Neuropeptide Y (NPY) and the pig heart: release and coronary vasoconstrictor effects

The effects of electrical stimulation of the stellate ganglia on the arterio-venous concentration differences of neuropeptide Y (NPY)-like immunoreactivity (LI) over the pig heart were studied in vivo in relation to changes in heart rate and left ventricular pressure. Furthermore, the effects of NPY on coronary vascular tone were analysed in vivo and in vitro. Stellate ganglion stimulation at a high frequency (10 Hz) caused a clear-cut, long lasting increase in plasma levels of NPY-LI in the coronary sinus compared to the aorta, suggesting release of this peptide from sympathetic terminals within the heart. The stimulation-evoked overflow of NPY-LI from the heart was enhanced about 3-fold by alpha-adrenoceptor blockade using phenoxybenzamine, suggesting that NPY release is under prejunctional inhibitory control by noradrenaline (NA). Combined alpha- and beta-adrenoceptor blockade abolished most of the positive inotropic response of the heart upon stellate ganglion stimulation, while a considerable positive chronotropic effect remained. After guanethidine treatment, stellate ganglion stimulation still produced a small positive inotropic and chronotropic effect on the heart. The stimulation evoked NPY overflow was markedly reduced by guanethidine indicating an origin from sympathetic nerve terminals. Injection of NPY into the constantly perfused left anterior descending artery in vivo caused a long lasting, adrenoceptor antagonist resistant increase in perfusion pressure, suggesting coronary vasoconstriction. NPY contracted coronary arteries in vitro via a nifedipine-sensitive mechanism. NA dilated coronary vessels both in vivo and in vitro via beta-adrenoceptor activation. It is concluded that sympathetic nerve stimulation increases overflow of NPY-LI from the heart suggesting release from cardiac nerves in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)     

Presynaptic effects of neuropeptide Y on [3H]noradrenaline and [3H]acetylcholine release

The electrically evoked release of radioactivity from mouse vas deferens and rat hypothalamic slices preloaded with [3H]noradrenaline was measured. In addition the release of [3H]acetylcholine from longitudinal muscle strip of guinea-pig ileum was also measured. Neurochemical evidence has been obtained that neuropeptide Y (NPY), although it co-exists and is released with (-)-noradrenaline (NA), it behaves differently as far as its effect on presynaptic modulation of chemical neurotransmission is concerned. It exerts a frequency-dependent presynaptic inhibitory effect on noradrenaline release from mouse vas deferens but has no effect on the electrically evoked release of NA from rat hypothalamus. Unlike NA, NPY does not influence the release of [3H]acetylcholine from the longitudinal muscle strip of guinea-pig ileum and does not potentiate the presynaptic effect of NA. It seems very likely, that the inhibitory effect of NPY is mediated via receptors. Its action is concentration dependent. While exogenous noradrenaline inhibited the release of noradrenaline by 91%, the maximum inhibition reached with NPY was not higher than 60%, indicating that either the intrinsic activity of NPY is lower or much less axon terminals are equipped with NPY receptors. Peptide YY (PYY) also reduced the release of NA from mouse vas deferens.     

Neuropeptide Y and sympathetic vascular control in man

A parallel increase in systemic plasma levels of neuropeptide Y (NPY)-like immunoreactivity (LI) and noradrenaline (NA) was found during thoracotomy and surgery involving cardiopulmonary bypass in man. Thus, plasma levels of NPY-LI increased from 29 +/- 4 pmol/l before anaesthesia to 59 +/- 10 after thoracotomy and to 87 +/- 8 pmol/l upon cardiopulmonary bypass. The corresponding NA levels increased from 1.3 +/- 0.1 nmol/l before anaesthesia to 3.0 +/- 0.6 and 4.2 +/- 5 nmol/l after thoracotomy and cardiopulmonary bypass, respectively. A significant correlation was found between plasma levels of NPY-LI and NA during the operation but not between NPY-LI and adrenaline. The NPY-LI in human plasma was found to be similar to synthetic porcine NPY on reversed phase high performance liquid chromatography. Human submandibular arteries contained high levels of NPY-LI (24 +/- 3 pmol/g). In in vitro experiments on isolated human submandibular arteries, NPY in low concentrations (1000 pmol/l) was found to potentiate the contractile effects of NA or transmural nerve stimulation and to exert vasoconstrictor activity per se in higher concentrations. The calcium-entry antagonist nifedipine abolished both the NPY-induced contractions and the enhancement of NA-evoked contractions. NPY depressed the nerve stimulation-evoked 3H-NA release from human submandibular arteries via a prejunctional mechanism which was resistant to nifedipine. NPY contracted human mesenteric veins and renal arteries, but not mesenteric arteries. In conclusion, NPY seems to be co-released with NA upon sympathetic activation in man. Furthermore, NPY exerts both pre- and postjunctional effects on sympathetic control of human blood vessels.     

