Differential regulation of the release of norepinephrine and neuropeptide Y]

The release of catecholamines and their co-neurotransmitter neuropeptide Y was investigated in conscious dogs with neurogenic arterial hypertension elicited by sinoaortic denervation. One month after denervation, an elevation of catecholamine levels (measured by HPLC) without elevation of neuropeptide Y levels in plasma (evaluated by RIA) has been found. This dissociation could be explained by a transient release of neuropeptide Y during the first weeks after surgery; a depletion of neuronal neuropeptide Y due to the permanent sympathetic stimulation; or an insufficient increase in sympathetic tone. To test these three hypotheses, we investigated the time courses of catecholamine and neuropeptide Y levels in arterial plasma during the first five weeks after sinoaortic denervation; and the responses to yohimbine (an alpha 2 antagonist which enhances transmitter release). Resting neuropeptide Y levels in plasma remained normal during the first five weeks after sinoaortic denervation. In normal dogs, a high dose of yohimbine (0.5 mg/kg i.v.) elevated both catecholamine (6-fold) and neuropeptide Y levels (1.5-fold), whereas a lower dose (0.05 mg/kg i.v.) induced a two fold elevation of catecholamine levels without changing neuropeptide Y concentrations. In sinoaortically denervated dogs, yohimbine elicited elevation of both catecholamines and neuropeptide Y whatever the dose used. Thus, neurogenic arterial hypertension in dogs seams to involve catecholamines but not neuropeptide Y. Moreover, the present work suggests that a high level of sympathetic stimulation is required for a co-release of catecholamines and neuropeptide Y.     

Sympathetic stimulation-evoked overflow of norepinephrine and neuropeptide Y from the heart.

Neuropeptide Y (NPY) and norepinephrine are released together on sympathetic activation. To compare the time courses of NPY and norepinephrine washout from cardiac tissues, we measured the overflow of NPY-like immunoreactivity (NPY-LI) and norepinephrine in coronary sinus blood before, during, and after 3-minute trains of ansae subclaviae stimulation in 13 anesthetized dogs. We also measured vagally induced cardiac cycle length responses before and after ansae stimulation. Ansae stimulation increased NPY-LI and norepinephrine overflow from the heart in a frequency-dependent manner (p less than 0.02). After stimulation of the ansae at 5 and 10 Hz, the peak norepinephrine overflows decayed by 90% within 2 minutes, but the NPY-LI overflows required 17 +/- 11 and 35 +/- 21 minutes, respectively, to decay by 90%. Cardiac vagal effects were inhibited after 5- and 10-Hz ansae stimulations, and the peak inhibitions decayed by 90% after 19 +/- 7 and 39 +/- 16 minutes, respectively. The 90% decay times of the NPY-LI overflows were longer (p less than 0.003) than those of the norepinephrine overflows but did not differ significantly (p greater than 0.4) from the 90% decay times of the inhibition of vagal effects. We characterized NPY-LI in coronary sinus and arterial plasma by reversed-phase high-performance liquid chromatography. Before ansae stimulation, the main peak of NPY-LI in the plasma had a retention time similar to that of the oxidized human NPY-(1-36) standard. During ansae stimulation, however, there was a substantial increase in the peak of NPY-LI that eluted in a position similar to that of the monoxidized human NPY-(1-36) standard. These data support the hypothesis that neurally released NPY mediates the sympathetically evoked inhibition of vagal effects and indicate that the time course of removal of NPY from the heart differs substantially from that of norepinephrine. Moreover, under basal conditions, most NPY in the circulation is present in the oxidized form or as a fragment of the 36-amino-acid peptide. In contrast, cardiac sympathetic stimulation evokes the overflow of monoxidized NPY-(1-36) into the coronary sinus plasma.     

