neuropeptide-y and Hypertension

Intrauterine growth restriction (IUGR) has been identified as a risk factor for adult chronic kidney disease (CKD), including hypertension (HTN). Accelerated postnatal catch-up growth superimposed to IUGR has been shown to further increase the risk of CKD and HTN. Although the impact of excessive postnatal growth without previous IUGR is less clear, excessive postnatal overfeeding in experimental animals shows a strong impact on the risk of CKD and HTN in adulthood. On the other hand, food restriction in the postnatal period seems to have a protective effect on CKD programming. All these effects are mediated at least partially by the activation of the renin-angiotensin system, leptin and neuropeptide Y (NPY) signaling and profibrotic pathways. Early nutrition, especially in the postnatal period has a significant impact on the risk of CKD and HTN at adulthood and should receive specific attention in the prevention of CKD and HTN.

Topics: Animals; Child Development; Disease Models, Animal; Fetal Growth Retardation; Humans; Hypertension; Infant Nutritional Physiological Phenomena; Infant, Low Birth Weight; Infant, Newborn; Leptin; Metabolic Networks and Pathways; Neuropeptide Y; Nutritional Status; Renal Insufficiency, Chronic; Renin-Angiotensin System

High levels of sympathetic drive in several cardiovascular diseases including postmyocardial infarction, chronic congestive heart failure and hypertension are reinforced through dysregulation of afferent input and central integration of autonomic balance. However, recent evidence suggests that a significant component of sympathetic hyperactivity may also reside peripherally at the level of the postganglionic neuron. This has been studied in depth using the spontaneously hypertensive rat, an animal model of genetic essential hypertension, where larger neuronal calcium transients, increased release and impaired reuptake of norepinephrine in neurons of the stellate ganglia lead to a significant tachycardia even before hypertension has developed. The release of additional sympathetic cotransmitters during high levels of sympathetic drive can also have deleterious consequences for peripheral cardiac parasympathetic neurotransmission even in the presence of β-adrenergic blockade. Stimulation of the cardiac vagus reduces heart rate, lowers myocardial oxygen demand, improves coronary blood flow, and independently raises ventricular fibrillation threshold. Recent data demonstrates a direct action of the sympathetic cotransmitters neuropeptide Y (NPY) and galanin on the ability of the vagus to release acetylcholine and control heart rate. Moreover, there is as a strong correlation between plasma NPY levels and coronary microvascular function in patients with ST-elevation myocardial infarction being treated with primary percutaneous coronary intervention. Antagonists of the NPY receptors Y1 and Y2 may be therapeutically beneficial both acutely during myocardial infarction and also during chronic heart failure and hypertension. Such medications would be expected to act synergistically with β-blockers and implantable vagus nerve stimulators to improve patient outcome.

Topics: Animals; Cardiovascular Diseases; Disease Models, Animal; Galanin; Heart; Hypertension; Neuropeptide Y; Neuropeptides; Rats; Rats, Inbred SHR; Sympathetic Nervous System

Work from our laboratory has established that angiotensin II (Ang II) produces a greater enhancement of the nerve stimulation (NS)-induced release (overflow) of both norepinephrine (NE) and neuropeptide Y (NPY) and a greater increase in perfusion pressure of the mesenteric arterial bed obtained from the spontaneously hypertensive rat (SHR) compared to age-matched Wistar-Kyoto (WKY) or Sprague-Dawley rats. The enhancement of NS-induced NPY release was blocked by the AT1 receptor antagonist EMD 66684 and the AT2 receptor antagonist PD 123319. Both captopril and EMD 66684 decreased NPY and NE overflow from SHR mesenteric beds, suggesting an endogenous renin-angiotensin system (RAS) is active in the mesenteric artery. We also observed that the recently discovered new arm of the RAS, namely, angiotensin (1-7) (Ang-(1-7)), attenuated the NS-induced increase in NE and NPY release and the accompanied increased perfusion pressure. These inhibitory effects were greater in blood vessels obtained from SHR compared to WKY. We suggest that inhibition of sympathetic neurotransmission contributes to the mechanism(s) by which Ang-(1-7) acts to inhibit the vasoconstrictor effect of Ang II. Administration of the MAS receptor antagonist D-Ala(7)Ang-(1-7) attenuated the decrease in both NE and NPY release due to Ang-(1-7) administration. The AT2 receptor antagonist PD 123391 attenuated the effect of Ang-(1-7) on NE release without affecting the decrease in NPY release. We observed a shift in the balance between Ang II and Ang-(1-7) levels in the SHR with an increase in Ang II and a decrease in Ang-(1-7) in the blood and mesenteric artery. This appears to be due to an increase in angiotensin-converting enzyme (ACE) in the mesenteric artery of the SHR.

Topics: Angiotensin I; Angiotensin II; Animals; Catecholamines; Humans; Hypertension; Neuroeffector Junction; Neuropeptide Y; Peptide Fragments; Sympathetic Nervous System

Obesity and hypertension frequently coexist and both represent important risk factors for cardiovascular disease. The mechanisms implicated in the regulation of food intake have not been completely elucidated. Recent data suggests that peripheral and central neuropeptides play an important role in the maintenance of energy balance. More specifically, leptin, neuropeptide Y (NPY) and alpha-melanocyte-stimulating hormone (a-MSH) appear to be implicated in the pathogenesis of obesity and also contribute to the development of hypertension in obesity.. Analysis of the pertinent bibliography published in PubMed database.. Leptin is produced in the adipose tissue directly correlated with fat tissue mass. Leptin acts on two distinct neural populations in the hypothalamus: the first expresses the orexigenic peptides NPY and agouti-related protein (AgRP), the second pro-opiomelanocortin (POMC). The activation of POMC neurons increases the production of the anorexigenic hormone a-MSH and inhibits the release of NPY and AgRP. In addition, the hypothalamus integrates the neuroendocrine systems with the autonomic nervous system and controls the activity of the latter. Stimulation of hypothalamic nuclei elicits sympathetic responses including blood pressure elevation. Both NPY and a-MSH appears to be implicated in the hypothalamic regulation of sympathetic nervous system (SNS) activity.. Alterations in leptin, NPY and a-MSH are frequently observed in obesity and might stimulate SNS activity, contributing to the development of hypertension in obese patients. These neuropeptides might provide a pathophysiologic link between excess weight and hypertension. However, more research is needed before the pharmacologic manipulation of these complex neuroendocrine systems can be applied in the treatment of obesity and hypertension.

Topics: alpha-MSH; Appetite Regulation; Body Weight; Humans; Hypertension; Leptin; Neuropeptide Y; Obesity; Sympathetic Nervous System

Topics: Animals; Disease Models, Animal; Humans; Hypertension; Muscle, Smooth, Vascular; Neuropeptide Y; Sympathetic Nervous System

Obesity in humans causes hypertension, myocardial hypertrophy and coronary atherosclerosis, and increased cardiovascular morbidity and mortality that is thought to be related to sympathetic overactivity. Leptin is an adipocyte-derived hormone that acts in the hypothalamus to regulate appetite, energy expenditure and sympathetic nervous system outflow. One of the major mechanisms leading to the development of obesity-induced hypertension appears to be leptin-mediated sympatho-activation. Leptin adversely shifts the renal pressure-natriuresis curve, leading to relative sodium retention. Although obesity is generally associated with resistance to the anorexic and weight-reducing actions of leptin, our work has shown preservation of its sympatho-excitatory and pressor actions. This selective leptin resistance of obesity, coupled with hyperleptinaemia, may play a critical role in the cardiovascular complications of obesity. Increased information about leptin and its mechanisms of actions should help the development of safe and effective pharmacological treatments of obesity and obesity-related hypertension.

Topics: alpha-MSH; Animals; Blood Pressure; Corticotropin-Releasing Hormone; Drug Resistance; Humans; Hypertension; Leptin; Neuropeptide Y; Obesity; Receptors, Cell Surface; Receptors, Leptin; Sympathetic Nervous System

Topics: Adrenal Gland Neoplasms; Alzheimer Disease; Anorexia Nervosa; Autonomic Nervous System Diseases; Biomarkers; Humans; Hypertension; Immunoradiometric Assay; Neuroblastoma; Neuropeptide Y; Pheochromocytoma; Radioimmunoassay; Reference Values

Topics: Humans; Hypertension; Neuropeptide Y; Polymorphism, Genetic; Predictive Value of Tests; Risk Factors

The distribution and characteristics of adrenomedullin (AM)-containing perivascular nerves in the rat mesenteric artery were investigated using immunohistochemical techniques. Many fibers containing AM-like immunoreactivity (LI) were observed in the adventitia of mesenteric arteries, which were densely innervated by calcitonin gene-related peptide (CGRP)- and neuropeptide Y (NPY)-LI fibers. AM-LI, CGRP-LI, and NPY-LI fibers were abolished by cold storage denervation. Capsaicin pretreatment abolished AM-LI and NPY-LI fibers but not NPY-LI fibers. NPY-LI fibers but not AM-LI and CGRP-LI fibers disappeared after treatment with 6-hydroxydopamine. There were many AM-LI positive cells in the dorsal root ganglia, where AM mRNA was detected. In a double immunofluorescence study, AM-LI was found in CGRP-LI fibers, although some fibers contained AM-LI alone. The density of AM-LI fibers was lower in SHR than in WKY mesenteric arteries. These results suggest that the mesenteric artery is innervated by AM-containing perivascular nerves and AM may have a neurotransmitter role in the regulation of vascular tone.

Topics: Adrenomedullin; Age Factors; Animals; Calcitonin Gene-Related Peptide; Humans; Hypertension; Immunohistochemistry; Mesenteric Arteries; Neuropeptide Y; Peptides; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Pheochromocytoma and paragangliomas are rare tumors of chromaffin tissue that secrete catecholamines either intermittently or continuously, producing hypertension with a constellation of symptoms and signs that can be frightening to the patient and that continue to provide perplexing problems for clinicians. With surgical treatment, symptoms will be relieved and hypertension normalized or ameliorated for patients who do not have malignant tumors. Appropriate antihypertensive drugs are used to manage hypertension, to control associated cardiovascular symptoms, and to prepare patients for operation. The question debated most often regarding medical therapy of pheochromocytoma is whether antihypertensive treatment regimens other than nonspecific alpha-blockade are just as effective and safe. Understanding the pathophysiologic mechanisms that sustain the hypertension and the pharmacology of antihypertensive agents allows better selection of antihypertensive therapy.