Neuropeptide Y and catecholamine release in the piglet during hypoxia: enhancement by theophylline.

Sympathoadrenal activity was studied in 13 young piglets during hypoxia. The piglets were anaesthetized with chloralose/urethane, tracheostomized, paralyzed with gallamine and artificially ventilated. A femoral artery catheter was inserted and used for blood sampling. The piglets were challenged with 6 min of 6% CO2, 10 min of 12% O2 and 6 min of 6% O2 before and after theophylline (an adenosine receptor antagonist) treatment 20 mg/kg (n = 9) or saline (n = 4). Plasma samples were obtained before, during and after each hypercapnic or hypoxic period and analysed for their content of noradrenaline, adrenaline and neuropeptide Y. Hypercapnia with 6% CO2 and moderate hypoxia with 12% O2 did not lead to any significant increase of either noradrenaline (NA), adrenaline (A) or neuropeptide Y (NPY). However, severe hypoxia with 6% O2 increased the NA level from 30 to 66 nmol/l; the A level from 1 to 28 nmol/l and NPY from 140 to 213 pmol/l. After treatment with theophylline the baseline NA increased from 27 to 40 nmol/l, A rom 1.5 to 4.0 and NPY concentration from 65 to 171 pmol/l. Theophylline moderately enhanced the release of NPY, NA and A during the 12% O2 challenge. However, during the severe hypoxia (6%), the increase of NA (from 49 to 333 nmol/l), A (from 8 to 214 nmol/l) and NPY (from 184 to 385 pmol/l) showed considerably enhancement after the theophylline treatment. The results obtained before and after saline were similar showing that the duration of the experiments per se did not change the baseline levels or the effect of the challenges on NA, A or NPY levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Innervation of human omental arteries and veins and vasomotor response to noradrenaline, neuropeptide Y, substance P and vasoactive intestinal peptide

Human omental arteries and veins are supplied with nerve fibers containing noradrenaline (NA) and neuropeptide Y (NPY); these two agents probably co-exist in perivascular sympathetic nerve fibers. Substance P (SP)- or vasoactive intestinal peptide (VIP)-containing fibers could not be detected. In studies on isolated omental vessels NA produced constriction. The results of blockade experiments suggest that human omental arteries are equipped predominantly with alpha 1-adrenoceptors and omental veins with a mixture of alpha 1- and alpha 2-adrenoceptors. NPY at a concentration of 10(-7) M or higher had a weak contractile effect on veins and virtually no effect on arteries. NPY at a concentration of 3 X 10(-8) M shifted the NA concentration response curve to the left in arteries (pD2 = 5.8 for NA versus 6.6. for NA in the presence of NPY; P less than 0.001) but not in veins. Both SP and VIP relaxed arteries precontracted with NA or prostaglandin F2 alpha (PGF2 alpha). The potency of SP as a relaxant agent was similar in arteries and veins; the effect of VIP was elicited at lower concentrations in veins than in arteries.     

神经肽Y和去甲肾上腺素在杏仁内侧核内影响血压和心率中的相互作用

分别向杏仁内侧核（ＭＡＮ）内微量注射去甲肾上腺素（ＮＡ）或神经肽Ｙ（ＮＰＹ）。ＮＡ引起血压升高,心率加快;而ＮＰＹ引起血压降低,心率减慢。如果注入不能改变血压的小剂量ＮＰＹ,则可抑制ＮＡ引起的升压作用,反映ＮＰＹ与ＮＡ共同参与心血管活动的中枢性调节过程。向ＭＡＮ中注射ＮＰＹ后血中ＮＡ的含量也相应降低,表明在ＭＡＮ中注射ＮＰＹ引起的血压、心率反应是通过降低血浆中ＮＡ含量而实现的。     