Elevated basal insulin secretion and normal dynamic insulin sensitivity in borderline hypertension

BACKGROUND AND AIM: Borderline hypertension is often the initial stage of stabilized hypertension. This study aimed to provide insight on insulin behavior and its relationship with glucose metabolism by investigating insulin secretion and hepatic clearance in non-steady-state conditions in borderline hypertensive patients. METHODS AND RESULTS: We studied 15 patients (6 F, 9M, 44 +/- 2 yr, 78 +/- 2 kg, systolic pressure 155 +/- 10 mmHg, diastolic 93 +/- 5) and 15 comparable healthy controls. All underwent an intravenous glucose test, with minimal model analysis to measure insulin sensitivity S1, glucose effectiveness SG, insulin pre-hepatic release, hepatic extraction, and insulin appearance rate in the systemic circulation. Basal glucose (3.98 +/- 0.12 vs 3.94 +/- 0.11 mmol/L, hypertensive vs control subjects respectively), i.v. glucose tolerance factor KG (2.0 +/- 0.2 vs 2.2 +/- 0.1% min-1), SG (0.035 +/- 0.004 vs 0.032 +/- 0.007 min-1) and S1 [3.5 +/- 0.5 vs 3.8 +/- 0.3 10(4) min-1 (microU/mL)] were similar, both basal insulin and C-peptide exhibited a marked increase (87 +/- 8 vs 46 +/- 6 pmol/L, p = 0.0003; 637 +/- 62 vs 381 +/- 76 pmol/L, p < 0.03) demonstrating insulin resistance in basal conditions. Insulin secretion per unit volume was greater in patients, both at basal (43 +/- 5 vs 24 +/- 5 pmol/L/min, p = 0.01) and after stimulation (total hormone released = 18 +/- 2 vs 11 +/- 2 nmol/L in 4 h, p = 0.022). Post-hepatic insulin delivery was also elevated (basal = 11 +/- 1 vs 6 +/- 1 pmol/L/min, p < 0.002, total = 5 +/- 1 vs 3 +/- 0.3 nmol/L in 4 h, p = 0.02), while no difference was detected in hepatic extraction (66 +/- 4% vs 66 +/- 3). CONCLUSION: Borderline hypertensive patients display normal glucose tolerance with basal insulin resistance and normal dynamic insulin sensitivity. Peripheral hyperinsulinemia derives from the combination of normal hepatic extraction with an overproduction of hormone, mostly due to the basal component. Because borderline hypertension often degenerates into overt disease, our results point to a progression that leads to the well-known insulin resistance proper to sustained hypertension.     

Prevention of renal hypertension in the rat by neuropeptide Y

Neuropeptide Y is known to enhance blood pressure responsiveness to various constrictors, including angiotensin II, and to suppress renin secretion. This study was undertaken to assess the effect of neuropeptide Y on the development of two-kidney, one clip renal hypertension. Normotensive rats either had a silver clip placed on the left renal artery or were sham-operated upon. An osmotic minipump, which was connected via a catheter to a jugular vein, was implanted subcutaneously in all rats. These pumps delivered either neuropeptide Y (0.001 microgram/min) or saline intravenously. Eight days later, an intra-arterial catheter was inserted and the rats were studied while not anesthetized on the following day. Neuropeptide Y did not affect body weight. In clipped rats, neuropeptide Y prevented the development of hypertension and suppressed renin secretion. Neuropeptide Y significantly decreased blood pressure also in sham-operated rats, although it had no effect on plasma renin activity. These data indicate that prolonged neuropeptide Y infusion may lower blood pressure by different mechanisms, one of which is probably a suppression of renin release.     

Inhibition of hypothalamic neuropeptide Y gene expression by insulin.