Topics: Adrenal Gland Neoplasms; Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Catecholamines; Clonidine; Hemodynamics; Humans; Hypertension; Neuropeptide Y; Phenoxybenzamine; Pheochromocytoma

The prevalence of obesity is rising at an alarming rate worldwide, with consequent increases in type 2 diabetes, hypertension and cardiovascular morbidity and mortality. Central neural mechanisms, via the activation of the sympathetic nervous system may contribute to obesity-related cardiovascular diseases through the promotion of hypertension, dysrhythmia and atherosclerosis. However, the mechanisms responsible for this sympatho activation have not been identified. Leptin is an adipocyte-derived hormone that promotes weight loss by reducing appetite and by increasing energy expenditure through sympathetic stimulation to thermogenic tissue. Leptin also produces sympathoactivation to kidneys, hindlimb and adrenal glands, suggesting that the obesity-associated increase in sympathetic nerve activity could be due in part to these sympathetic effects of leptin. However, most human obesity appears to be associated with leptin resistance. Recent studies indicate that leptin resistance may be selective, with preservation of adverse sympathetic effects despite the loss of the metabolic actions of leptin. The leptin receptor is expressed in several hypothalamic nuclei including the arcuate nucleus. The melanocortin system, neuropeptide Y and corticotrophin-releasing factor have emerged as principal neuropeptide mediators of leptin action in the arcuate nucleus. These neuropeptides exert varying effects by different pathways. Several other candidate hypothalamic pathways that can mediate the effects of leptin have been identified. The understanding of neuronal signaling pathways involved in leptin signaling and energy balance has opened new research possibilities for the treatment of obesity.

Topics: Animals; Anti-Obesity Agents; Brain; Drug Resistance; Humans; Hypertension; Hypothalamus; Leptin; Neuropeptide Y; Obesity; Receptors, Cell Surface; Receptors, Corticotropin; Receptors, Leptin; Receptors, Melanocortin; Receptors, Neuropeptide Y; Sympathetic Nervous System

Several studies have shown the association between obesity and hypertension. The pathophysiologic mechanisms of obesity-related hypertension remain unknown. Clinical and experimental studies have shown that obesity is associated with enhanced sympathetic nervous activity. Thus, sympathetic nerve activation seems to play a major role in obesity-associated hypertension. However, the factors responsible for this sympathoactivation have not been identified. Leptin is an adipocyte-derived hormone that promotes weight loss by reducing appetite and food intake and by increasing energy expenditure through sympathetic stimulation to brown adipose tissue. Leptin also produces sympathoactivation to kidneys, hindlimb, and adrenal glands, indicating that the obesity-associated increase in sympathetic nerve activity could be due in part to these sympathetic effects of leptin. However, obesity is associated with leptin resistance, since high circulating levels of leptin were observed in obese subjects. Recent evidences indicate that this leptin resistance could be selective with preservation of sympathetic effects despite the loss of metabolic action of leptin. This suggests divergent central pathways underlying metabolic and sympathetic effects of leptin. Several neuropeptides have emerged as potent candidate mediators of leptin action in the central nervous system, including the melanocortin system, neuropeptide Y, and cortico-trophin releasing factor. A detailed understanding of the multitude and complexity of integrated neuronal circuits and neuropeptide-containing pathways in leptin action will help in understanding the pathogenesis of obesity and related disorders.

Topics: Animals; Cardiovascular System; Humans; Hypertension; Hypothalamus; Leptin; Neuropeptide Y; Obesity; Sympathomimetics

Outcomes of recently published studies showed that cause of primary hypertension may lay in dysregulation of one of physiological mechanisms. Accordingly to current knowledge one can state that disturbance of every of these mechanisms results in cascade of changes in function of sympathetic and endocrine systems with special impact in renin-angiotensin-aldosterone system. Better understanding of mechanisms underlying the pathogenesis of primary hypertension is crucial in development of such a treatment that not only reduces blood pressure but also prevents cardiovascular complications of hypertension.

Topics: Aldosterone; Angiotensin II; Endothelins; Humans; Hypertension; Neuropeptide Y; Nitric Oxide; Renin; Vasopressins

Topics: Angiotensinogen; Animals; Disease Models, Animal; Genes; Humans; Hypertension; Neuropeptide Y; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Receptors, Angiotensin; Renin; Type C Phospholipases

To evaluate whether neuropeptide Y (NPY) is likely to be relevant as a regulator of cardiovascular function in general and of blood pressure control in arterial hypertension in particular, based on a literature survey.. NPY is a putative cotransmitter of many central and peripheral sympathetic neurons. It and its receptors are present in brain areas and peripheral tissues involved in cardiovascular regulation, and administration of exogenous NPY to these sites can elicit functional cardiovascular responses by acting on specific pre- and postsynaptic receptors. Moreover, NPY may act as a growth factor for the development of vascular and cardiac hypertrophy. The release of NPY and postsynaptic vasoconstriction responses to NPY may be enhanced in hypertension, whereas presynaptic inhibitory responses may be attenuated. Some of these alterations may precede the development of blood pressure elevations in the spontaneously hypertensive rat model of genetic hypertension.. NPY might be an important physiological and pathophysiological modulator of cardiovascular function, but further studies using specific high-affinity antagonists are required.

Topics: Animals; Brain; Cardiovascular System; Humans; Hypertension; Neuropeptide Y; Receptors, Neuropeptide Y

Neuropeptide Y is a 36 amino acid peptide that was originally discovered in extracts of porcine brain. The peptide has a broad distribution in the central or peripheral nervous system. Receptors for this peptide were originally subdivided into postsynaptic Y-1 receptors and presynaptic Y-2 receptors. The Y-1 receptor has recently been cloned and appears to mediate several effects of NPY including vasoconstriction and an anxiolytic effect in animal models of anxiety. The Y-2 receptor inhibits the release of neurotransmitters in the CNS by the inhibition of the mobilization of intracellular calcium. Additional receptors have been proposed including a Y-3 receptor that recognizes NPY but not the related endocrine peptide, PYY. The functional importance of these newer receptors remains to be established. The absence of useful antagonists has made the study of NPY a challenge for investigators in the field. The potential utility of such molecules is discussed.

Topics: Animals; Brain; Cardiovascular Physiological Phenomena; Cognition; Feeding Behavior; Humans; Hypertension; Neuropeptide Y; Neurotransmitter Agents; Peptide YY; Peptides; Receptors, Neuropeptide Y; Receptors, sigma

To assess the potential for development of new classes of pharmacological drugs in the treatment of hypertension and cardiovascular disease.. Basis of pharmacological blood pressure reduction: Since the discovery of the renin-angiotensin system by Tigerstedt almost 100 years ago, a large number of vasoactive peptides have been discovered. By interaction with such peptides of endocrine, perivascular or endothelial origin, blood pressure may be modulated. BLOCKADE OF THE RENIN-ANGIOTENSIN SYSTEM: The success of the angiotensin converting enzyme (ACE) inhibitors in hypertension and congestive heart failure is generally attributed to reduced generation of angiotensin II. The recent development of specific and highly potent Ang II type 1 subtype receptor antagonists such as losartan (DuP753, MK954) have provided a new opportunity to inhibit the renin-angiotensin system, and this is currently being explored in hypertensive patients. In addition, blockade of the first and rate-limiting reaction of the renin-angiotensin system, inhibition of renin activity, is also a target for the development of antihypertensive drugs. However, this development is hampered at present by a compensatory increase in active renin that clinically offsets the antihypertensive action of renin inhibitors. PHARMACOLOGICALLY INDUCED INCREASE IN ATRIAL NATRIURETIC PEPTIDE (ANP): The availability of circulating or tissue ANP may be increased by inhibiting its metabolic clearance by NEP-24.11 inhibitor drugs. These agents induce a reduction in blood pressure and diuretic effects in animal models, and may become a new class of drugs for the clinical management of patients with hypertension and congestive heart failure. OTHER POTENTIAL PHARMACOLOGICAL TARGETS IN THE MANAGEMENT OF HYPERTENSION: There are several potential pharmacological targets that may lead to the development of novel antihypertensive agents in the future. These include the interaction or blockade of vasopressor peptides. Routes of development include neuropeptide Y1 receptor antagonists, which block the postjunctional vasopressor effect of neuropeptide Y, or endothelin antagonists, which block endothelin pressor actions at the endothelin A receptor site. The cardiovascular actions of the functional neuropeptide Y inhibitor alpha-trinositol (PP 56) provide a potential new mechanism for reducing blood pressure in hypertension. In addition, the recent discovery of small molecular agents with high potency and specificity for the endothelin A receptor subtype may also be of value in specific vascular disease states.. Future development is likely to provide us with novel drugs based on interactions with vasoactive peptides that may improve the management of specific cardiovascular disease states.

Topics: Amino Acid Sequence; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Endothelins; Humans; Hypertension; Molecular Sequence Data; Neprilysin; Neuropeptide Y; Renin; Renin-Angiotensin System

Topics: Adenosine; Animals; Blood Pressure; Glucagon; Histamine; Humans; Hypertension; Lipids; Neuropeptide Y; Platelet Activating Factor; Thyroid Hormones

Yet another 'orphan' molecule that had to find its place in life after isolation and sequencing, neuropeptide Y appears to be an important cardiovascular neuroregulator and also links the sympathetic and renin-angiotensin systems. The peptide's physiologic and pathophysiologic roles, as well as its potential therapeutic value, are examined.