Cardiovascular effects of neuropeptide Y in the nucleus tractus solitarius of rats: relationship with noradrenaline and vasopressin

The central haemodynamic effects of neuropeptide Y (NPY), both alone and together with either noradrenaline (NA) or vasopressin (AVP), have been investigated by microinjecting synthetic peptide into the nucleus tractus solitarius (NTS) of anaesthetized rats. NPY alone elicited dose-dependent changes in blood pressure (BP) and heart rate (HR); 470 fmol inducing a pressor response, and 4.7 pmol a fall in BP. The hypotensive response to 20 nmol NA was significantly modified by both simultaneous and prior injection of an ineffective dose (47 fmol) of NPY. Prior injection of a similar dose of NPY also modified the NTS pressor effect of 10 ng AVP. A relationship between the action of AVP and NPY in the NTS was further indicated by the finding that prior injection of an ineffective dose of AVP (1 ng) reduced the hypotensive response to 4.7 pmol NPY, and by the demonstration of contrasting effects of 4.7 pmol NPY in AVP-deficient Brattleboro rats compared to parent strain LE rats. These results, taken together with the recent localization of NPY-like immunoreactivity in the NTS, suggest a role for NPY in central cardiovascular control. In addition, NPY has been shown to exhibit functional interactions with both an amine neurotransmitter and a neuropeptide present in the NTS of rats.     

Stress-induced changes of circulating neuropeptide Y in the rat: comparison with catecholamines

Circulating concentrations of neuropeptide Y-like immunoreactivity (NPY), noradrenaline (NA) and adrenaline (AD) were measured in conscious, chronically catheterized rats submitted to various stress protocols. Basal plasma levels of NPY, NA and AD (194 +/- 52 fmol/ml, 0.90 +/- 0.11 pmol/ml and 0.52 +/- 0.07 pmol/ml) were increased by handling (+132%, +76% and +629%, respectively) and rose further during electric shock treatment. Adrenalectomy resulted in the complete disappearance of circulating adrenaline but did not alter either control or stress values of noradrenaline. In comparison circulating levels of NPY were reduced, but not significantly in adrenalectomized animals. Insulin stress induced a large increase in plasma AD levels and cold stress induced an increase in plasma NA levels, without any parallel change in NPY concentrations. These results demonstrate that NPY, which is colocalized with catecholamines in the peripheral nervous systems, is also released during stress responses and that its release parallels more closely changes in circulating NA than AD. Furthermore, stress-induced changes in circulating NPY-like immunoreactivity do not originate from the adrenal gland but mainly from the peripheral nervous system, and the release of NPY is dependent upon the nature of the stimulus.     

Roles of neuropeptide Y and noradrenaline in sympathetic neurotransmission to the thoracic vena cava and aorta of guinea-pigs.

The roles of neuropeptide Y (NPY) and noradrenaline (NA) in sympathetic neurotransmission to large arteries and veins were studied in vitro using the thoracic portions of the aorta and inferior vena cava from guinea-pigs. Both vessels are densely innervated by axons containing NA and NPY. Repetitive transmural stimulation at 2-30 Hz produced contractions of the aorta, which were abolished by prazosin. NPY did not have significant postsynaptic or presynaptic effects on vascular tone of the aorta. Transmural stimulation of the vena cava produced long-lasting contractions which were enhanced by alpha- and beta-adrenoceptor antagonists, and were blocked by guanethidine. Precontracted venae cavae responded to sympathetic stimulation with beta-adrenoceptor-mediated relaxation, followed by contraction. alpha-Adrenoceptor blockade delayed the onset of neurogenic contractions. NPY was a potent contractile agent of the vena cava (EC50 approximately 1.5 x 10(-8) M). A high concentration (3 x 10(-6) M) of NPY, or the specific NPY Y1 receptor agonist, [Leu31, Pro34]NPY, caused parallel, and reversible, desensitization of contractions produced by sympathetic nerve stimulation, and by low concentrations of exogenous NPY. This provides good evidence that NPY is the mediator of the non-adrenergic sympathetic contractions of the vena cava. Furthermore, these results demonstrate that differential location or coupling of postsynaptic receptors for NA and NPY in the aorta and vena cava, leads to differential participation by these substances in sympathetic vasomotor responses. This is likely to be related to the different functions of these two parts of the systemic circulation.     