Insulin acts in the brain to suppress feeding, whereas neuropeptide Y (NPY) has the opposite effect. Since fasting lowers plasma insulin levels and increases hypothalamic synthesis of NPY, we proposed that insulin may inhibit hypothalamic NPY gene expression. To test this hypothesis, we used RIA and in situ hybridization histochemistry to determine if centrally administered insulin could reduce levels of both NPY and its messenger RNA (mRNA) in discreet hypothalamic regions during fasting. Three groups of Long-Evans rats were entered into a 72-h study protocol. One group was fed ad libitum during this period, while the others were fasted. Fed rats received intracerebroventricular (icv) injections of saline vehicle at 12-h intervals, whereas fasted groups received icv vehicle alone or with insulin (4 mU/12 h). In vehicle-only treated rats, fasting significantly increased expression of preproNPY mRNA in the arcuate nucleus to 179 +/- 20% of fed controls. Administration of icv insulin during fasting abolished this increase (99 +/- 14% of fed controls; P less than 0.05 vs. fasted, vehicle-treated rats). Central insulin administration during fasting also reduced immunoreactive NPY concentrations in samples punched from the paraventricular nucleus (PVN) (875 +/- 122 pg/punch) to levels below vehicle-only treated rats (1396 +/- 435 pg/punch; P less than 0.05), similar to free-feeding control values (814 +/- 170 pg/punch). By comparison, neither fasting nor central insulin administration altered NPY levels in four other hypothalamic regions (supraoptic, ventromedial, dorsomedial, and arcuate nuclei). Continuous icv insulin infusion at a lower dose (2 mU/day) produced a similar result during a shorter period (48 h) of food deprivation in Wistar rats. In this study, central insulin infusion also inhibited the fasting-related increase in arcuate preproNPY mRNA levels and did not affect plasma glucose or insulin levels. This suggests that insulin acts locally to inhibit hypothalamic NPY mRNA expression. We conclude that the increase of levels of NPY in the PVN and preproNPY mRNA in the arcuate nucleus during fasting are inhibited by icv insulin. Fasting, therefore, increases NPY biosynthesis along an arcuate nucleus-PVN pathway in the hypothalamus via a mechanism dependent on low insulin levels.     

Effects of intravenous neuropeptide Y on insulin secretion and insulin sensitivity in skeletal muscle in normal rats

Summary Intracerebroventricular administration of neuropeptide Y to normal rats induces a syndrome characterised by obesity, hyperinsulinaemia, insulin resistance and over expression of the adipose tissue ob gene. Little is known about the effect of circulating neuropeptide Y on glucose metabolism, insulin secretion and leptin. We therefore aimed to evaluate the effect of an intravenous infusion of neuropeptide Y on glucose disposal, endogenous glucose production, whole body glycolytic flux, and glucose storage as assessed during euglycaemic hyperinsulinaemic clamp. In addition, the insulin-stimulated glucose utilisation index in individual tissues was measured by the 2-deoxy-[1-³H]-glucose technique. The effect of neuropeptide Y on insulin secretion was evaluated by hyperglycaemic clamp. Infusion did not induce any change in endogenous glucose production during basal conditions or at the end of the clamp. Glucose disposal was significantly increased in the rats given neuropeptide Y compared with controls (27.8 ± 1.3 vs 24.3 ± 1.6 mg · min^–1· kg^–1; p < 0.05) as was the glycolytic flux (18.9 ± 1.6 vs 14.4 ± 0.8 mg · min^–1· kg^–1; p < 0.05), while glucose storage was comparable in the two groups. In skeletal muscle, the glucose utilisation index was increased significantly in rats given neuropeptide Y. The glucose utilisation index in subcutaneous and epididimal adipose tissue was not significantly different between the two groups. Plasma leptin was significantly increased by hyperinsulinaemia, but was not affected by neuropeptide Y infusion. Both the early and late phase of the insulin response to hyperglycaemia were significantly reduced by neuropeptide Y. In conclusion neuropeptide Y infusion may increase insulin-induced glucose disposal in normal rats, accelerating its utilisation through the glycolytic pathway. Neuropeptide Y reduces both phases of the insulin response to hyperglycaemia. [Diabetologia (1998) 41: 1361–1367] Received: 4 March 1998 and in revised form: 27 May 1998     

