Splanchnic and renal vasoconstrictor and metabolic responses to neuropeptide Y in resting and exercising man

The local clearance of neuropeptide Y (NPY) and whether NPY influences splanchnic and renal metabolism in man have not been investigated previously. The influence of NPY on splanchnic and renal blood flows at physiologically elevated levels has also not been investigated. The effects of a 40-min constant NPY infusion (3 pmol kg^-1 min^-1) at rest and during 130 min of exercise (50% of Vo_2max) were studied in six healthy subjects and compared with resting and exercising subjects receiving no NPY. Blood samples were drawn from arterial, hepatic and renal vein catheters for the determination of blood flows (indicators: cardiogreen and paraaminohippuric acid [PAH]), NPY, catecholamines, glucose, lactate and glycerol. NPY infusion was accompanied by: (1) significant fractional extraction of NPY-like immunoreactivity (NPY-Li) by splanchnic tissues at rest (58±5%) and during exercise (53±6%), while no arterial–venous differences could be detected across the kidney; (2) a reduction in splanchnic and renal blood flows of up to 18 and 13% respectively (P < 0.01–0.001) at rest without any additional changes during exercise; and (3) metabolic changes as reflected in: (a) a more marked fall in arterial glucose during exercise compared to the reference group (P < 0.05); (b) a 35% lower splanchnic glucose release (P < 0.01) during exercise due to diminished glycogenolysis (P < 0.01); and (c) a lower arterial lactate level (18%P < 0.05) together with unchanged splanchnic lactate uptake during exercise, suggesting reduced lactate production by extrahepatic tissues. The disappearance of plasma NPY-Li after the infusions was biphasic with two similar half-lives at rest (4 and 39 min) and during exercise (3 and 43 min).     

Splanchnic and renal vasoconstrictor and metabolic responses to neuropeptide Y in resting and exercising man.

The local clearance of neuropeptide Y (NPY) and whether NPY influences splanchnic and renal metabolism in man have not been investigated previously. The influence of NPY on splanchnic and renal blood flows at physiologically elevated levels has also not been investigated. The effects of a 40-min constant NPY infusion (3 pmol kg-1 min-1) at rest and during 130 min of exercise (50% of VO2max) were studied in six healthy subjects and compared with resting and exercising subjects receiving no NPY. Blood samples were drawn from arterial, hepatic and renal vein catheters for the determination of blood flows (indicators: cardiogreen and para-aminohippuric acid [PAH]), NPY, catecholamines, glucose, lactate and glycerol. NPY infusion was accompanied by: (1) significant fractional extraction of NPY-like immunoreactivity (NPY-Li) by splanchnic tissues at rest (58 +/- 5%) and during exercise (53 +/- 6%), while no arterial-venous differences could be detected across the kidney; (2) a reduction in splanchnic and renal blood flows of up to 18 and 13% respectively (P less than 0.01-0.001) at rest without any additional changes during exercise; and (3) metabolic changes as reflected in: (a) a more marked fall in arterial glucose during exercise compared to the reference group (P less than 0.05); (b) a 35% lower splanchnic glucose release (P less than 0.01) during exercise due to diminished glycogenolysis (P less than 0.01); and (c) a lower arterial lactate level (18% P less than 0.05) together with unchanged splanchnic lactate uptake during exercise, suggesting reduced lactate production by extrahepatic tissues. The disappearance of plasma NPY-Li after the infusions was biphasic with two similar half-lives at rest (4 and 39 min) and during exercise (3 and 43 min).     

Co-existence of neuropeptides and differential inhibition of vasodilator responses by neuropeptide Y in guinea pig uterine arteries

The co-localization of substance P (SP) with calcitonin gene-related peptide (CGRP), and vasoactive intestinal peptide (VIP) with neuropeptide Y (NPY) of the guinea pig uterine artery were investigated with immunocytochemistry. The SP/CGRP fibre population was distinct from the VIP/NPY fibre population. Both types of fibres ran in the medial-adventitial border, and appeared as coarsed and fine varicosed. Uterine arterial dilatation was evoked by acetylcholine (ACh), SP, CGRP, and VIP in precontracted arteries as examined by a sensitive in vitro method. Strong relaxations were seen by ACh, CGRP and VIP. NPY had no relaxant effect per se but was found to be a potent inhibitor of vasodilation induced by ACh and SP, while relaxations induced by VIP and CGRP were unaffected. The functional significance of NPY in the uterine artery may to a large extent be to increase tension not only by potentiation of contraction but additionally by inhibiting vasodilator responses.     

