic nerve.     

Noradrenaline increases high-frequency firing at the calyx of held synapse during development by inhibiting glutamate release

The mammalian auditory brain stem receives profuse adrenergic innervation, whose function is poorly understood. Here we investigate, during postnatal development, the effect of noradrenaline (NA) at the calyx of Held synapse in the rat medial nucleus of the trapezoid body (MNTB). We observed that NA inhibits the large glutamatergic EPSC, evoked by afferent fiber stimulation, in a dose-dependent manner. The inhibition was maximal (approximately 48%) at the concentration of 2 microM. It was antagonized by yohimbine and mimicked by the alpha2-adrenergic specific agonist UK14304. Both AMPA and NMDA receptor-mediated EPSCs were inhibited in parallel by NA, suggesting a presynaptic effect. Presynaptic recordings showed that NA inhibits the action potential (AP) generated Ca current by about 20%; however, NA did not significantly affect the presynaptic AP waveform. We thus conclude that the calyx of Held presynaptic terminal expresses alpha2-adrenergic receptors that inhibit its Ca current and thus glutamate release. Noradrenaline was effective in all cells tested from postnatal days 6 to 7 (P6-P7), and thereafter the number of responsive cells diminished, although half of the P14 cells tested still had EPSCs that were inhibited by NA. By contrast, activation by L-2-amino-5-phosphonovaleric acid-sensitive metabotropic glutamate receptors strongly inhibited the EPSCs of all cells tested from P6 to P14. The effect of NA on postsynaptic action potential firing was dependent on the stimulus frequency. At 10 Hz, NA had no effect on firing probability; however, NA helped MNTB cells fire more action potentials during a 100-Hz train of stimuli, even though it did not increase the steady-state depressed EPSC, because it produced a smaller N-methyl-D-aspartate (NMDA) receptor-activated depolarizing plateau. We therefore suggest that the reduction by NA of the first few EPSCs in a train leads to a smaller NMDA depolarizing plateau and thus to increased firing probability at 100 Hz in young synapses. Surprisingly, the inhibition of glutamate release by NA can thus actually increase the excitability of MNTB neurons during early postnatal development.     

Effects of Mg2+ and Ca2+ on Noradrenaline Release and Uptake in Adrenergic Nerve Granules in Different Media

Euler , U. S. V. and F. Lishajko . Effects of Mg²⁺ and Ca²⁺ on noradrenaline release and uptake in adrenergic nerve granules in different media. Acta physiol. scand. 1973. 89. 415–422. Uptake and release of noradrenaline (NA) from a suspension of storage granules from bovine splenic nerves was measured after incubation in various media and effects of added Mg²⁺ and Ca²⁺ observed. No significant differences in NA release rate were observed in different media when NA uptake was prevented by addition of potassium ferricyanide to the medium. Uptake was facilitated by phosphate ions 5–30 mM but counteracted by monovalent cations. In sucrose-phosphate media uptake of NA almost balanced spontaneous release. Mg²⁺ and Ca²⁺ had only a small action on NA release in the absence of NA uptake. In sucrose phosphate media Mg²⁺ facilitated uptake, whereas Ca²⁺ enhanced NA release. This action was associated with the formation of a calcium phosphate precipitate. No release or uptake of NA was observed during incubation at ice-water temperature, nor did Mg²⁺ or Ca²⁺ have any effect. The results tend to show that release and uptake of NA in storage granules are separate, temperature-dependent processes, influenced by mono- and divalent cations and phosphate ions.     

Relationship between the overflow of endogenous and radiolabelled noradrenaline from canine blood perfused gracilis muscle

The effects of sympathetic nerve stimulation (SNS) on the overflow of endogenous noradrenaline (NA) and on vasoconstrictor responses were studied in blood perfused canine gracilis muscle in situ. A conventional tracer technique with 3H-labelled NA (3H-NA) was used in parallel. At rest there was a net extraction of endogenous NA and adrenaline across the tissue. The SNS evoked overflow of endogenous NA was frequency-dependent and logarithmically correlated to the vasoconstrictor responses. The neuronal uptake inhibitor desipramine doubled the SNS induced overflow of endogenous NA without enhancing the vasoconstrictor responses. A further fourfold increase in NA overflow was caused by a dose of the alpha-blocker phenoxybenzamine which reduced the vasoconstrictor responses by 50-75%. Less than 10% of the spontaneous 3H efflux was recovered as unmetabolized 3H-NA, whereas virtually all 3H overflow evoked by SNS was 3H-NA. The fractional release of NA or 3H-NA per nerve impulse increased with increasing frequencies of SNS under all conditions studied. Although there was a preferential release of the newly stored radiolabelled transmitter, results concerning endogenous NA and 3H-NA overflow were qualitatively similar, also under conditions with marked changes in transmitter overflow. Endogenous NA gave a more reproducible index of transmitter overflow than did 3H-NA and, in particular, total 3H. The overflow of endogenous NA closely reflects SNS evoked neuronal release of NA in blood perfused skeletal muscle and seems more suitable than conventional radiotracer techniques for studies of NA release under in vivo conditions.     