Genetic studies of neuropeptide Y and neuropeptide Y receptors Y1 and Y5 regions in morbid obesity

Summary Synthesis and release of neuropeptide Y (NPY) are both regulated by leptin binding to its hypothalamic receptor mediating some of the effects of leptin on food intake. Moreover, NPY administration is a powerful stimulant of feeding behaviour. Thus, we investigated the potential implication of NPY, NPY-Y1 and -Y5 subtype receptors [rNPY-Y1/-Y5] in the development of human obesity. Two complementary genetic approaches were used: 1) linkage analyses between obesity and polymorphic markers located nearby NPY and rNPY-Y1/-Y5 genes (respectively on chromosomes 7p15.1 and 4q[31.3–32]) in 93 French Caucasian morbidly obese families; 2) single strand conformation polymorphism (SSCP) scanning of the coding region of the NPY and rNPY-Y1 genes performed in 50 unrelated obese patients ascertained on the basis of a body mass index of 27 kg/m² or more and a family history of obesity. No evidence of linkage between morbid obesity or obesity-related quantitative traits and NPY and rNPY-Y1/Y5 regions was found in this population. Moreover, SSCP scanning revealed no mutation in the coding region of NPY and rNPY-Y1 genes among obese subjects. These results suggest that NPY and NPY-Y1/Y5 receptors are unlikely to be implicated in the development of human morbid obesity, at least in the French Caucasian population. [Diabetologia (1997) 40: 671–675] Received: 27 December 1996 and in revised form: 26 February 1997     

高血压病患者血浆神经肽Y、神经降压素水平的变化及意义

目的 :观察高血压病患者血浆神经肽 Y（NPY）、神经降压素 （NT）水平的变化 ,探讨其在高血压发病机制中的作用及其与高血压靶器官损害的关系。方法 :用放射免疫分析法检测符合高血压病诊断标准的 80例高血压病患者血浆 NPY,NT浓度 ,同时检查患者心、肾等靶器官功能。结果 :1高血压病患者血浆 NPY水平高于对照组 （P<0 .0 5 ）、而 NT水平明显低于对照组 （P<0 .0 1）。 2高血压病 , , 期患者间血浆 NPY,NT水平差异明显 （P<0 .0 1） ,NPY水平逐渐升高 ,而 NT水平逐渐下降。心功能 , , 级高血压病患者间 NPY,NT水平差异明显 （P<0 .0 1） ,随心功能恶化 ,NPY水平升高 ,而 NT水平降低。伴有室间隔和 （或 ）左室后壁肥厚组血浆 NPY水平高于室间隔和左室后壁正常组 （P<0 .0 1） ,而 NT水平则肥厚组低于正常组 （P<0 .0 1）。肾功能 Ccr≤ 4 9m l/ min组血浆NPY水平高于 Ccr≥ 5 0 m l/ min组 （P<0 .0 1） ,二组间 NT水平无明显差异 （P>0 .0 5 ）。 3高血压病患者血浆 NPY与 NT水平呈负相关 （r=- 0 .4 5 ,P<0 .0 1）。结论 :NPY,NT参与了高血压病的发病过程 ,与高血压病患者心脏、肾脏功能损害程度相关 ,观察血浆 NPY与 NT水平变化有助于判断高血压病患者的病情和预后     