Topics: Animals; Blood Pressure; Coronary Vessels; Humans; Hypertension; Neuroeffector Junction; Neuropeptide Y; Rats; Renin-Angiotensin System; Sodium, Dietary; Sympathetic Nervous System; Vasoconstriction

Topics: Female; Humans; Hypertension; Labor, Obstetric; Neuropeptide Y; Pregnancy; Spasm

Renal sympathetic denervation (RSD) represents a safe and effective treatment option for certain patients with resistant hypertension and has been shown to decrease sympathetic activity. Neuropeptide Y (NPY) is a neurotransmitter that is co-released with norepinephrine and is up-regulated during increased sympathetic activity. The aim of the present study was to examine the effect of RSD on NPY and to analyze the association between changes in NPY levels and blood pressure reduction after RSD.. A total of 150 consecutive patients (age 64.9 ± 10.2 years) from three clinical centers undergoing RSD were included in this study. Response to RSD was defined as an office systolic blood pressure (SBP) reduction of >10 mmHg 6 months after RSD. Venous blood samples for measurement of NPY were collected prior to and 6 months after RSD.. BP and NPY levels were significantly reduced by 23/9 mmHg (p = 0.001/0.001) and 0.24 mg/dL (p < 0.01) 6 months after RSD. There was a significant correlation between baseline SBP- and RSD-related systolic BP reduction (r = -0.43; p < 0.001) and between serum NPY baseline values and NPY level changes (r = -0.52; p < 0.001) at the 6-month follow-up. The BP response to RSD (>10 mmHg) was associated with a significantly greater reduction in NPY level when compared with BP non-responders (p = 0.001).. This study demonstrates an effect of RSD on serum NPY levels, a specific marker for sympathetic activity. The association between RSD-related changes in SBP and NPY levels provides further evidence of the effect of RSD on the sympathetic nervous system.

Topics: Aged; Blood Pressure; Female; Follow-Up Studies; Humans; Hypertension; Male; Middle Aged; Neuropeptide Y; Sympathectomy; Treatment Outcome

Beyond their hypolipidemic effect, statins reduce cardiovascular risk in hypertensive subjects via various mechanisms; one suggested mechanism is that they reduce sympathetic activity. We investigated the hypothesis that simvastatin decreased muscle sympathetic nerve activity (MSNA) in 31 hypertensive subjects with hypercholesterolemia (aged 38.7 ± 10 years). In this randomized, placebo-controlled, double-blinded study, patients were treated with simvastatin (40 mg day(-1); n=15) or placebo (n=16) for 8 weeks. Before and after treatment, we measured MSNA, blood pressure and heart rate. Baroreceptor control of the heart rate, or baroreceptor sensitivity (BRS), was computed by the sequence method, a cross-analysis of systolic blood pressure and the electrocardiogram R-R interval. Blood samples were tested for plasma levels of catecholamines, neuropeptide Y, aldosterone, endothelin and renin activity. Simvastatin significantly reduced MSNA (from 36.5 ± 5 to 27.8 ± 6 bursts per min, P=0.001), heart rate (from 77 ± 6.7 to 71 ± 6.1 beats per min, P=0.01) and both total and low-density lipoprotein cholesterol (from 249 ± 30.6 to 184 ± 28.3 mg dl(-1), P=0.001 and from 169 ± 30.6 to 117 ± 31.2 mg dl(-1), P=0.01, respectively). Simvastatin also improved BRS (from 10.3 ± 4.1 to 17.1 ± 4.3 ms per mm Hg, P=0.04). No changes were observed in systolic or diastolic blood pressures, or in plasma levels of catecholamines, neuropeptide Y, endothelin, aldosterone and renin activity. After simvastatin therapy, MSNA and BRS were inversely related (r=-0.94, P<0.05). In conclusion, we found that, in patients with hypertension and hypercholesterolemia, simvastatin reduced MSNA, and this was related to increased baroreceptor sensitivity.

Topics: Adult; Aldosterone; Anticholesteremic Agents; Blood Pressure; Catecholamines; Comorbidity; Double-Blind Method; Endothelins; Heart Rate; Humans; Hypercholesterolemia; Hypertension; Male; Middle Aged; Neuropeptide Y; Pressoreceptors; Renin; Simvastatin; Sympathetic Nervous System; Treatment Outcome

To compare the effect of ARB and ACE inhibitor on sympathetic activity in 32 hypertensives.. After a four-week wash-out period, patients were randomized to four weeks of therapy with enalapril or telmisrtan, with crossover to another drug for another four weeks. Blood pressure (BP), NPY, and catecholamine levels and HRV (frequency analysis) were measured during wash-out, in basal condition, and after postural stimulation test (PST).. Both drugs significantly reduced BP and NPY as compared to initial values, while no differences in BP and NPY between drugs were observed. Increase in NPY during PST was significantly higher in the enalapril than in the telmisartan group and during the wash-out period. No differences between enalapril and telmisartan in plasma catecholamines were observed. Telmisartan decreased low frequency/high frequency ratio as compared to initial values and enalapril values.. Despite similar BP control, telmisartan attenuated autonomic balance more effectively than enalapril.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Cross-Over Studies; Enalapril; Epinephrine; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Neuropeptide Y; Norepinephrine; Posture; Sympathetic Nervous System; Telmisartan; Treatment Outcome

To observe the effect of Jiangya Capsule (JYC) on serum levels of nitric oxide synthase (NOS) activity and malondialdehyde (MDA), and plasma concentration of neuropeptide Y (NPY) and homocysteine (Hcy) in patients with senile simple systolic hypertension.. Randomized, double-blinded controlled method was adopted, the patients were divided into two groups, the treated group treated with JYC and the control group treated with Nimodipine. Changes of blood pressure, serum level of NOS and MDA, and plasma concentration of NPY and Hcy were observed.. The effect of lowering blood pressure in the two groups were similar with insignificant difference (u = 0.24, P > 0.05). The total effective ratio in alleviating TCM syndrome was 90% (18/20) in the treated group and 60% (9/15) in the control group, comparison between them showed significant difference (u = 2.18, P < 0.05). After treatment, the NOS activity increased and MDA, NPY and Hcy levels decreased in the treated group, which showed significant difference as compared with those before treatment, and the improvement were better than those in the control group (all P < 0.05 or P < 0.01). While in the control group after treatment, only level of MDA was lowered significantly (P < 0.05).. JYC has good effect in treating senile simple systolic hypertension, it also could increase the NOS activity, lower the serum MDA level, obviously reduce the plasma concentration of Hcy and NPY.

Topics: Aged; Capsules; Double-Blind Method; Drugs, Chinese Herbal; Female; Homocysteine; Humans; Hypertension; Male; Malondialdehyde; Middle Aged; Neuropeptide Y; Nitric Oxide Synthase; Phytotherapy

This study investigates the release of Neuropeptide Y from eight human pheochromocytomas. Profil immunoreactive Neuropeptide Y (Ir-NPY) levels during the management of surgery were compared with these of norepinephrine (NE) while hemodynamics were monitored. Plasma IrNPY and NE levels increased during tumor manipulation and returned to near normal one hour after operation. However, Ir-NPY levels remained high just after tumor resection while NE levels were significantly decreased. At tumor manipulation and just after tumor resection, plasma Ir-NPY levels were correlated with the systemic vascular resistances (SVR) (r = 0.74; P<0.04 and r = 0.86; P<0.006 respectively). No correlation was found either between plasma Ir-NPY and NE levels or between plasma NE levels and SVR. The release of Ir-NPY from tumor tissue, studied by a superfusion method, exhibited a significant correlation with the plasma Ir-NPY concentrations at the time of corresponding tumor resection (r = 0.95; P<0.007). Chromatographic analysis showed that Ir-NPY in plasma and outflow migrate as human NPY (1-36). These results confirmed that in pheochromocytoma, plasma NPY mainly originates from the tumor and argue for an important role of NPY in pheochromocytoma hypertension as indicated by the correlation between the Ir-NPY levels and the SVR.

Topics: Adrenal Gland Neoplasms; Adult; Analysis of Variance; Female; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Neuropeptide Y; Norepinephrine; Pheochromocytoma; Vascular Resistance

To observe the effect of Yimai Jiangya extract (YMJYE) on plasma neuropeptide Y (NPY) level in patients of senile hypertension at stage II with Qi-Deficiency and blood stasis Syndrome (QDBSS).. Sixty-eight patients were randomly divided into two groups, 36 patients in the treated group treated with YMJYE and 32 patients in the control group treated with captopine. Radioimmunoassay was used to examine the level of plasma NPY before and after treatment in the two groups.. Before treatment, plasma NPY level was significantly higher in both groups than that in the old healthy persons (P < 0.01), it lowered significantly after treatment and the decrement was more obvious in the treated group in comparing with that in the control group (P < 0.01). Blood pressure was significantly lowered in both groups after treatment (P < 0.01) but with no significant difference between them.. Plasma NPY level was increased in patients of senile hypertension with QDBSS. YMJYE had good effect in lowering plasma NPY level and reducing blood pressure. It is presumed that the NPY lowering effect of YMJYE might be one of its mechanisms in lowering blood pressure.