Inhibitory effect of hypertonic mannitol on vasoconstrictor and vasodilator responses of isolated coronary arteries.

The effect of hypertonic mannitol on pressor responses to vasoactive agents was studied in isolated canine coronary arteries perfused with physiologic salt solution at a constant flow. When perfusion pressure was increased with 60 mM KCl, mannitol (50 mosM) consistently caused a decrease in perfusion pressure that lasted for at least 1 h. Withdrawal of mannitol from the perfusion media was associated with a vasoconstrictor response that was not prevented by alpha- or beta-adrenoceptor blockade or by the presence of either nitroglycerin or norepinephrine. Hypertonic mannitol also reduced the responsiveness of the isolated smooth muscle preparations to several different mechanistically unrelated vasodilator agents. The mechanism(s) responsible for the paradoxical ability of hypertonic mannitol to reduce vascular responsiveness to both vasoconstrictor and vasodilator interventions in isolated canine coronary arteries is not known, but future studies should be directed at elucidating it as well as determining whether similar phenomena occur in vivo.     

C-peptide potentiates the vasoconstrictor effect of neuropeptide Y in insulin-dependent diabetic patients

Recent findings suggest that proinsulin C-peptide improves renal and nerve function as well as microcirculation in patients with insulin-dependent diabetes possibly by stimulating Na-K+-ATPase activity. Furthermore, in vitro studies on proximal rat renal tubule cells show that the effect of C-peptide on Na+, K+-ATPase activity is potentiated in the presence of the vasoconstrictor peptide neuropeptide Y. The aim of the present study was to examine whether the effects of neuropeptide Y on resting forearm blood flow in insulin-dependent patients is altered in the presence of C-peptide. Forearm blood flow was measured by a plethysmographic method in eight insulin-dependent patients and six healthy control subjects. Neuropeptide Y (20, 200 and 2000 pmol min(-1)) was infused into the brachial artery before and during an i.v. infusion of C-peptide (5 pmol kg(-1) min(-1)). Basal blood flow was 36.7 +/- 2.2 mL min(-1) L(-1) tissue. It decreased in a dose dependent manner by 11 +/- 2, 18 +/- 3 and 25 +/- 3%, respectively, during infusion of neuropeptide Y. Administration of C-peptide increased basal blood flow by 25 +/- 6%, to 46.3 +/- 3.5 mL min(-1) L(-1) tissue (P < 0.01) and forearm glucose uptake by 76 +/- 34% (P < 0.05). Infusion of the three doses of neuropeptide Y during administration of C-peptide decreased forearm blood flow by 14 +/- 4, 22 +/- 3 and 42 +/- 4%. There was a significant difference (43%, P < 0.001) between the reduction in blood flow evoked by the high dose (2000 pmol min(-1)) of neuropeptide Y before and during C-peptide infusion. Similar differences were also obtained when data were calculated as changes in vascular resistance. C-peptide did not affect resting forearm blood flow or the response to neuropeptide Y in healthy controls. In conclusion, the present data demonstrate that C-peptide increases resting forearm blood flow and augments the vasoconstrictor effects of neuropeptide Y in insulin-dependent patients.     

Vasodilator responses to alpha-human-atrial natriuretic peptide in isolated omental and pulmonary arteries from rabbit and man

In isolated vessels from the pulmonary and mesenteric/omental arterial circulations of rabbit and man, the effects of synthetic α-human atrial natriuretic peptide (α-hANP) were investigated. The vessels had an outer diameter of 0.6–1.2 mm and were contracted by noradrenaline (NA) and prostaglandin (PG) F_2α, (mesenteric/omental arteries) or by 5–hydroxytryptamine (5–HT) and PGF_2α (pulmonary arteries). It was found that in rabbits, mesenteric vessels contracted by NA and PGF_2α were not significantly relaxed by α-hANP. Rabbit pulmonary vessels contracted by PGF_2α or 5–HT were concentration-dependently relaxed by α-hANP (maximum 70%). Human omental vessels contracted by NA and PGF_2α showed a moderate (30%) relaxation after addition of the peptide. Human pulmonary arteries contracted by 5–HT were relaxed by α-hANP almost to baseline, while PGF_2α-contracted vessels showed a maximum relaxation of 65%. It is concluced that α-hANP has a relatively selective effect on pulmonary arterial vessels from rabbit as well as man. The results suggest that the peptide may be involved in the regulation of pulmonary vascular tone.     