老年人单纯收缩期高血压血清瘦素、抵抗素及血浆同型半胱氨酸、神经肽的水平

目的探讨老年单纯收缩期高血压(ISH)患者血清瘦素(Lep)、抵抗素(Res)与血浆同型半胱氨酸(Hcy)、神经肽Y(NPY)的水平,及与其他类型老年高血压患者、健康老年人之间的差异. 方法对ISH组28例、全期型高血压(SDH)组26例、单纯舒张期高血压(IDH)组25例及老年健康对照组21例,采用酶免疫法检测血清Lep、Res,放射免疫法测定血浆Hcy、NPY,同时检测受试者体质指数(BMI)和体内脂肪(BF)百分比. 结果 ISH组、SDH组、IDH组血清Lep[(13.18±1.66)μg/L、(11.91±2.16)μg/L、(10.88±2.31)μg/L]、Res[(31.2±10.3)μg/L、(26.3±8.91)μg/L、(24.2±5.66)μg/L]水平均高于对照组[(7.71±1.28)μg/L和(19.8±7.21)μg/L,P<0.05或P<0.01],ISH组显著高于SDH、IDH组(P<0.05,P<0.01);3个不同类型高血压组患者的血浆Hcy、NPY较对照组增高(P<0.01,P <0.05),而老年ISH组又较SDH、IDH组增高(P<0.01);老年ISH组平均年龄较其他各组明显增高(P <0.01),老年SDH组较IDH组、对照组也增高(P<0.05, P<0.01);老年ISH组BMI也较其他各组明显增高(P<0.05,P<0.01),而且SDH组较老年健康组显著增高(P<0.05).ISH患者 BF百分比与IDH组、老年健康组差异均有显著性(P<0.05).收缩压与Lep、NPY呈正相关(γ=0.256,P <0.05;γ=0.374,P<0.01). 结论 Lep、Res、Hcy及NPY与老年人高血压发病,尤其是老年ISH的发病有关,控制患者血清Lep、Res、血浆Hcy及NPY浓度对预防老年高血压,尤其是ISH的发生或发展可能有积极作用.     

Evidence that neuropeptide Y and norepinephrine mediate electrical field-stimulated vasoconstriction of rabbit middle cerebral artery.

We investigated the contractile response of isolated rabbit middle cerebral artery (MCA) segments to electrical field stimulation (EFS). The dynamics of the EFS contraction were compared with a similar-sized branch of rabbit ear artery. In comparison with the ear artery, the EFS contractions of the MCA displayed a longer latency and a higher stimulus frequency threshold. Greater stimulation train lengths were required to attain equilibrium, and the time course of EFS response--including force development, plateau, and return to rest tension--was significantly slower than in the ear artery. Morphological and pharmacological studies of the MCA showed that it receives sympathetic adrenergic innervation: whole-mount preparations displayed catecholamine histofluorescence; electron micrographs of MCA sections revealed a population of varicosities containing chromaffin positive large and small vesicles; and EFS contractions were blocked by tetrodotoxin (30 nM) and guanethidine (5 microM) and by chronic surgical sympathectomy. Exposure to prazosin (10 microM) or phenoxybenzamine (1 microM) blocked norepinephrine contractions but did not significantly influence the EFS contraction. Procedures and drugs that antagonized the responses to neuropeptide Y, serotonin, or histamine were also ineffective in blocking the EFS contraction. The involvement of ATP could not be assessed, since the purinergic P2 agonist alpha,beta-methylene ATP was ineffective in blocking ATP-mediated contractions. The EFS contraction, however, could be blocked by a combination of neuropeptide Y desensitization and phenoxybenzamine (30 nM) or prazosin (0.1 microM). These results suggest that norepinephrine and neuropeptide Y are released from sympathetic nerves and mediate EFS contraction by occupation of postjunctional alpha-adrenoceptor and neuropeptide Y receptors. Since the blockade of only one of these components does not diminish the response to EFS, the adrenergic neuroeffector system in this artery may involve complex prejunctional regulatory mechanisms.     