Topics: Aged; Diagnosis, Differential; Drugs, Chinese Herbal; Female; Humans; Hypertension; Male; Medicine, Chinese Traditional; Middle Aged; Neuropeptide Y; Phytotherapy; Qi; Yang Deficiency

Leptin is produced and released by adipocytes in proportion to fat stores. Leptin as an anorectic hormone plays an important role in the regulation of food intake, energy expenditure, and insulin secretion. In contrast, neuropeptide Y, insulin, cortisol, and growth hormone are presumed to be appetite modulators. Leptin and neuropeptide Y are both involved in the activation of sympathetic tone. Increased body fat stores in obese patients are involved in the pathogenesis of some metabolic disorders (e.g., hyperinsulinaemia, glucose intolerance) and arterial hypertension.. Based on this pathophysiological background, we tried to assess the relationship between plasma leptin and blood pressure in 41 patients with essential hypertension (EHP; 20 females, 21 males, mean age 38.7+/-1.9 years, mean body mass index - BMI - 25.8+/-0.5 kg/m2) and in an appropriately sex- and BMI-matched control group of 27 normotensive healthy subjects (NHS; 11 females, 16 males, mean age 39.7+/-2.5 years, mean BMI 24.8+/-0.6 kg/m2). The plasma leptin concentration did not differ significantly between EHP and NHS (13.0+/-1.9 vs. 8.1+/-1.0 ng/ml, respectively). In both groups a significant positive correlation was found between BMI and plasma leptin concentration (p<0.0001). A significant positive correlation (p<0.02) was found between leptinaemia and mean (MAP), systolic and diastolic blood pressures, if data were analyzed for all examined subjects or separately only for women. Such a correlation could not be confirmed for male NHS and EHP subjects. The plasma neuropeptide Y concentration was higher in EHP than in NHS (77.1+/-23.0 vs. 63.6+/-9.8pg/ml, p = 0.05). In contrast to neuropeptide Y plasma insulin, cortisol, and growth hormone concentrations were similar in EHP and in NHS.. Both EHP and NHS are characterized by a positive correlation between BMI and leptinaemia. Leptin may be indirectly involved in blood pressure regulation, especially in women of both NHS and EHP.

Topics: Adult; Appetite; Blood Pressure; Body Mass Index; Female; Hormones; Humans; Hypertension; Leptin; Male; Neuropeptide Y; Proteins; Sex Characteristics; Sympathetic Nervous System

We aimed to study the white-coat effect (WCE) of clinic blood pressure (BP) and its relation to plasma cortisol, neuropeptide Y (NPY) and demographic variables. Henry et al. have earlier suggested two stress-reaction patterns. The "defeat reaction" mainly involves the cortisol-axis and the "fight-flight-response" is mediated by the sympathoadrenal-system. Ninety-one men and 88 women 20-70 years of age, randomly selected from the population were recruited in this cross-sectional study. Clinic BP, plasma cortisol and plasma NPY (both analysed by radio-immunoassay) were obtained at 0800 h and 24h ambulatory BP (ABP) was performed. WCE was defined as supine clinic BP - mean daytime ABP. Cortisol correlated to the systolic WCE in the total material* (r = 0.22, p = 0.005) and in men 45-70 years of age (r = 0.45, p = 0.002, n = 47) and to diastolic WCE in women 45-70 years of age* (r = 0.37, p = 0.02, n = 38). (*women treated with oestrogens, or being pregnant, excluded, n = 21). Only in women did NPY correlate weakly to the systolic WCE (r = 0.22, p = 0.044). Subjects with one or more first degree hypertensive relative had a more marked systolic WCE than those without (-0.02 +/- 10 mmHg and -4.1 +/- 9.3 mmHg, respectively, p = 0.01). In conclusion cortisol correlated stronger to the WCE than did NPY. This would suggest the WCE to be a defeat reaction rather than a fight-flight-response.

Topics: Aged; Blood Pressure Determination; Blood Pressure Monitoring, Ambulatory; Cross-Sectional Studies; Female; Humans; Hydrocortisone; Hypertension; Linear Models; Male; Middle Aged; Neuropeptide Y; Physician-Patient Relations; Stress, Psychological

Obesity increases the risk of developing hypertension by two-to fourfold, with more that one third of all cases of hypertension attributable to obesity. The present study tested the role of atrial natriuretic peptide (ANP), endothelin-1,2 (ET-1,2) and neuropeptide Y (NPY) in pathogenesis of obesity hypertension. The plasma concentrations of ANP, ET-1,2 and NPY were determined in the peripheral venous blood by radioimmunoassay in 27 obese hypertensive patients (group I), in 24 obese normotensive patients (group II), and in 35 normal subjects (group III).. Mean plasma ANP was significantly higher in obese than in normal subjects. ANP levels were higher in patients group I than in those group II and I. In patients of group I plasma ANP concentrations correlated with III BMI and mean blood pressure. Plasma levels of ET-1,2 and NPY were similar in patients group I, II and III.

Topics: Adolescent; Adult; Aged; Atrial Natriuretic Factor; Catecholamines; Endothelin-1; Endothelin-2; Humans; Hypertension; Male; Middle Aged; Neuropeptide Y; Obesity; Peptides

Neuropeptide Y (NPY) has been recently characterized as a circulating vasoconstrictor peptide which is co-stored with noradrenaline in sympathetic neurons. To investigate the role of NPY concentration in hypertension we measured the circulating NPY, endothelin-1,2 (ET-1,2), atrial natriuretic peptide (ANP), aldosterone, plasma renin activity (PRA) and noradrenaline (NA) in patients with stable mild to moderate primary hypertension. Circulating levels of NPY, ET-1,2, ANP, aldosterone and PRA were measured with radioimmunoassay, NA by double-isotope radioenzymatic assay. There were significant increase in concentrations NPY, ET-1,2, ANP and NA in patients with moderate primary hypertension, and significant positive correlations between the plasma levels of NPY, ET-1,2 and NA.

Topics: Adult; Aged; Aldosterone; Atrial Natriuretic Factor; Endothelins; Female; Humans; Hypertension; Male; Middle Aged; Neuropeptide Y; Norepinephrine; Renin

To study the relations between neuropeptide Y (NPY) and age, gender, blood pressure (BP) and risk factors for cardiovascular disease and the renin angiotensin system, we performed a population-based study through random selection of 220 subjects (49% men). Subjects on antihypertensive therapy were excluded and participation rate was 67%. Venous blood was drawn at 08.00 h in the fasting state and a Spacelab 90202/90207 ambulatory BP device was then fitted. Plasma NPY levels were normally distributed and the mean level was 144 +/- 17 pmol/L (mean +/- SD). There was a trend towards higher levels in women than in men (147 +/- 17 pmol/L and 142 +/- 17 pmol/L, respectively, p = 0.053). No correlations were found between NPY and ambulatory BP or clinic BP in either gender. Angiotensin II correlated positively with NPY in men but not in women (r = 0.27, p = 0.007). There were no correlations between NPY and body mass index, waist/hip ratio, BP or C-peptide in either gender. Total cholesterol (r = 0.39, p < 0.0001) and LDL-cholesterol (r = 0.35, p = 0.0001) were positively correlated with NPY in women only. The correlation remained in multiple regression analysis with plasma total or LDL- cholesterol as second independent variable to age, and NPY as dependent variable (total cholesterol: standardised r = 0.43, p = 0.0002, LDL-cholesterol: standardised r = 0.34, p = 0.002, respectively).. The positive correlation between LDL-cholesterol and NPY in women, independent of age, and components of the metabolic syndrome, makes it a possible gender-specific cardiovascular riskmarker.

Topics: Blood Pressure; Cholesterol, LDL; Female; Humans; Hypertension; Male; Neuropeptide Y; Renin-Angiotensin System; Risk Factors

Neuropeptide Y, a potent vasoconstrictor peptide with 36 amino acid residues, is co-stored and released with catecholamines in sympathetic nerve endings. In this study responses in circulating neuropeptide Y induced by baroreceptor activation during change from the supine to the head-up position was measured in normal subjects and untreated essential hypertensives. Furthermore, the relationships with plasma catecholamines, endothelin-1, renin and serotonin were studied. No significant differences of plasma neuropeptide Y were found between normotensive and hypertensive subjects, before or after postural changes, and there was no correlation with a range of the vasoactive substances studied. Our results suggest that plasma neuropeptide Y does not increase with noradrenaline on sympathetic activation during postural stress both in normals and in hypertensive subjects. In man, measurement of plasma neuropeptide Y during head-up tilt does not provide a useful estimation of sympathetic nervous activity.

Topics: Adult; Catecholamines; Endothelins; Female; Humans; Hypertension; Male; Middle Aged; Neuropeptide Y; Posture; Renin; Serotonin

The aim or the study was to assess plasma neuropeptide Y immunoreactivity concentration (NPY-ir) during dynamic exercise in pts with different stages of essential hypertension (ESH). We studied 25 males aged 29.4 +/- 6.3 yrs with established ESH (ESH) and 12 healthy males aged 27.3 +/- 5.1 yrs (C). Plasma concentrations of NPY-ir, NA, A, BP were measured before treadmill test, in the last minute of two six-min. work loads corresponding to 60% and 80% of maximal individual load and 30 min. after cessation of exercise. Plasma NPY-ir was evaluated with RIA, NA and A with REA. Gradual exercise resulted in an increase of NPY-ir in ESH (from 14.4 +/- 5.8 to 18.1 +/- 6.4 and 20.7 +/- 8.1 fmol/ml p = 0.036, p = 0.02) and in C (from 11.7 +/- 4.6 to 13.4 +/- 5.0 and 15.2 +/- 5.9 fmol/ml, p < 0.01). Likewise plasma NA and A increased in both groups. Plasma NPY-ir during exercise was significantly higher in ESH than in C (p = 0.041 and p = 0.047) while no such differences were observed in plasma NA and A. According to the left ventricle mass index (LVMI) ESH was divided into two subgroups: with left ventricular hypertrophy (LVH+) n = 10, LVMI = 159.7 +/- 7.7 g/m2 and without the hypertrophy (LVH-) n = 15 LVMI = 112.3 +/- 19.2g/m2. LVH- presented significant increase in plasma NPY-ir during exercise (from 14.7 +/- 5.7 to 18.2 +/- 6.5, 22.8 +/- 8.3 fmol/ml p < 0.01), while no changes in LVH+ were observed (from 14.1 +/- 5.8 to 17.8 +/- 6.0 and 17.8 +/- 6.7 fmol/ml, ns). LVH+ were older than LVH- (33.4 +/- 7.1 yrs vs 26.7 +/- 4.2 p = 0.04), but no correlation between age and plasma NPY-ir was noticed. No differences in plasma NA and A were present between these subgroups.. Patients at different stages of essential hypertension display various patterns of sympatho-adrenal activation during dynamic exercise.