Reserpine-induced potentiation of the inhibitory action of neuropeptide Y on the rat vas deferens neurotransmission

The inhibitory action of neuropeptide Y (NPY) on the muscular activity of the prostatic end of the rat vas deferens elicited by transmural electrical stimulation was examined in control and in reserpinized rats. Pretreatment with 1 mg/kg reserpine for 48 h induced a 6-fold increase in NPY potency. Likewise, the potency of clonidine to inhibit the electrically induced muscular activity or noradrenaline to contract the ductus musculature was also potentiated. It is hypothesized that reserpine via a denervation super-sensitivity-like process increases the density of the NPY receptors. The functional significance of NPY in the motor activity of the vas deferens is discussed.     

Sympathetic neurogenic Ca2+ signalling in rat arteries: ATP, noradrenaline and neuropeptide Y

The sympathetic nervous system (SNS) plays an essential role in the control of total peripheral vascular resistance by controlling the contraction of small arteries. The SNS also exerts long-term trophic influences in health and disease; SNS hyperactivity accompanies most forms of human essential hypertension, obesity and heart failure. At their junctions with smooth muscle cells, the peri-arterial sympathetic nerves release ATP, noradrenaline (NA) and neuropeptide Y (NPY) onto smooth muscle cells. Confocal Ca²⁺ imaging studies reveal that ATP and NA each produce unique types of postjunctional Ca²⁺ signals and consequent smooth muscle cell contractions. Neurally released ATP activates postjunctional P2X₁ receptors to produce local, non-propagating Ca²⁺ transients, termed 'junctional Ca²⁺ transients', or 'jCaTs'. Neurally released NA binds to α₁-adrenoceptors and can activate Ca²⁺ waves or more uniform global changes in [Ca²⁺]. Neurally released NPY does not appear to produce Ca²⁺ transients directly, but significantly modulates NA-induced Ca²⁺ signalling. The neural release of ATP and NA, as judged by postjunctional Ca²⁺ signals, electrical recording of excitatory junction potentials and carbon fibre amperometry to measure NA, varies markedly with the pattern of nerve activity. This probably reflects both pre- and postjunctional mechanisms, which are not yet fully understood. These phenomena, together with different temporal patterns of sympathetic nerve activity in different regional circulations, are probably an important mechanistic basis of the important selective regulation of regional vascular resistance and blood flow by the sympathetic nervous system.     

Release of neuropeptide Y upon haemorrhagic hypovolaemia in relation to vasoconstrictor effects in the pig

Neuropeptide Y is co-stored with noradrenaline in peripheral sympathetic nerves, but is not present in the adrenal chromaffin cells in the pig. Plasma levels of neuropeptide Y-like immunoreactivity and catecholamines were studied upon haemorrhagic shock in the anaesthetized pig. The animals were bled in two successive steps (30 and 10 ml kg^–), resulting in a reduction of the mean arterial blood pressure by 44% and 53 %, respectively. Plasma levels of noradrenaline increased abruptly after the first bleeding from 1.21 ± 0.27 to 26.5 ± 6.3 nmol 1^-1. Plasma neuropeptide Y showed a progressive increase from 62 ± 8 pmol 1^–1 in the basal state to 365 ± 98 pmol 1^–1 at 60 min after the first bleeding. After the second bleeding plasma neuropeptide Y and noradrenaline showed a largely parallel increase and finally reached levels of 2524 ± 580 pmol 1^–1 and 316 ± 117 nmol 1^–1, respectively. A veno-arterial gradient of neuropeptide Y and noradrenaline indicating local release was present over the spleen after both bleeding steps. The overflow of neuropeptide Y was delayed about 15 min compared to noradrenaline after the initial bleeding. Depletion of the neuropeptide Y content after shock in the heart and skeletal muscle supported local release also from these organs. Infusions of neuropeptide Y to obtain similar plasma concentrations as during shock (nM range) caused reduction in blood flow as determined by the radionuclide-labelled microsphere technique in several organs including spleen and skeletal muscle (threshold response at 319 ± 22 pmol 1^–1) but not in heart and brain. In conclusion, both neuropeptide Y and noradrenaline were markedly elevated in plasma upon haemorrhagic shock, suggesting release from sympathetic nerve terminals. Neuropeptide Y could therefore have a role as a sympathetic neurotransmitter, and during severe stress, circulating plasma levels are in the range where vasoconstriction is evoked by exogenous NPY.     