Normalization of renin secretion by neuropeptide Y in adrenalectomized rats with glucocorticoid-induced hypertension

In the periphery, neuropeptide Y is present in the circulation, in the adrenal medulla as well as at the level of nerve endings and of the juxtaglomerular apparatus. The aim of the present study was to assess the effect of this neuropeptide on renin secretion. Normotensive rats were biadrenalectomized or sham-operated and made hypertensive with methylprednisolone acetate (20 mg/kg s.c. once weekly). Deoxycorticosterone pivalate (10 mg/kg s.c. once weekly) was also given to prevent mineralocorticoid deficiency. Two weeks after that initial surgery 12 adrenalectomized rats and 8 sham-operated rats were infused for 30 min with neuropeptide Y (0.1 microgram/min) whereas 8 adrenalectomized rats and 9 sham-operated rats received in similar conditions the vehicle of neuropeptide Y (10 microliters/min). At that time, the rats were conscious and there was no significant difference in blood pressure and heart rate between the 4 groups of rats. At the end of the experiment, adrenalectomized rats exhibited a markedly stimulated renin-angiotensin system. Neuropeptide Y made it possible to normalize plasma renin activity in these rats, thus suggesting that neuropeptide Y plays an important role in regulating renin secretion.     

老年单纯收缩期高血压患者血浆中神经肽Y浓度的变化

目的　观察老年单纯收缩期高血压 (ISH)患者血浆神经肽Y(NPY)浓度的变化 ,并探讨其临床意义。方法　采用放射免疫法测定 40例ISH患者血浆NPY浓度 ,其中 30例应用彩色多普勒超声心动图仪测定左室射血分数。结果　 (1)ISH患者NPY浓度较正常对照组明显升高 (P <0 .0 1)。且NPY的浓度与收缩压增高的幅度呈正相关。(2 )ISH患者血浆NPY浓度 1级最低 ,2级居中 ,3级最高 ,各级之间差异有显著性意义 (F =6 7.5 8,P <0 .0 1)。(3)血浆NPY浓度随心功能损害程度加重而上升 (F=5 9.6 8,P <0 .0 1)。结论　NPY可能参与高血压的发生和发展 ,并与病情有关。检测血浆NPY浓度可作为判断ISH患者病情的指标     

Increased neuropeptide Y content in individual hypothalamic nuclei, but not neuropeptide Y mRNA, in diet-induced obesity in rats.

Neuropeptide Y (NPY) is the most powerful appetite stimulant known, and chronic administration leads to obesity. The hypothalamic content of NPY varies with nutritional status, suggesting that it is of physiological importance. We measured NPY in specific hypothalamic nuclei and NPY mRNA in the hypothalamus by Northern blotting in rats made obese by feeding a highly palatable diet compared with controls fed standard chow. In animals fed the palatable diet, NPY concentrations were increased in the paraventricular nucleus (mean +/- S.E.M.; 19.5 +/- 2.3 vs 11.1 +/- 1.1 fmol/micrograms protein, P less than 0.02), the arcuate nucleus (20.4 +/- 3.3 vs 9.3 +/- 0.6 fmol/micrograms protein, P less than 0.01), the medial preoptic area (9.1 +/- 0.9 vs 5.9 +/- 0.7 fmol/micrograms protein, P less than 0.02) and the anterior hypothalamus (2.7 +/- 0.2 vs 2.0 +/- 0.1 fmol/micrograms, P less than 0.02). Hypothalamic NPY mRNA measured by Northern blot analysis was, however, unchanged. These results suggest that the increase in NPY was due to decreased release rather than increased NPYergic activity. The findings are in accord with the neuroendocrine disturbance and increased thermogenesis observed in this model of obesity.     

Elevated fasting serum insulin level predicts future development of hypertension

Background

Studies have investigated clinical association between fasting insulin level and hypertension. However, it is still debatable whether elevated fasting insulin actually increases the risk of hypertension with the passage of time. Thus, this study was aimed at investigating the association between baseline fasting insulin level and the development of hypertension.

Methods

25,062 normotensive, non-diabetic Korean men participating in a medical health check-up program were followed up from 2005 until 2010. They were divided into 4 groups according to baseline fasting insulin levels (first quartile–fourth quartile). The incidence of hypertension was compared among 4 groups, and Cox proportional hazards model was used to determine if hypertension was associated with higher baseline fasting insulin level.