Topics: Adult; Blood Pressure; Epinephrine; Exercise; Exercise Test; Heart Rate; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Neuropeptide Y; Norepinephrine; Prohibitins

1. Cortisol-induced blood pressure rises in men are not accompanied by increases in plasma catecholamines. The present study examines the effects of cortisol on the sympathetic co-transmitter, neuropeptide Y (NPY). 2. Eight normal men were given cortisol 200 mg/day over 5 days and haemodynamic, metabolic and hormonal measures were taken. Plasma NPY-like immunoreactivity (NPY-LI) concentrations were measured by direct radio-immunoassay. 3. Cortisol significantly increased systolic, diastolic and mean arterial pressure, bodyweight, plasma glucose and total white cell concentration and decreased plasma potassium and total eosinophil count, as in previous studies. Plasma NPY concentrations were not altered significantly during cortisol treatment, but increased following cessation of cortisol treatment (P = 0.006). 4. The essentially unchanged pattern for NPY concentration with cortisol treatment resembles that previously reported for adrenaline and noradrenaline, but the increase in NPY on cortisol withdrawal was not seen for adrenaline or noradrenaline. These data do not support a role for sympathetic activation in the genesis of cortisol-induced hypertension.

Topics: Adult; Analysis of Variance; Blood Glucose; Blood Pressure; Body Weight; Eosinophils; Humans; Hydrocortisone; Hypertension; Leukocyte Count; Male; Neuropeptide Y; Potassium; Pulse; Radioimmunoassay; Time Factors

The aim of this study was to examine the effects of D-myo-inositol-1,2,6-trisphosphate (alpha-trinositol) on haemodynamic variables and neuropeptide Y (NPY) levels in hypertensives and healthy volunteers.. Hypertensives (n = 13) and normotensives (n = 11) were recruited after a screening of cardiovascular risk factors of all men aged 40 living in a well defined area. The hypertensives were previously unmedicated. The effect of alpha-trinositol was studied after intravenous infusion at rest, and during and after a maximal exercise test in a double-blind crossover manner with placebo.. Haemodynamic variables and NPY levels were recorded. NPY levels did not differ between normotensives and mild hypertensives at the start of the study. However, a significant increase was seen in hypertensives after they had risen to the sitting position. During exercise, the NPY levels increased significantly both in normotensives and hypertensives. After the exercise test, the NPY levels were significantly higher in hypertensives than in normotensives; alpha-trinositol did not modify these responses. In normotensives no significant difference in systolic blood pressure was seen during or after the exercise test whether they were on alpha-trinositol or placebo. In the hypertensives on active drug, however, the blood pressure tended to be approximately 5 mmHg lower during the exercise test as compared with the placebo group. In the hypertensives on active drug, the heart rate increased significantly more during exercise as compared with the placebo groups. In normotensives, the same tendency was seen, but it did not reach statistical significance.. The NPY antagonist, alpha-trinositol, tends to reduce the increase in systolic blood pressure induced by maximal exercise and increases the heart rate in hypertensives but not in normotensives.

Topics: Adult; Blood Pressure; Cross-Over Studies; Double-Blind Method; Heart Rate; Hemodynamics; Humans; Hypertension; Inositol Phosphates; Male; Neuropeptide Y; Pilot Projects

Neuropeptide Y (NPY), a potent vasoconstrictor agent reported to be released, in addition to norepinephrine (NE), by sympathetic nerve endings during stress, may contribute to the pressor response to various stimuli. The objectives of this study were to determine (a) whether plasma NPY concentrations are altered during different types of stress (cold pressor test, mental stress, and active orthostatism) and (b) whether clonidine, via its central sympatholytic effect, affects the stress-induced blood pressure, NPY, and/or catecholamine changes. Eighteen untreated patients with mild essential or borderline hypertension participated in an acute randomized, double-blind, parallel study. The blood pressure and heart rate were recorded during three control periods, each followed by either a cold pressor test (CPT), a mental stress test (MS: mental arithmetic), or active orthostatism (AO), performed in a random order. Venous blood samples for catecholamines and NPY determination were taken at the end of each control and test period. This entire procedure was repeated after oral clonidine (150 micrograms) or placebo. Before treatment, a CPT, MS, or AO increased the blood pressure to the same extent. The stress-induced increase in plasma NE was greater during AO (+99 +/- 23%) than during CPT (+35 +/- 8%) and MS (+55 +/- 12%). The stress-induced increase in plasma epinephrine was only significant during MS (+142 +/- 69%). A small but significant increase in NPY (p < 0.05) was observed during AO only (+10 +/- 7%). Compared to placebo, clonidine significantly decreased the basal blood pressure and the pressor response to CPT, but did not change the pressor response to MS and AO.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Catecholamines; Clonidine; Cold Temperature; Double-Blind Method; Epinephrine; Female; Humans; Hypertension; Hypotension, Orthostatic; Male; Middle Aged; Neuropeptide Y; Norepinephrine; Rest; Stress, Physiological; Stress, Psychological

The purpose of this study was to examine the effects of short-term captopril therapy during sodium restriction on several markers of the sympathetic nervous system, including plasma norepinephrine, neuropeptide Y, beta-adrenergic receptors and cortisol.. Recent studies suggest that the therapeutic effects of converting enzyme inhibitors involve not only the renin-angiotensin and prostaglandin systems but also the sympathetic system.. Twelve hypertensive and 20 normotensive men were studied after 2 5-day hospital stays during which they consumed a 10-mEq sodium diet and received captopril (25 mg twice daily) or placebo in a double-blind crossover study.. Captopril decreased neuropeptide Y (p < 0.05) and angiotensin II (p < 0.01) and increased isoproterenol-stimulated cyclic adenosine monophosphate (AMP) in lymphocytes (p < 0.03), plasma norepinephrine (p < 0.02), cortisol (p < 0.05) and renin (p < 0.001) in both hypertensive and normotensive subjects. Hypertensive subjects had an increased beta-adrenergic receptor density (p < 0.02) and a greater decrease in diastolic blood pressure compared with normotensive subjects (p < 0.02).. The results of this study suggest that the short-term therapeutic effects of captopril may involve concerted changes in key components of the sympathetic nervous system. These findings, such as decreased neuropeptide Y combined with increased norepinephrine and beta-adrenergic receptors, are compatible with the observation of increased cardiac output and decreased peripheral resistance after short-term angiotensin-converting enzyme inhibition.

Topics: Analysis of Variance; Captopril; Diet, Sodium-Restricted; Double-Blind Method; Humans; Hydrocortisone; Hypertension; Lymphocytes; Male; Neuropeptide Y; Norepinephrine; Receptors, Adrenergic, beta; Reference Values; Renin-Angiotensin System; Sympathetic Nervous System; Time Factors

Although studies indicate that converting enzyme inhibitors such as captopril influence beta-adrenergic physiology, the data on alpha-adrenergic physiology is inconsistent. This study therefore examined the effects of captopril (50 mg/day for 5 days) during sodium restriction on the pressor response and on angiotensin II and neuropeptide Y levels to infused norepinephrine (0.01 to 0.1 micrograms/kg/min) in 17 hypertensive and 27 normotensive subjects. Angiotensin II increased significantly in response to infused norepinephrine during placebo administration (p < 0.001) but not during captopril administration (p = 0.15). Neuropeptide Y levels decreased in response to captopril (p = 0.02). Despite these changes the pressor response to infused norepinephrine was unchanged with captopril. These data support the conclusion that the antihypertensive action of captopril is unrelated to alterations in norepinephrine-mediated alpha-adrenergic pressor regulation. The finding of a decrease in neuropeptide Y levels may have relevance to the therapeutic effects of captopril.

Topics: Adult; Analysis of Variance; Angiotensin II; Blood Pressure; Captopril; Diet, Sodium-Restricted; Double-Blind Method; Heart Rate; Humans; Hypertension; Male; Middle Aged; Neuropeptide Y; Norepinephrine

Chronic high salt intake is one of the leading causes of hypertension. Salt activates the release of the key neurotransmitters in the hypothalamus such as vasopressin to increase blood pressure, and neuropepetide Y (NPY) has been implicated in the modulation of vasopressin levels. NPY in the hypothalamic arcuate nucleus (Arc) is best known for its control in appetite and energy homeostasis, but it is unclear whether it is also involved in the development of salt-induced hypertension. Here, we demonstrate that wild-type mice given 2% NaCl salt water for 8 weeks developed hypertension which was associated with marked downregulation of NPY expression in the hypothalamic Arc as demonstrated in NPY-GFP reporter mice as well as by in situ hybridization analysis. Furthermore, salt intake activates neurons in the hypothalamic paraventricular nucleus (PVN) where mRNA expression of brain-derived neurotrophic factor (BDNF) and vasopressin was found to be upregulated, leading to elevated serum vasopressin levels. This finding suggests an inverse correlation between the Arc NPY level and expression of vasopressin and BDNF in the PVN. Specific restoration of NPY by injecting AAV-Cre recombinase into the Arc only of the NPY-targeted mutant mice carrying a loxP-flanked STOP cassette reversed effects of salt intake on vasopressin and BDNF expression, leading to a normalization of salt-dependent blood pressure. In summary, our study uncovers an important Arc NPY-originated neuronal circuitry that could sense and respond to peripheral electrolyte signals and thereby regulate hypertension via vasopressin and BDNF in the PVN.