Characterization of the contractile effect of neuropeptide Y in feline cerebral arteries

The action of neuropeptide Y (NPY), which coexists with noradrenaline (NA) in perivascular sympathetic nerves, has been examined on feline cerebrovascular smooth muscle using a sensitive in vitro system. The direct cerebrovascular responses of peptides with structural similarities with NPY, peptide YY (PYY), avian (APP), and bovine (BPP) and human (HPP) pancreatic polypeptides, have been compared with that of NPY on isolated feline cerebral arteries. The relative potency for contractions induced by the peptides is: NPY, PYY greater than APP greater than BPP, HPP. The alpha-adrenoceptor antagonist rauwolscine, which blocked the response to noradrenaline (NA), had no effect on NPY-induced contractions. Neuropeptide Y significantly potentiated contractions induced by 10(-6) M NA, but not by 10(-5) M. Withdrawal of Ca2+ from the extracellular medium for 30 min reduced the contractile response to NPY in cerebral vessels by about 80%. Subsequent readdition of Ca2+ caused reproducible contractions which were inhibited by the calcium entry blocker nimodipine. Nimodipine also relaxed isolated middle cerebral artery segments contracted by NPY and NA in a concentration-dependent manner. The data suggest that NPY mediates contraction of cerebrovascular smooth muscle via a mechanism that is dependent on the concentration of extracellular calcium.     

Changes in pituitary-adrenal activity regulate the central vasodepressor responses induced by neuropeptide Y and adrenaline in the awake unrestrained male rat

The central cardiovascular responses induced by neuropeptide Y (0.25 nmol) and adrenaline (2.00 nmol) given i.c.v. in close to maximal doses in the awake, unrestrained male rat were studied following changes in the pituitary-adrenal activity. Adrenalectomy (1 week) alone significantly reduced the vasodepressor response to i.c.v. adrenaline but not to i.c.v. neuropeptide Y. Corticosterone replacement treatment (5 mg kg-1 x 2, i.p., 1 week) significantly reduced both the maximal (peak) and overall (area) vasodepressor responses to i.c.v. adrenaline and neuropeptide Y (only overall responses) in the adrenalectomized rat. Corticosterone treatment alone in the sham-operated rat highly significantly reduced the vasodepressor responses to both i.c.v. adrenaline and neuropeptide Y. The bradycardic action of centrally administered neuropeptide Y was no longer significant after alterations in pituitary-adrenal activity. The present results suggest that corticosterone treatment can abolish the centrally evoked vasodepressor responses to close to maximal doses of adrenaline and neuropeptide Y, which may contribute to their hypertensive properties in man. Finally, after adrenalectomy the central vasodepressor responses to neuropeptide Y dominate, since the adrenergic vasodepressor responses are selectively reduced. This dominance is reduced by corticosterone replacement treatment. The results indicate an antagonistic role of adrenocortical steroids in control of centrally induced acute vasodepressor responses to neuropeptide Y and adrenaline.     

Multiple neuropeptide Y receptors regulate K+ and Ca2+ channels in acutely isolated neurons from the rat arcuate nucleus

We examined the effects of neuropeptide Y (NPY) and related peptides on Ca2+ and K+ currents in acutely isolated neurons from the arcuate nucleus of the rat. NPY analogues that activated all of the known NPY receptors (Y1-Y5), produced voltage-dependent inhibition of Ca2+ currents and activation of inwardly rectifying K+ currents in arcuate neurons. Both of these effects could occur simultaneously in the same cells. In some cells, activation of Y4 NPY receptors also caused oscillations in [Ca2+]i. NPY hyperpolarized arcuate neurons through the activation of a K+ conductance and increased the spike threshold. Molecular biological studies indicated that arcuate neurons possessed all of the previously cloned NPY receptor types (Y1, Y2, Y4, and Y5). Thus activation of multiple types NPY receptors on arcuate neurons can regulate both Ca2+ and K+ conductances leading to a reduction in neuronal excitability and a suppression of neurotransmitter release.     