Results

The incidence of hypertension increased according to the baseline fasting insulin level (first quartile: 13.3%, second quartile: 15.4%, third quartile: 17.5%, fourth quartile: 23.2%, P < 0.001). Even after adjusting for multiple covariates, the HRs (95% CI) for hypertension were higher for the second (1.12; 0.96–1.31), third (1.39; 1.20–1.62) and fourth quartile group (1.75; 1.51–2.03), compared to the first quartile group, respectively (P for trend < 0.001).

Conclusion

The risk of hypertension was in proportion to the baseline fasting insulin level. In addition, hyperinsulinemia was an independent risk factor for the future development of hypertension. These findings suggest the value of fasting insulin level as an early predictor of hypertension.     

Plasma insulin, cholecystokinin, galanin, neuropeptide Y and leptin levels in obese women with and without type 2 diabetes mellitus

Obesity is an important factor predisposing to type 2 diabetes mellitus, especially for postmenopausal women. Experimental studies provided evidences that leptin, cholecystokinin (CCK), galanin (GAL), neuropeptide Y (NPY) and insulin are involved in feeding behaviour. The aim of the study was to evaluate their possible relationships in obese and diabetic women. Three groups of postmenopausal women (FSH > 30 mIU/ml) were evaluated: 8 diabetic (mean age 56.6 +/- 6.9 y, BMI 29.8 +/- 5.3 kg/m2), 10 obese non-diabetic (mean age 49.6 +/- 5.4 y, BMI 36.0 +/- 3.7 kg/m2) and 12 non-diabetic controls (mean age 52.7 +/- 3.5 y, BMI 27.3 1.9 kg/m2). For each patient BMI and WHR were measured and calculated. Blood samples were collected at 8:00 a.m. after an overnight fast. Plasma concentrations of FSH, leptin, CCK, GAL, NPY and insulin were determined using commercial RIA kits. Mean plasma NPY concentration was significantly higher in diabetic women than in controls (190.1 pg/ml +/- 85.4 vs 120.4 +/- 36.6). Compared to controls, mean plasma leptin level was significantly higher in obese non-diabetic women (32.9ng/ml +/- 9.2 vs 18.9 +/- 9.1). No significant differences were found between obese non-diabetic and diabetic women. In diabetic subjects positive correlations were found between: CCK and leptin (r= 0.8295; P= 0.011), CCK and insulin (r=0.7832; P=0.022), leptin and insulin (r=0.9302; P=0.001). In obese subjects a positive correlation between WHR and GAL (r= 0.6624; P= 0.037) and a negative between GAL and insulin (r= -0.6795; P= 0.031) were found. In controls positive correlations were found between WHR and CCK (r=0.6412; P=0.025), GAL and insulin (r=0.630; P=0.028) and negative between CCK and NPY (r = -0.6505; P= 0.022). Our results, ie higher mean plasma NPY levels in postmenopausal diabetic women and positive correlation of CCK with leptin and insulin, may suggest the role of these neuropeptides in metabolic disorders leading to type 2 diabetes mellitus.     

Epistatic interaction between beta2-adrenergic receptor and neuropeptide Y genes influences LDL-cholesterol in hypertension