Topics: Animals; Brain-Derived Neurotrophic Factor; Hypertension; Mice; Neuropeptide Y; Sodium Chloride; Sodium Chloride, Dietary; Vasopressins

By reducing their metabolism, dipeptidyl peptidase 4 inhibition (DPP4I) enhances the effects of numerous peptides including neuropeptide Y

Topics: 2-Methoxyestradiol; Animals; Cell Proliferation; Cells, Cultured; Chemokine CXCL12; Collagen; Dipeptidyl-Peptidase IV Inhibitors; Female; Hypertension; Male; Neuropeptide Y; Peptide Fragments; Peptide YY; Rats; Rats, Inbred SHR; Rats, Inbred WKY

To investigate the features of neuropeptide Y (NPY), α-melanocyte stimulating hormone (α-MSH), and agouti-related protein (AgRP) in type 2 diabetes mellitus (T2DM) patients with hypertension.. Patients with T2DM (n = 384) and healthy volunteers (n = 80) were enrolled into this study. Serum NPY, α-MSH, and AgRP levels were detected using ELISA.. Significantly higher NPY and lower α-MSH and AgRP levels were observed in patients with diabetes compared with those without diabetes, and the mean NPY levels increased, while α-MSH and AgRP levels decreased, with the development of hypertension compared with diabetic patients without hypertension. α-MSH and AgRP levels decreased with an increase in blood pressure in hypertension compared with the non-hypertension patients. Multiple stepwise linear regression analysis showed that NPY, α-MSH, and AgRP levels were closely associated with blood pressure and glucose control. Receiver operating characteristic (ROC) curve analyses indicated that α-MSH may be a better marker compared with NPY and AgRP for regulating glucose and blood pressure and to distinguish between T2DM patients with and without hypertension.. NPY, α-MSH, and AgRP might play different roles and be closely related to the occurrence and development of diabetes and hypertension.

Topics: Aged; Agouti-Related Protein; alpha-MSH; Animals; Biomarkers; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Healthy Volunteers; Humans; Hypertension; Male; Middle Aged; Neuropeptide Y; ROC Curve

To determine whether renal denervation (RDN) in hypertensive patients affects the platelet activation status.. We investigated the effect of RDN on the platelet activation status in 41 hypertensive patients undergoing RDN. Ambulatory blood pressure (BP), plasma sympathetic neurotransmitter Neuropeptide Y, and platelet activation markers were measured at baseline, at 3 months, and 6 months after RDN. RDN significantly decreased BP at 3 months (150.6 ± 11.3/80.9 ± 11.4 mmHg to 144.7 ± 12.0/77.1 ± 11.1 mmHg; P < 0.01) and at 6 months (144.3 ± 13.8/78.3 ± 11.1 mmHg; P < 0.01). Plasma levels of the sympathetic neurotransmitter Neuropeptide Y, an indicator of sympathetic nerve activity, were significantly decreased at 3 months (0.29 ± 0.11 ng/mL to 0.23 ± 0.11 ng/mL; P < 0.0001) and at 6 months (0.22 ± 0.12 ng/mL; P < 0.001) after RDN. This was associated with a reduction in platelet membrane P-selectin expression (3 months, P < 0.05; 6 months, P < 0.05), soluble P-selectin (6 months, P < 0.05), circulating numbers of platelet-derived extracellular vesicles (EVs) (3 months, P < 0.001; 6 months, P < 0.01), and phosphatidylserine expressing EVs (3 months, P < 0.001; 6 months, P < 0.0001), indicative of a reduction in platelet activation status and procoagulant activity. Only patients who responded to RDN with a BP reduction showed inhibition of P-selectin expression at 3 months (P < 0.05) and 6 months (P < 0.05) as well as reduction of glycoprotein IIb/IIIa activation at 3 months (P < 0.05). Notably, 13 patients who took aspirin did not show significant reduction in platelet P-selectin expression following RDN.. Our results imply a connection between the sympathetic nervous system and the platelet activation status and provide a potential mechanistic explanation by which RDN can have favourable effects towards reducing cardiovascular complications.

Topics: Aged; Biomarkers; Blood Coagulation; Blood Platelets; Blood Pressure; Catheter Ablation; Extracellular Vesicles; Female; Humans; Hypertension; Kidney; Male; Middle Aged; Neuropeptide Y; P-Selectin; Phosphatidylserines; Platelet Activation; Platelet Glycoprotein GPIIb-IIIa Complex; Renal Artery; Sympathectomy; Time Factors; Treatment Outcome

Diabetic retinopathy (DR) is one of the major complications of diabetes, which eventually leads to blindness. Up to date, no animal model has yet shown all the co-morbidities often observed in DR patients. Here, we investigated whether obese 42 weeks old ZSF1 rat, which spontaneously develops diabetes, hypertension and obesity, would be a suitable model to study DR. Although arteriolar tortuosity increased in retinas from obese as compared to lean (hypertensive only) ZSF1 rats, vascular density pericyte coverage, microglia number, vascular morphology and retinal thickness were not affected by diabetes. These results show that, despite high glucose levels, obese ZSF1 rats did not develop DR. Such observations prompted us to investigate whether the expression of genes, possibly able to contain DR development, was affected. Accordingly, mRNA sequencing analysis showed that genes (i.e. Npy and crystallins), known to have a protective role, were upregulated in retinas from obese ZSF1 rats. Lack of retina damage, despite obesity, hypertension and diabetes, makes the 42 weeks of age ZSF1 rats a suitable animal model to identify genes with a protective function in DR. Further characterisation of the identified genes and downstream pathways could provide more therapeutic targets for the treat DR.

Topics: Animals; Blood Glucose; Crystallins; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Diabetic Retinopathy; Disease Models, Animal; Gene Expression Profiling; Hypertension; Male; Metabolic Syndrome; Neuropeptide Y; Obesity; Rats; Retina

Topics: Animals; Blood Pressure; Cell Proliferation; Cells, Cultured; Chemokine CXCL12; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Fibroblasts; Fibrosis; Hypertension; Insulysin; Myocardium; Neuropeptide Y; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, CXCR4; Signal Transduction; Sitagliptin Phosphate; Ubiquitin

The preglomerular microcirculation of spontaneously hypertensive rats (SHR) is hypersensitive to angiotensin (ANG) II, and studies have shown that this is likely due to enhanced coincident signaling between G protein subunits α

Topics: Angiotensin II; Animals; Cell Membrane; Cells, Cultured; Disease Models, Animal; GTP-Binding Protein beta Subunits; GTP-Binding Protein gamma Subunits; GTP-Binding Proteins; Hypertension; Juxtaglomerular Apparatus; Male; Microvessels; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neuropeptide Y; Phospholipase C beta; Protein Binding; Protein Transport; Rats, Inbred SHR; Rats, Inbred WKY; Receptors for Activated C Kinase; RNA Interference; Signal Transduction; Transfection; Vasoconstriction; Vasoconstrictor Agents

High-fat diet (HFD)-induced hypertension in rabbits is neurogenic because of the central sympathoexcitatory actions of leptin. Hypothalamic melanocortin and neuropeptide Y (NPY) neurons are recognized as the major signalling pathways through which leptin exerts its central effects. In this study, we assessed the effects of specific antagonists and agonists to melanocortin and NPY receptors on HFD-induced sympathoexcitation and hypertension.. Rabbits were instrumented with intracerebroventricular cannula, renal sympathetic nerve activity (RSNA) electrode, and blood pressure telemetry transmitter.. After 3 weeks HFD (13.5% fat, n = 12) conscious rabbits had higher RSNA (+3.8  nu, P = 0.02), blood pressure (+8.6  mmHg, P < 0.001) and heart rate (+15  b/min, P = 0.01), and brain-derived neurotrophic factor levels in the hypothalamus compared with rabbits fed a control diet (4.2% fat, n = 11). Intracerebroventricular administration of the melanocortin receptor antagonist SHU9119 reduced RSNA (-2.7  nu) and blood pressure (-8.5  mmHg) in HFD but not control rabbits, thus reversing 100% of the hypertension and 70% of the sympathoexcitation induced by a HFD. By contrast, blocking central NPY Y1 receptors with BVD10 increased RSNA only in HFD rabbits. Intracerebroventricular α-melanocortin stimulating hormone increased RSNA and heart rate (P < 0.001) in HFD rabbits but had no effect in control rabbits.. These findings suggest that obesity-induced hypertension and increased RSNA are dependent on the balance between greater activation of melanocortin signalling through melanocortin receptors and lesser activation of NPY sympathoinhibitory signalling. The amplification of the sympathoexcitatory effects of α-melanocortin stimulating hormone also indicates that the underlying mechanism is related to facilitation of leptin-melanocortin signalling, possibly involving chronic activation of brain-derived neurotrophic factor.

Topics: alpha-MSH; Animals; Blood Pressure; Brain-Derived Neurotrophic Factor; Diet, High-Fat; Heart Rate; Hormones; Hypertension; Hypothalamus; Kidney; Leptin; Male; Melanocyte-Stimulating Hormones; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Rabbits; Receptors, Corticotropin; Receptors, Melanocortin; Receptors, Neuropeptide Y; Sympathetic Nervous System

High fat diet (HFD)-induced hypertension in rabbits is neurogenic and caused by the central action of leptin, which is thought to be dependent on activation of α-melanocortin-stimulating hormone (α-MSH) and neuropeptide Y-positive neurons projecting to the dorsomedial hypothalamus (DMH) and ventromedial hypothalamus (VMH). However, leptin may act directly in these nuclei. Here, we assessed the contribution of leptin, α-MSH, and neuropeptide Y signaling in the DMH and VMH to diet-induced hypertension. Male New Zealand white rabbits were instrumented with a cannula for drug injections into the DMH or VMH and a renal sympathetic nerve activity (RSNA) electrode. After 3 weeks of an HFD (13.3% fat; n=19), rabbits exhibited higher RSNA, mean arterial pressure (MAP), and heart rate compared with control diet-fed animals (4.2% fat; n=15). Intra-VMH injections of a leptin receptor antagonist or SHU9119, a melanocortin 3/4 receptor antagonist, decreased MAP, heart rate, and RSNA compared with vehicle in HFD rabbits (P<0.05) but not in control diet-fed animals. By contrast, α-MSH or neuropeptide Y injected into the VMH had no effect on MAP but produced sympathoexcitation in HFD rabbits (P<0.05) but not in control diet-fed rabbits. The effects of the leptin antagonist, α-MSH, or neuropeptide Y injections into the DMH on MAP or RSNA of HFD rabbits were not different from those after vehicle injection. α-MSH into the DMH of control diet-fed animals did increase MAP, heart rate, and RSNA. We conclude that the VMH is the likely origin of leptin-mediated sympathoexcitation and α-MSH hypersensitivity that contribute to obesity-related hypertension.