Changes in pitutary-adrenal activity regulate the central vasodepressor responses induced by neuropeptide Y and adrenaline in the awake unrestrained male rat

The central cardiovascular responses induced by neuropeptide Y (0.25 nmol) and adrenaline (2.00 nmol) given i.c.v. in close to maximal doses in the awake, unrestrained male rat were studied following changes in the pituitary-adrenal activity. Adrenalectomy (1 week) alone significantly reduced the vasodepressor response to i.c.v. adrenaline but not to i.c.v. neuropeptide Y. Corticosterone replacement treatment (5 mg kg^-1 x 2, i.p., 1 week) significantly reduced both the maximal (peak) and overall (area) vasodepressor responses to i.c.v. adrenaline and neuropeptide Y (only overall responses) in the adrenalectomized rat. Corticosterone treatment alone in the sham-operated rat highly significantly reduced the vasodepressor responses to both i.c.v. adrenaline and neuropeptide Y. The bradycardic action of centrally administered neuropeptide Y was no longer significant after alterations in pituitary-adrenal activity. The present results suggest that corticosterone treatment can abolish the centrally evoked vasodepressor responses to close to maximal doses of adrenaline and neuropeptide Y, which may contribute to their hypertensive properties in man. Finally, after adrenalectomy the central vasodepressor responses to neuropeptide Y dominate, since the adrenergic vasodepressor responses are selectively reduced. This dominance is reduced by corticosterone replacement treatment. The results indicate an antagonistic role of adrenocortical steroids in control of centrally induced acute vasodepressor responses to neuropeptide Y and adrenaline.     

The relationship of terminals containing neuropeptide Y-like immunoreactivity to lumbar sympathetic vasoconstrictor neurones in the rabbit

The distributions of preganglionic neurones retrogradely labelled with horseradish peroxidase and of immunohistochemically identified varicose axons reactive for neuropeptide Y (NPY-IR) in the intermediate zone of rabbit lumbar spinal segments have been compared. Neurones projecting in the caudal lumbar sympathetic chain (LSC), which are mainly vasoconstrictor, were located laterally, associated with dense accumulations of NPY-IR terminals in mid L3 to caudal L4. In all other regions of the lumbar intermediate zone, there was relatively little correlation between the location of either LSC neurones, or those projecting to the pelvic viscera, and aggregations of NPY-IR axons. Most of these axons probably arise in the C1 nucleus, but it seems possible that this nucleus innervates only some groups of lumbar vasoconstrictor neurones.     

异丙酚舒张离体大鼠肺内动脉的作用及机制

目的: 观察异丙酚对预收缩离体大鼠肺内动脉张力的影响及其作用机制。方法: 分离SD雄性大鼠肺内动脉, 制备血管条, 采用微血管张力测定技术, 分别测定异丙酚对离体血管高钾(60 mmol/L KCl)和血栓素A₂的类似物U46619(100 nmmol/L)诱导收缩反应的张力影响。结果: 异丙酚可以明显舒张高钾预收缩的血管环, 呈浓度依赖性(EC₅₀=41.50 μmmol/L); 异丙酚也可以浓度依赖性地舒张U46619预收缩的血管环(EC₅₀ =63.38 μmmol/L), 无明显内皮依赖性; 不同浓度异丙酚(10、30、100和300 μmmol/L)孵育后, 钙离子反应曲线明显右移; 在L-型钙通道拮抗剂硝苯地平(nifedipine,1 μmmol/L)存在的条件下, 异丙酚仍可以舒张U46619预收缩的血管(EC₅₀ =89.03 μmmol/L)。结论: 异丙酚可舒张高钾及U46619预收缩的肺内动脉, 且不依赖于内皮, 其部分机制可能与抑制电压门控性钙内流与受体操纵钙内流有关。