Storage and fast transport of noradrenaline, dopamine beta-hydroxylase and neuropeptide Y in dog sciatic nerve axons.

The axonal transport and subcellular distribution of noradrenaline (NA), dopamine beta-hydroxylase (DBH) and neuropeptide Y (NPY) were determined in dog sciatic nerve using an accumulation technique. The results were compared with those obtained by application of the same procedures and methods on the splenic nerve in the same animal species. Evidence was found for the coexistence of NA and NPY in large dense-cored vesicles in dog sciatic nerve axons. After differential centrifugation and isopyenic sucrose density gradient centrifugation of 24 h ligated sciatic nerve pieces NA and NPY equilibrated around 1M sucrose. The DBH activity was dispersed broadly on the gradient. Subsequently, the accumulation of NA, DBH and NPY was studied in proximal and sital segments of 8, 12 and 24 h dog ligated sciatic nerve and inferences were made concerning the axonal transport of these compounds. NA, DBH and NPY displayed a divergent accumulation proximal to the ligation. After 12 h of ligation a transport rate was calculated of 4.8 +/- 1.8 mm/h for NA, of 5.9 +/- 1.5 mm/h for DBH and of 4.9 +/- 2.0 mm/h for NPY. With a correction for the stationary fractions, a similar fast transport rate of approximately 10 to 12 mm/h was proposed for NA, DBH and NPY. The occurrence was shown of a limited retrograde transport of DBH and possibly NPY, but not of NA.     

The role of adenosine A2A and A3 receptors on the differential modulation of norepinephrine and neuropeptide Y release from peripheral sympathetic nerve terminals

The pre-synaptic sympathetic modulator role of adenosine was assessed by studying transmitter release following electrical depolarization of nerve endings from the rat mesenteric artery. Mesentery perfusion with exogenous adenosine exclusively inhibited the release of norepinephrine (NA) but did not affect the overflow of neuropeptide Y (NPY), establishing the basis for a differential pre-synaptic modulator mechanism. Several adenosine structural analogs mimicked adenosine's effect on NA release and their relative order of potency was: 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride = 1-[2-chloro-6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-1-deoxy-N-methyl-beta-d-ribofuranuronamide = 5'-(N-ethylcarboxamido)adenosine > adenosine > N(6)-cyclopentyladenosine. The use of selective receptor subtype antagonists confirmed the involvement of A(2A) and A(3) adenosine receptors. The modulator role of adenosine is probably due to the activation of both receptors; co-application of 1 nM 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride plus 1 nM 1-[2-chloro-6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-1-deoxy-N-methyl-beta-D-ribofuranuronamide caused additive reductions in NA released. Furthermore, while 1 nM of an A(2A) or A(3) receptor antagonist only partially reduced the inhibitory action of adenosine, the combined co-application of the two antagonists fully blocked the adenosine-induced inhibition. Only the simultaneous blockade of the adenosine A(2A) plus A(3) receptors with selective antagonists elicited a significant increase in NA overflow. H 89 reduced the release of both NA and NPY. We conclude that pre-synaptic A(2A) and A(3) adenosine receptor activation modulates sympathetic co-transmission by exclusively inhibiting the release of NA without affecting immunoreactive (ir)-NPY and we suggest separate mechanisms for vesicular release modulation.     

Gonadal steroids and neuropeptide Y-opioid-LHRH axis: interactions and diversities