Topics: alpha-MSH; Animals; Blood Pressure; Diet, High-Fat; Dorsomedial Hypothalamic Nucleus; Hypertension; Leptin; Male; Melanocyte-Stimulating Hormones; Neuropeptide Y; Obesity; Rabbits; Receptors, Leptin; Receptors, Melanocortin; Signal Transduction; Sympathetic Nervous System; Ventromedial Hypothalamic Nucleus

Spontaneously hypertensive rats (SHR) have high sympathetic tone and progressive hypertension. Chronic calorie-restriction prevents hypertension. Their food intake (FI) and body weight are lower than in normotensive (NT) controls, even on a high-fat diet, suggesting a dysregulation of energy homeostasis. We assumed enhanced activity of hypothalamic anorexigenic melanocortins and diminished tone of orexigenic neuropeptide Y (NPY) in the background. FI of male SHR and NT Wistar rats was recorded in a FeedScale system upon intracerebroventricular injection of NPY, melanocortin ligands alpha-melanocyte-stimulating hormone (alpha-MSH), and agouti-related peptide (AgRP) or during a 7-day intracerebroventricular infusion of melanocortin antagonist HS024. Alpha-MSH, NPY, and AgRP immunoreactivities were semi-quantified in the arcuate (ARC) and paraventricular (PVN) nuclei of the hypothalamus in NT vs. SHR. Proopiomelanocortin gene expression was also assessed by quantitative RT-PCR in the ARC. Melanocortin-induced anorexia was stronger, FI induced by NPY or HS024 was smaller and delayed in SHR. Cellular alpha-MSH-specific signal density was higher in the ARC of SHR as evaluated by immunofluerescence, which was supported by PCR data. In the PVN, no differences in alpha-MSH-, NPY-, or AgRP-immunosignal were observed. Our results suggest that a higher melanocortin production/responsiveness and lower NPY responsiveness may contribute to the body weight dysregulation of SHR.

Topics: Agouti-Related Protein; alpha-MSH; Animals; Body Weight; Energy Metabolism; Homeostasis; Hormones; Hypertension; Hypothalamus; Male; Neuropeptide Y; Peptide Fragments; Pro-Opiomelanocortin; Rats; Rats, Inbred SHR; Rats, Wistar

Cardiac sympathetic nerves release neuropeptide Y (NPY)1-36, and peptide YY (PYY)1-36 is a circulating peptide; therefore, these PP-fold peptides could affect cardiac fibroblasts (CFs). We examined the effects of NPY1-36 and PYY1-36 on the proliferation of and collagen production ([(3)H]proline incorporation) by CFs isolated from Wistar-Kyoto (WKY) normotensive rats and spontaneously hypertensive rats (SHRs). Experiments were performed with and without sitagliptin, an inhibitor of dipeptidyl peptidase 4 [DPP4; an ectoenzyme that metabolizes NPY1-36 and PYY1-36 (Y1 receptor agonists) to NPY3-36 and PYY3-36 (inactive at Y1 receptors), respectively]. NPY1-36 and PYY1-36, but not NPY3-36 or PYY3-36, stimulated proliferation of CFs, and these effects were more potent than ANG II, enhanced by sitagliptin, blocked by BIBP3226 (Y1 receptor antagonist), and greater in SHR CFs. SHR CF membranes expressed more receptor for activated C kinase (RACK)1 [which scaffolds the Gi/phospholipase C (PLC)/PKC pathway] compared with WKY CF membranes. RACK1 knockdown (short hairpin RNA) and inhibition of Gi (pertussis toxin), PLC (U73122), and PKC (GF109203X) blocked the proliferative effects of NPY1-36. NPY1-36 and PYY1-36 stimulated collagen production more potently than did ANG II, and this was enhanced by sitagliptin and greater in SHR CFs. In conclusion, 1) NPY1-36 and PYY1-36, via the Y1 receptor/Gi/PLC/PKC pathway, activate CFs, and this pathway is enhanced in SHR CFs due to increased localization of RACK1 in membranes; and 2) DPP4 inhibition enhances the effects of NPY1-36 and PYY1-36 on CFs, likely by inhibiting the metabolism of NPY1-36 and PYY1-36. The implications are that endogenous NPY1-36 and PYY1-36 could adversely affect cardiac structure/function by activating CFs, and this may be exacerbated in genetic hypertension and by DPP4 inhibitors.

Topics: Angiotensin II; Animals; Cell Proliferation; Collagen; Dipeptidyl-Peptidase IV Inhibitors; Estrenes; Fibroblasts; GTP-Binding Proteins; Hypertension; Indoles; Maleimides; Myocardium; Neuropeptide Y; Peptide Fragments; Peptide YY; Pertussis Toxin; Protein Kinase C; Pyrrolidinones; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors for Activated C Kinase; Signal Transduction; Sitagliptin Phosphate; Type C Phospholipases

Schlager BPH/2J hypertensive mice have high blood pressure (BP) likely due to overactivity of the sympathetic nervous system regulated by neurons in amygdala-hypothalamic pathways. These areas are normally under tonic inhibition by GABA containing neurons that may be deficient in Schlager hypertensive mice as suggested by microarray analysis. In the present study, cardiovascular effects of chronic activation of GABAA receptors were examined in BPH/2J mice.. Male normotensive BPN/3J and hypertensive BPH/2J mice were administered diazepam in drinking water for 7 days. BP, heart rate and locomotor activity were recorded by telemetry.. Diazepam (2.5 mg/kg) reduced BP of BPN/3J mice during the night-time by -7.1 ± 2.0 mmHg (P = 0.001) but had no effect in BPH/2J mice (+2 ± 2 mmHg) and no effect on heart rate or locomotor activity in either strain. Diazepam reduced the responses to restraint stress in BPN/3J mice by 20% (P = 0.01) and there was no association between Fos-immunoreactive neurons and neurons expressing GABAA receptors or neuropeptide Y in the medial amygdala and paraventricular nucleus of the hypothalamus. By contrast diazepam had no effect on the pressor response to stress in BPH/2J mice and ~50% of stress-activated neurons in these regions also expressed GABAA receptors and ~45% were neuropeptide Y-containing.. These findings show that BPH/2J mice are resistant to the effects of diazepam and suggest that GABAA receptor dysfunction in BPH/2J mice may be contributing to the neurogenic hypertension by not suppressing arousal-induced sympathetic activation within amygdala and hypothalamic nuclei.

Topics: Amygdala; Animals; Baroreflex; Blood Pressure; Diazepam; GABA Modulators; Ganglionic Blockers; Hypertension; Male; Mice; Mice, Inbred Strains; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Pentolinium Tartrate; Proto-Oncogene Proteins c-fos; Receptors, GABA-A; Restraint, Physical; Stress, Physiological

Adverse conditions prenatally increase the risk of cardiovascular disease, including hypertension. Chronic hypoxia in utero (CHU) causes endothelial dysfunction, but whether sympathetic vasoconstrictor nerve functioning is altered is unknown. We, therefore, compared in male CHU and control (N) rats muscle sympathetic nerve activity, vascular sympathetic innervation density, and mechanisms of sympathetic vasoconstriction. In young (Y)-CHU and Y-N rats (≈3 months), baseline arterial blood pressure was similar. However, tonic muscle sympathetic nerve activity recorded focally from arterial vessels of spinotrapezius muscle had higher mean frequency in Y-CHU than in Y-N rats (0.56±0.075 versus 0.33±0.036 Hz), and the proportions of single units with high instantaneous frequencies (1-5 and 6-10 Hz) being greater in Y-CHU rats. Sympathetic innervation density of tibial arteries was ≈50% greater in Y-CHU than in Y-N rats. Increases in femoral vascular resistance evoked by sympathetic stimulation at low frequency (2 Hz for 2 minutes) and bursts at 20 Hz were substantially smaller in Y-CHU than in Y-N rats. In Y-N only, the neuropeptide Y Y1-receptor antagonist BIBP3226 attenuated these responses. By contrast, baseline arterial blood pressure was higher in middle-aged (M)-CHU than in M-N rats (≈9 months; 139±3 versus 126±3 mm Hg, respectively). BIBP3226 had no effect on femoral vascular resistance increases evoked by 2 Hz or 20 Hz bursts in M-N or M-CHU rats. These results indicate that fetal programming induced by prenatal hypoxia causes an increase in centrally generated muscle sympathetic nerve activity in youth and hypertension by middle age. This is associated with blunting of sympathetically evoked vasoconstriction and its neuropeptide Y component that may reflect premature vascular aging and contribute to increased risk of cardiovascular disease.

Topics: Aging; Animals; Blood Vessels; Disease Models, Animal; Female; Hypertension; Hypoxia; Male; Muscle, Skeletal; Neuropeptide Y; Pregnancy; Pregnancy, Animal; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Signal Transduction; Sympathetic Nervous System; Vascular Resistance; Vasoconstriction

It has been reported that plasma NPY levels were increased in obesity, type 2 diabetes mellitus and hypertension. The symptoms of metabolic syndrome frequently appear in patients with acute ischemic stroke. The association between plasma NPY levels and metabolic markers in women with acute ischemic stroke was investigated in the current study.. Plasma NPY concentrations were determined using radioimmunoassay in 58 women aged 60-85 (mean age: 76.5±0.8) with acute ischemic stroke and in 24 women aged 63-67 (mean age: 65.6±0.6) of the control group. Stroke was defined according to the NIHSS (National Institute of Health Stroke Scale) and was confirmed using CT or MR scan.. The prevalence of type 2 diabetes, hypertension and insulin resistance was higher in the group of patients with stroke. Plasma NPY levels measured during the 1st day and 10 days after the acute phase of stroke were significantly lower (p<0.001) compared to the control group.. In women with acute ischemic stroke plasma NPY concentrations were decreased in spite of higher frequency of the occurrence of the symptoms of metabolic syndrome.