Neuropeptide Y is released together with noradrenaline from the human heart during exercise and hypoxia

The myocardial release of neuropeptide Y-like immunoreactivity (NPY-LI) and noradrenaline (NA) during exercise with and without arterial hypoxia was measured in 18 healthy men by arterial (a) and coronary sinus (cs) catheterization. Exercise was performed in the supine position on a cycle ergometer at a load, selected to produce a heart rate during air breathing of 120 beats min-1. Coronary sinus blood flow (CSBF) was measured and a and cs samples for NPY-LI, NA, oxygen and lactate analyses were taken at rest and after 6 min exercise. The inspiratory gas was then switched to 15% (n = 8) or 12% (n = 10) oxygen in nitrogen, exercise continued at the same load and measurements repeated after 6 min. At rest no significant release and during normoxic exercise a very small myocardial release of NPY-LI and NA was detected. During hypoxia compared to normoxia the cardiac NPY-LI release increased four-fold and the NA net release doubled at the same time as the arterial NPY-LI remained unaltered or only slightly increased. Both the NPY-LI and the NA net release from the heart correlated with the heart rate and the arterial but not the cs oxygen tension. The NPY-LI release was correlated with the NA net release. The findings suggest that arterial hypoxia stimulates cardiac NPY together with NA release which derives from local sympathetic nerves. The release from the heart seems to be greater than from other tissues.     

Effects of noradrenaline and flow on lactate uptake in the perfused rat hindlimb

Skeletal muscle can release or take up lactate depending on the lactate concentration gradient across the cell membrane. In the perfused rat hindlimb without arterial lactate, both noradrenaline (NA) infusion and increased flow promote lactate release and oxygen consumption (VO ₂). However, it is unclear whether NA or increased flow rate have similar effects on lactate uptake. The present study compares these effects in the rat hindlimb perfused at a basal flow rate of 0.33 mL min^?1 g^?1 and 25 °C in the presence of added arterial lactate. When 10 mmol L^?1 L-(+)-lactate was added to the arterial perfusate, lactate was taken up (16 ± 1.0 μmol g^?1 h^?1, n = 13) by the hindlimb with a 35% higher VO ₂ than that without added lactate. Doubling perfusion flow rate enhanced lactate uptake and VO ₂ by 120% and 40%, respectively. Glucose uptake was also increased (by 253%) with increased flow. Infusion of NA increased perfusion pressure, VO ₂ and glucose uptake similarly to those induced by increased flow rate. However, lactate uptake was inhibited by NA. This inhibition was not altered by the β-adrenergic antagonist propranolol. Vasopressin also showed similar effects to NA to decrease lactate uptake associated with increased VO ₂ and vasoconstriction. These data indicate that in the presence of a high arterial lactate concentration, NA has opposite effects from increased flow rate on skeletal muscle lactate uptake although both have similar effects on lactate release in the absence of arterial lactate. Inhibition of lactate uptake may relate to the vasoconstrictive action of NA.     

Prejunctional beta 2-adrenoreceptor blockade reduces nerve stimulation evoked release of endogenous noradrenaline in skeletal muscle in situ

Prejunctional beta-adrenoceptor-mediated modulation of endogenous noradrenaline (NA) overflow elicited by sympathetic nerve stimulation was studied in blood-perfused canine gracilis muscle in situ. An attempt was made to subclassify these beta-adrenoceptors by comparing the effects of beta 1-selective (metoprolol) and non-selective (propranolol) beta-adrenoceptor blockade. Animals were pre-treated with desipramine and phenoxybenzamine in order to counteract possible influences of neuronal uptake and stimulation-evoked changes in vascular resistance on the diffusion of NA into the blood stream. Metoprolol did not decrease stimulation-evoked NA overflow, as compared with control experiments (-10 and -8%, respectively). However, propranolol reduced stimulation-evoked NA overflow by 30% in metoprolol pre-treated animals (P less than 0.05 vs. control experiments). Both antagonists elevated basal perfusion pressure, suggesting that vascular post-junctional beta 1- as well as beta 2-adrenoceptors are present. Propranolol increased stimulation-evoked vasoconstriction in metoprolol pre-treated animals, indicating that neuronally released NA may activate postjunctional beta 2-adrenoceptors under these experimental conditions. In conclusion, our findings suggest that NA release can be enhanced by activation of prejunctional beta 2-adrenoceptors in vivo.     