We report that the two classes of regulatory neuropeptides, neuropeptide Y (NPY) and endogenous opioid peptides (EOP), modulate luteinizing hormone (LH) release in diverse fashion in gonad-intact rats. Each neuropeptide acts at two loci, the hypothalamus and pituitary, to excite (NPY) or inhibit (EOP) LH release. At the hypothalamic level, NPY stimulates luteinizing hormone releasing hormone (LHRH) release, a response mediated by alpha 2-adrenoreceptors and amplified in the presence of adrenergic agonists. At the pituitary level, NPY acts in concert with LHRH to amplify the LH response. In contrast, EOP inhibit LHRH release by decreasing the supply of excitatory adrenergic signals in the vicinity of LHRH neurons in the preoptic-tuberal pathway, and at the pituitary level, they decrease LH release in response to LHRH. Further, the gonadal steroidal milieu facilitates NPY neurosecretion and postsynaptic expression of NPY in concert with adrenergic system; a similar clear-cut facilitatory effect of gonadal steroids on EOP secretion is not yet obvious. Our additional studies imply that the EOP system has the potential to increase sensitivity towards gonadal steroids and that to induce the preovulatory LH surge the neural clock may decrease the inhibitory EOP tone prior to the critical period on proestrus. This antecedent neural event allows the excitatory adrenergic and NPY signals to evoke LHRH secretion at a higher frequency approximating that seen in ovariectomized rats. Further studies are under way to delineate the steroid-induced subcellular events that integrate the action of these regulatory peptides in the control of the episodic LHRH secretion pattern which sustains basal and cyclic gonadotropin release in the rat.     

Vasoconstrictor effects in vivo and plasma disappearance rate of neuropeptide Y in man

Vascular effects of neuropeptide Y (NPY) and noradrenaline (NA) were studied in six human volunteers. Systemic infusion of human NPY for 40 min (5 pmol X kg-1 X min-1) increased arterial plasma NPY-like immunoreactivity (NPY-LI) from 12 +/- 2 to 356 +/- 30 pM. This concentration caused no systemic cardiovascular effects. The disappearance curve for NPY-LI was biphasic; the slopes of the two phases corresponding to half lives of 4.1 +/- 0.4 and 20 +/- 2 min respectively. Close i.a. infusion of human NPY in the forearm caused a slowly developing and dose dependent decrease in forearm blood flow (FBF) and increase in venous tone with maximal values of 44 +/- 6 and 235 +/- 81% of control respectively at 5 nmol X min-1. The corresponding values for NA (5 nmol X min-1) were 21 +/- 9 and 489 +/- 78% of control. A threshold concentration for a decrease in FBF was obtained at a plasma NPY-LI of 3.7 +/- 0.6 nM. The decrease in FBF caused by NPY was maintained for a much longer period compared to that of NA.     

NPY and NPY Y1 receptor effects on noradrenaline overflow from the rat brain in vitro

Neurotransmitters and neuropeptides play important roles in the regulation of various neuroendocrine functions particularly feeding. The aim of this study was to investigate whether a functional interaction occurs among neuropeptide Y (NPY) at NPY Y₁ receptors and noradrenaline overflow, as this may contribute to the regulation of appetite. The release of endogenous noradrenaline and its metabolite 3,4-dihydroxyphenylglycol (DHPG) were examined from hypothalamic and medullary prisms using the technique of in vitro superfusion and high performance liquid chromatography (HPLC) with coulometric detection. Noradrenaline and DHPG overflow was investigated at rest, in response to NPY (0.1 μM) and in response to the NPY Y₁ receptor agonist, [Leu³¹,Pro³⁴]NPY (0.1 μM). Perfusion with NPY and [Leu³¹,Pro³⁴]NPY significantly reduced noradrenaline overflow from the hypothalamus and medulla. Perfusion with NPY and [Leu³¹,Pro³⁴]NPY was without significant effect on hypothalamic DHPG overflow, while medullary DHPG overflow was significantly reduced by NPY and [Leu³¹,Pro³⁴]NPY. Results from this study provide evidence of NPY Y₁ receptor-mediated inhibition of noradrenaline release in the hypothalamus and medulla, further illustrating a complex interaction between neurotransmitters and neuropeptides within the rat brain.     

Neuropeptide Y,enkephalin and noradrenaline coexist in sympathetic neurons innervating the bovine spleen