Beta2-adrenergic receptor gene and neuropeptide Y gene may potentially influence lipid metabolism and overall energy balance. Therefore, we examined associations of these genes with lipid fractions and obesity-related phenotypes in hypertensive subjects. A total of 638 white individuals from 212 Polish families with clustering of essential hypertension were phenotyped for cardiovascular risk determinants. Each subject was genotyped for functional polymorphisms of beta2-adrenergic receptor gene (Arg16Gly and Gln27Glu) and neuropeptide Y (Leu7Pro). Of 3 common haplotypes of beta2-adrenergic receptor gene, Arg16Gln27 was overtransmitted to offspring with elevated levels of total cholesterol (Z=2.2; P=0.026) and LDL-cholesterol (Z=3.2; P=0.002). Individually, Leu7Pro was not associated with any of the metabolic phenotypes in family-based tests or case-control analyses. However, in the presence of Arg allele of Arg16Gly and Gln allele of Gln27Glu, homozygosity for Leu variant of the Leu7Pro polymorphism was associated with 2.1-increased odds ratio (confidence interval, 1.10 to 3.81; P=0.024) of elevated LDL in hypertensive subjects, independent of age, gender, body mass index, adjusted blood pressures, antihypertensive therapy, and use of nonselective beta-blockers and diuretics. Consistently, there was a significant multilocus association among variants of Arg16Gly, Gln27Glu, and Leu7Pro in hypertensive probands with elevated LDL (cases; P=0.028) but not in hypertensive subjects with normal LDL (controls). This study revealed an association of LDL-cholesterol with beta2-adrenergic receptor gene haplotype and provided evidence for epistatic interaction between beta2-adrenergic receptor gene and neuropeptide Y gene in determination of LDL-cholesterol in patients with essential hypertension.     

神经肽Y对肝硬化大鼠血流动力学及水钠代谢的影响

近年来，人们发现神经肽Ｙ（ＮＰＹ）与肝脏疾病有密切关系［１，２］。正常肝组织中ＮＰＹ阳性神经纤维分布于门脉系统周围，在肝小叶中ＮＰＹ阳性神经纤维沿肝窦状隙行走，肝硬化时肝纤维化间隔中ＮＰＹ神经纤维显著增多，说明ＮＰＹ神经纤维的改变与肝硬化时病理生理变化有关［２］。本实验测定了肝硬化大鼠血浆和组织中ＮＰＹ的含量，并对其含量变化及对血流动力学和水钠代谢的影响进行了探讨。 １．材料与方迭：（１）动物分组及肝硬化模型的建立：健康雄性ＳＤ大鼠随机分为肝硬化组和假手术组，肝硬化组采用胆管结扎的方活建立模型。…     

Enhanced Y1-receptor-mediated vasoconstrictive action of neuropeptide Y (NPY) in superior mesenteric arteries in portal hypertension

BACKGROUND/AIMS: Vascular hyporeactivity to catecholamines contributes to arterial vasodilation and hemodynamic dysregulation in portal hypertension. Neuropeptide Y (NPY) is a sympathetic neurotransmitter facilitating adrenergic vasoconstriction via Y1-receptors on the vascular smooth muscle. Therefore, we investigated its role for vascular reactivity in the superior mesenteric artery (SMA) of portal vein ligated (PVL) and sham operated rats. METHODS: In vitro perfused SMA vascular beds of rats were tested for the cumulative dose-response to NPY dependent on the presence and level of alpha1-adrenergic vascular tone (methoxamine MT: 0.3-10 microM). Moreover, the effect of NPY (50 nM) on vascular responsiveness to alpha1-adrenergic stimulation (MT: 0.3-300 microM) was evaluated. Y1-receptor function was tested by Y1-selective inhibition using BIBP-3226 (1 microM). RESULTS: NPY dose-dependently and endothelium-independently enhanced MT-pre-constriction in SMA. This potentiation was increasingly effective with increasing adrenergic pre-stimulation and being more pronounced in PVL rats as compared to sham rats at high MT concentrations. NPY enhanced vascular contractility only in PVL rats correcting the adrenergic vascular hyporeactivity. Y1-receptor inhibition completely abolished NPY-evoked vasoconstrictive effects. CONCLUSIONS: NPY endothelium-independently potentiates adrenergic vasoconstriction via Y1-receptors being more pronounced in portal hypertension improving mesenteric vascular contractility and thereby correcting the splanchnic vascular hyporeactivity. This makes NPY a superior vasoconstrictor counterbalancing arterial vasodilation in portal hypertension.