Postnatal development of noradrenergic terminals in the rat trigeminal motor nucleus: A light and electron microscopic immunocytochemical analysis

The noradrenergic (NA) innervation in the trigeminal motor nucleus (Vmot) of postnatal and adult rats was examined by light and electron microscopic immunocytochemistry using antibodies against dopamine‐β‐hydroxylase or tyrosine hydroxylase. NA fibers were identified in the Vmot as early as the day of birth (postnatal day 0; P0). A continuous increase in the density of labeled fibers was observed during development up to P20, with a slight decrease at P30 and in the adult. Electron microscopic analysis of serial ultrathin sections revealed that, at P5, nearly half (46%) of the examined NA terminals made synaptic contact with other neuronal elements with membrane specializations. The percentage of examined NA varicosities engaged in synaptic contacts increased at P15 (74%), then decreased in the adult (64%). At all developmental ages, the majority of contacts made by these boutons were symmetrical, the postsynaptic elements being mainly dendrites and occasionally somata. Interestingly, some of the NA terminals made axo‐axon contacts with other unidentified boutons. These results show that, although the density of NA fibers increases during postnatal development, functional NA boutons are present in the Vmot at early postnatal ages. Some of these fibers might exert their effects via nonsynaptic release of noradrenaline, the so‐called volume transmission, but, in the main, they form conventional synaptic contacts with dendrites, somata, and other axonal terminals in the Vmot. These results are consistent with previous electrophysiological studies that propose an important role for the NA system in modulating mastication. Anat Rec, 290:96–107, 2007. © 2006 Wiley‐Liss, Inc.     

Spike conduction properties of T-shaped C neurons in the rabbit nodose ganglion

Noradrenaline (NA) and angiotensin II (A II) were infused intravenously in conscious dogs without (series I) and with (series II) additional infusions of sodium nitroprusside at doses re-establishing normal levels of mean arterial pressure (MAP). In series I, NA infusion (1.6 g/min per kg for 30 min) initially elevated MAP by some 25 mm Hg and lowered heart rate by some 30 beats/min. Plasma concentrations of arginine vasopressin (AVP) remained constant, while those of A II and atrial natriuretic factor were slightly, but significantly, increased. Infusion of A II (10 or 20 ng/min per kg for 30 min) induced similar rises in MAP and slight reductions of heart rate and increased plasma AVP by 70% and atrial natriuretic factor by 60%. In series II, sodium nitroprusside (1–4 g/min per kg) was added for 30 min to infusions of NE (1.6 g/min per kg) and A II (20 ng/min per kg) in order to maintain MAP at its control level. This resulted in an 11-fold increase in plasma AVP during NA infusion and a 19-fold increase during A II infusion. Infusing sodium nitroprusside (4 g/min per kg) alone lowered MAP to clearly hypotensive levels, but the resulting rises in plasma AVP were less than, rather than equal to, those seen at normotensive MAP levels during the combined infusions of sodium nitroprusside with A II or NA, respectively. It is concluded that both NA and A II exert strong stimulatory actions on AVP release which are, however, counteracted by inhibitory influences arising from the hypertensive effects of NA and A II.     

Sympathetic vascular control of the pig nasal mucosa (III): co-release of noradrenaline and neuropeptide Y

The overflows of noradrenaline (NA) and neuropeptide Y like immunoreactivity (NPYLI) and vascular responses upon sympathetic nerve stimulation were analysed in the nasal mucosa of pentobarbital anaesthetized pigs. In controls, a frequency-dependent increase in NA overflow was observed whereas detectable release of NPY-LI occurred only at 6.9 Hz. Parallel decreases in blood flow in the sphenopalatine artery and vein and in nasal mucosa volume (reflecting blood volume in the venous sinusoids) were observed. The laser Doppler flowmeter signal (reflecting superficial blood flow) increased upon low and decreased upon high frequency stimulation. Twenty-four hours after reserpine pretreatment and preganglionic decentralization, the NA overflow was abolished while a frequency-dependent release of NPY-LI occurred. Forty, 60 and 80% of the vasoconstrictor responses then remained upon stimulation with a single impulse, 0.59 and 6.9 Hz, respectively. Both the vasoconstriction and NPY-LI overflow, however, were subjected to fatigue upon repeated stimulation. In reserpinized animals release of NPY-LI and vasoconstrictor responses were larger upon stimulation with irregular bursts at 0.59 Hz compared to effects seen at stimulation with continuous impulses. Pre-treatment with the a-adrenoceptor antagonist phenoxybenzamine or the monoamine reuptake inhibitor, desipramine, enhanced NA overflow by 2–3 and 1.5 times at 0.59 and 6.9 Hz, respectively. Phenoxybenzamine significantly reduced the nerve-evoked vascular responses while the release of NPY-LI at 6.9 Hz was increased. Desipramine increased the functional responses but reduced the NPY-LI overflow. During tachyphylaxis to the vasoconstrictor effects of the stable adenosine 5′-triphosphate (ATP) analogue α-β-methylene ATP (mATP) in controls, the vasoconstrictor responses as well as the NA and NPY-LI overflow to nerve stimulation were unmodified. In reserpinized animals, however, the vascular responses and the overflow of NPY-LI were reduced after mATP tachyphylaxis. These data show that both NA and NPY are released upon sympathetic nerve stimulation in the nasal mucosa in vivo and this release seems to be regulated via prejunctional a-adrenoceptors. The lack of effect of mATP tachyphylaxis under control conditions makes it less likely that ATP serves as a major mediator of the large nonadrenergic vasoconstrictor component.