Summary The subcellular distribution of noradrenaline (NA), neuropeptide Y (NPY), Met and Leu-enkephalin (ENK), substance P (SP), somatostatin (SOM), and vasoactive intestinal polypeptide (VIP) was investigated in homogenates of bovine splenic nerve. The distribution of noradrenergic peptide-containing nerves in the bovine celiac ganglion, splenic nerve and terminal areas in spleen was studied by indirect immunofluorescence histochemistry using antisera to tyrosine hydroxylase (TH), dopamine--hydroxylase (DBH), NPY, enkephalin peptides, SP, SOM, VIP and peptide HI (PHI).After density gradient centrifugation, high levels of NPY and ENK-like immunoreactivity (LI) were found in high-density gradient fractions, coinciding with the main NA peak. SP, SOM and VIP were found in fractions with a lower density, VIP being also enriched in a heavy fraction; the latter three peptides were present in low concentrations.Immunohistochemistry revealed that staining for NPYLI and ENK-LI partly overlapped that for TH and DBH in celiac ganglia, splenic nerve axons and terminal areas of spleen. Almost all principal ganglion cells were TH- and DBH-immunoreactive. Many were also NPY-immunoreactive, whereas a smaller number were ENK-positive. In the celiac ganglion patches of dense SP-positive networks and some VIP/PHI- and ENK-immunoreactive fibers were seen around cell bodies.The results indicate that NPY and ENK are stored with NA in large dense-cored vesicles in unmyelinated axons of bovine splenic nerve. SP, SOM and VIP appear in different organelles in axon populations separate from sympathetic noradrenergic nerves.     

Neuropeptide Y stimulates DNA synthesis in human vascular smooth muscle cells through neuropeptide Y Y1 receptors

We investigated the mitogenic effect, measured as [3H]thymidine incorporation, of neuropeptide Y (NPY) on smooth muscle cells (SMCs) from human subcutaneous arteries (diameter: 0.4 mm). NPY stimulated DNA synthesis in a concentration-dependent manner, Emax 32 +/- 5% relative to control. The effect was potently antagonised by the NPY Y1 receptor antagonist BIBP3226 ((R)-N2-(diphenylacetyl)-N-[(4-hydroxy-phenyl)methyl]-D-arginine-a mide), indicating the effect to be mediated via the NPY Y1 receptor. Noradrenaline (NA) also induced mitogenesis, Emax 35 +/- 10% relative to control. When added together, NPY and NA potentiated the [3H]thymidine incorporation, Emax 109 +/- 38% relative to control. Also, this effect seems to be mediated by the NPY Y1 receptor, since BIBP3226 blocked the effect (44 +/- 9% relative to control). The mitogenic effect of NPY and NA, two important transmitters of the sympathetic nervous system, might have clinical consequences on conditions with elevated sympathetic nerve activity.     

Partial depletion of neuropeptide Y from noradrenergic perivascular and cardiac axons by 6-hydroxydopamine and reserpine

The effects of 6-hydroxydopamine (6-OHDA) and reserpine on the storage of neuropeptide Y (NPY) in noradrenergic cardiovascular nerves were examined with both immunohistochemistry and radioimmunoassay (RIA). Immunohistochemical double-labelling techniques demonstrated that NPY was located only in noradrenergic axons in the guinea-pig carotid artery, mitral valve, thoracic inferior vena cava, thoracic aorta, superior mesenteric artery and small saphenous vein. Treatment with 6-OHDA in vivo eliminated noradrenergic, NPY-containing axon terminals from all tissues, but preterminal axons were still prominent in the superior mesenteric artery. The greatest depletion of NPY detected by RIA after 6-OHDA treatment was found in tissues with a predominance of terminal noradrenergic axons, such as the small saphenous vein, whereas NPY accumulating in preterminal axons masked the loss of NPY from terminal axons in the superior mesenteric artery. After treatment with doses of reserpine that led to a rapid depletion of noradrenaline (NA) from perivascular nerves, NPY was still detected histochemically at all times although levels sometimes appeared to be reduced. RIA demonstrated that the partial depletion of NPY after reserpine consisted of a rapid phase seen in the vena cava and saphenous vein after the highest doses, and a slower phase of NPY depletion from all tissues after all doses of reserpine. The greatest depletion of NPY from terminal axons by reserpine (in small saphenous vein) was 85-90%. These results demonstrate that some NPY can be stored in noradrenergic perivascular axons in the absence of noradrenaline, but that partial depletion of NPY from axon terminals results when NA stores are depleted by reserpine. The variation in extent of NPY depletion between tissues after drug treatments can be explained by variation in the ratio of preterminal to terminal axons.     

Effects of neuropeptide Y on LH, FSH and TSH release in male rats

These experiments were undertaken to investigate the effects of systemically administered neuropeptide Y (NPY) on gonadotropin secretion in the intact male rat and to determine whether the effects observed might be mediated by a direct action of NPY alone on the anterior pituitary gland (APG). Subcutaneous administration of 10 micrograms of NPY caused a greater than 2-fold increase in serum luteinizing hormone (LH) concentration at 15 min after injection but was without effect on serum follicle-stimulating hormone (FSH) or thyrotropin-stimulating hormone (TSH) levels. The addition of NPY (final concentrations of 10(-8) to 10(-11) M) or the structurally similar neuropeptide, rat pancreatic polypeptide, to culture medium containing hemi-APG did not alter the release of LH, FSH, or TSH. The results indicate that systemically administered NPY can elevate serum LH concentration in intact male rats. This effect does not appear to be due to NPY acting alone at the level of the APG.     

Neuropeptide Y: presence in perivascular noradrenergic neurons and vasoconstrictor effects on skeletal muscle blood vessels in experimental animals and man

The presence of neuropeptide Y (NPY)-like immunoreactivity (-LI) in sympathetic perivascular nerves and the functional effects of NPY and noradrenaline (NA) on vascular tone were studied in skeletal muscle of various species. A dense network of NPY-LI was found around arteries and arterioles but not venules in the gluteus maximus muscle of man, gracilis muscle of dog, tenuissimus muscle of rabbit and quadriceps muscle of cat, rat, guinea pig and pig. The distribution of NPY-immunoreactive (-IR) nerves was closely correlated to the presence of tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH)-positive fibers, two markers for noradrenergic neurons. Double-staining experiments revealed that NPY- and TH-IR as well as NPY- and DBH-IR nerve fibers around arteries and arterioles were identical. The veins and venules, however, lacked or had a very sparse innervation of NPY-, TH- and DBH-positive fibers. The NPY- and TH-IR nerves in quadriceps muscle of the guinea pig were absent after treatment with 6-hydroxydopamine. Lumbosacral sympathetic ganglia from the same species contained many NPY-positive cells which were also TH- and DBH-IR. NPY-LI was also detected by radioimmunoassay in extracts of skeletal muscle from guinea pig, rabbit, dog, pig and man as well as of lumbosacral sympathetic ganglia. The content of NPY-LI in skeletal muscle was relatively low (0.1-0.4 pmol/g), whereas lumbosacral sympathetic ganglia had a much higher content (48-88 pmol/g). NPY (10(-7) M) contracted arterioles in the tenuissimus muscle of the rabbit to a similar extent (by 65%) as NA (10(-6) M), as studied by intravital microscopy in vivo. NPY had no effect on the corresponding venules while NA caused a slight contraction of these vessels. In vitro studies of small human skeletal muscle arteries and veins revealed that NPY was more potent than NA in contracting the arteries, and the highest concentration of NPY (5 x 10(-7) M) caused a contraction of a similar magnitude as NA 10(-5) M. NA contracted veins from human skeletal muscle, while NPY had only small effects. It is suggested that NPY, together with NA, could be of importance for sympathetic control of skeletal muscle blood flow.     

alpha2-Adrenoceptors control the release of noradrenaline but not neuropeptide Y from perivascular nerve terminals

Neuropeptide Y (NPY) and noradrenaline (NA) are co-transmitters at many sympathetic synapses, but it is not yet clear if their release is independently regulated. To address this question, we quantified the electrically evoked release of these co-transmitters from perivascular nerve terminals to the mesenteric circulation in control and drug-treated rats. 6-Hydroxydopamine reduced the tissue content and the electrically evoked release of ir-NPY and NA as well as the rise in perfusion pressure. A 0.001 mg/kg reserpine reduced the content of ir-NPY and NA, but did not modify their release nor altered the rise in perfusion pressure elicited by the electrical stimuli. However, 0.1mg/kg reserpine reduced both the content and release of NA but decreased only the content but not the release of ir-NPY; the rise in perfusion pressure was halved. Clonidine did not affect the release of ir-NPY while it lowered the outflow of NA, not altering the rise in perfusion pressure elicited by the electrical stimuli. Yohimbine, did not modify the release of ir-NPY but increased the NA outflow, it antagonized the clonidine effect. Therefore, presynaptic alpha2-adrenoceptors modulate the release of NA but not NPY, implying separate regulatory mechanisms.