Topics: Aged; Aged, 80 and over; Biomarkers; Brain Ischemia; Diabetes Mellitus, Type 2; Female; Humans; Hypertension; Middle Aged; Neuropeptide Y; Obesity; Radioimmunoassay; Stroke

We tested the hypothesis that tonic γ-aminobutyric acid-ergic activity in the hypothalamic arcuate nucleus (ARCN) modulates blood pressure control and attenuation of this inhibitory activity contributes to hypertension in the spontaneously hypertensive rats (SHR). Mean arterial pressure (MAP), heart rate (HR), and greater splanchnic nerve activity (GSNA) were recorded in urethane-anesthetized, artificially ventilated, adult male SHR and Wistar-Kyoto rats (WKY). Microinjections of gabazine into the ARCN elicited significantly smaller increases in MAP, HR, and GSNA in baroreceptor-intact SHR compared with baroreceptor-intact WKY. Attenuation of the responses to gabazine in SHR persisted, despite lowering of their baseline MAP to levels of WKY or barodenervation. Microinjections of N-methyl-d-aspartic acid (NMDA) into the ARCN elicited decreases in MAP and GSNA and increases in HR in baroreceptor-intact WKY. However, after microinjections of gabazine into the ARCN, microinjections of NMDA into the same nucleus elicited pressor responses in baroreceptor-intact WKY. In barodenervated WKY, increases in MAP and GSNA were elicited by ARCN stimulation by NMDA and the increases in HR were exaggerated. In baroreceptor-intact SHR, ARCN stimulation by NMDA elicited increases in MAP, GSNA, and HR which persisted, despite lowering of baseline MAP or barodenervation. Increases in MAP and GSNA elicited by ARCN stimulation by NMDA in barodenervated SHR were significantly greater than corresponding increases in barodenervated WKY. These results indicated that attenuated γ-aminobutyric acid-ergic activity in the ARCN and impaired baroreflex function may contribute to increases in blood pressure and sympathetic nerve activity after ARCN stimulation by NMDA and elevation of baseline blood pressure in SHR.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Arterial Pressure; Baroreflex; Denervation; Dose-Response Relationship, Drug; gamma-Aminobutyric Acid; Heart Rate; Hypertension; Male; N-Methylaspartate; Neuropeptide Y; Pyridazines; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Recent studies in prehypertensive spontaneously hypertensive rats (SHR) have shown larger calcium transients and reduced norepinephrine transporter (NET) activity in cultured stellate neurons compared with Wistar-Kyoto (WKY) controls, although the functional significance of these results is unknown. We hypothesized that peripheral sympathetic responsiveness in the SHR at 4 wk of age would be exaggerated compared with the WKY. In vivo arterial pressure (under 2% isoflurane) was similar in SHRs (88 ± 2/50 ± 3 mmHg, n = 18) compared with WKYs (88 ± 3/49 ± 4 mmHg, n = 20). However, a small but significant (P < 0.05) tachycardia was observed in the young SHR despite the heart rate response to vagus stimulation (3 and 5 Hz) in vivo being similar (SHR: n = 12, WKY: n = 10). In isolated atrial preparations there was a significantly greater tachycardia during right stellate stimulation (5 and 7 Hz) in SHRs (n = 19) compared with WKYs (n = 16) but not in response to exogenous NE (0.025-5 μM, SHR: n = 10, WKY: n = 10). There was also a significantly greater release of [(3)H]NE to field stimulation (5 Hz) of atria in the SHR (SHR: n = 17, WKY: n = 16). Additionally, plasma levels of neuropeptide Y sampled from the right atria in vivo were also higher in the SHR (ELISA, n = 12 for both groups). The difference in [(3)H]NE release between SHR and WKY could be normalized by the NET inhibitor desipramine (1 μM, SHR: n = 10, WKY: n = 8) but not the α2-receptor antagonist yohimbine (1 μM, SHR: n = 7, WKY: n = 8). Increased cardiac sympathetic neurotransmission driven by larger neuronal calcium transients and reduced NE reuptake translates into enhanced cardiac sympathetic responsiveness at the end organ in prehypertensive SHRs.

Topics: Adrenergic alpha-2 Receptor Antagonists; Adrenergic Uptake Inhibitors; Animals; Arterial Pressure; Calcium Signaling; Disease Models, Animal; Electric Stimulation; Heart; Heart Rate; Hypertension; Male; Neuropeptide Y; Norepinephrine; Prehypertension; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Stellate Ganglion; Sympathetic Nervous System; Time Factors; Vagus Nerve

This study sought to understand whether genetic variation at the Neuropeptide Y (NPY) locus governs secretion and stress responses in vivo as well as NPY gene expression in sympathochromaffin cells.. The NPY is a potent pressor peptide co-released with catecholamines during stress by sympathetic axons. Genome-wide linkage on NPY secretion identified a LOD (logarithm of the odds ratio) peak spanning the NPY locus on chromosome 7p15.. Our approach began with genomics (linkage and polymorphism determination), extended into NPY genetic control of heritable stress traits in twin pairs, established transcriptional mechanisms in transfected chromaffin cells, and concluded with observations on blood pressure (BP) in the population.. Systematic polymorphism tabulation at NPY (by re-sequencing across the locus: promoter, 4 exons, exon/intron borders, and untranslated regions; on 2n = 160 chromosomes of diverse biogeographic ancestries) identified 16 variants, of which 5 were common. We then studied healthy twin/sibling pairs (n = 399 individuals), typing 6 polymorphisms spanning the locus. Haplotype and single nucleotide polymorphism analyses indicated that proximal promoter variant ∇-880Δ (2-bp TG/-, Ins/Del, rs3037354) minor/Δ allele was associated with several heritable (h(2)) stress traits: higher NPY secretion (h(2) = 73 ± 4%) as well as greater BP response to environmental (cold) stress, and higher basal systemic vascular resistance. Association of ∇-880Δ and plasma NPY was replicated in an independent sample of 361 healthy young men, with consistent allelic effects; genetic variation at NPY also associated with plasma NPY in another independent series of 2,212 individuals derived from Australia twin pairs. Effects of allele -880Δ to increase NPY expression were directionally coordinate in vivo (on human traits) and in cells (transfected NPY promoter/luciferase reporter activity). Promoter -880Δ interrupts a novel glucocorticoid response element motif, an effect confirmed in chromaffin cells by site-directed mutagenesis on the transfected promoter, with differential glucocorticoid stimulation of the motif as well as alterations in electrophoretic mobility shifts. The same -880Δ allele also conferred risk for hypertension and accounted for approximately 4.5/approximately 2.1 mm Hg systolic BP/diastolic BP in a population sample from BP extremes.. We conclude that common genetic variation at the NPY locus, especially in proximal promoter ∇-880Δ, disrupts glucocorticoid signaling to influence NPY transcription and secretion, raising systemic vascular resistance and early heritable responses to environmental stress, eventuating in elevated resting BP in the population. The results point to new molecular strategies for probing autonomic control of the human circulation and ultimately susceptibility to and pathogenesis of cardiovascular and neuropsychiatric disease states.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alleles; DNA; Electrophoretic Mobility Shift Assay; Female; Gene Expression Regulation; Genetic Predisposition to Disease; Genetic Variation; Genotype; Humans; Hypertension; Male; Middle Aged; Neuropeptide Y; Promoter Regions, Genetic; Receptors, Glucocorticoid; Signal Transduction; Stress, Psychological

We examined morphological characteristics of the carotid body of spontaneously hypertensive rats (SHR), those of age-matched normotensive Wistar rats (NWR), and age-matched genetically comparable Wistar Kyoto rats (WKY). We examined the distribution and abundance of four different regulatory neuropeptides: substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP), and neuropeptide Y (NPY) in the carotid bodies of these three strains of rats. The carotid bodies of SHR were larger than those of NWR and WKY. The values of the long axis of the carotid bodies of SHR were significantly larger (1.3 times) than those of NWR and WKY. In the carotid bodies of SHR, the percentage of relatively large vessels was similar to that of the carotid bodies of WKY, although the carotid bodies themselves were significantly larger than in WKY. The density of VIP varicose fibers in the carotid bodies of SHR was lower than in the carotid bodies of WKY, although the density of SP, CGRP and NPY fibers was similar to that of the carotid bodies of NWR and WKY. These findings suggested that VIP was unrelated to enlargement of the carotid body of SHR, but it might modify the sensitivity of chemoreceptors in the carotid body.

Topics: Animals; Calcitonin Gene-Related Peptide; Carotid Body; Coloring Agents; Eosine Yellowish-(YS); Hematoxylin; Hypertension; Immunohistochemistry; Male; Nerve Fibers; Neuropeptide Y; Neuropeptides; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Wistar; Species Specificity; Substance P; Tyrosine 3-Monooxygenase; Vasoactive Intestinal Peptide

The hypothalamus has an important etiological role in the onset and maintenance of hypertension and stress responses in the Schlager high blood pressure (BP) (BPH/2J) mouse, a genetic model of neurogenic hypertension. Using Affymetrix GeneChip Mouse Gene 1.0 ST Arrays we identified 1,019 hypothalamic genes whose expression differed between 6 wk old BPH/2J and normal BP (BPN/3J) strains, and 466 for 26 wk old mice. Of these, 459 were in 21 mouse BP quantitative trait loci. We validated 46 genes by qPCR. Gene changes that would increase sympathetic outflow at both ages were: Dynll1 encoding dynein light chain LC8-type 1, which physically destabilizes neuronal nitric oxide synthase, decreasing neuronal nitric oxide, and Hcrt encoding hypocretin and Npsr1 encoding neuropeptide S receptor 1, each involved in sympathetic response to stress. At both ages we identified genes for inflammation, such as CC-chemokine ligand 19 (Ccl19), and oxidative stress. Via reactive oxygen species generation, these could contribute to oxidative damage. Other genes identified could be responding to such perturbations. Atp2b1, the major gene from genome-wide association studies of BP variation, was underexpressed in the early phase. Comparison of profiles of young and adult BPH/2J mice, after adjusting for maturation genes, pointed to the proopiomelanocortin-α gene (Pomc) and neuropeptide Y gene (Npy), among others, as potentially causative. The present study has identified a diversity of genes and possible mechanisms involved in hypertension etiology and maintenance in the hypothalamus of BPH/2J mice, highlighting both common and divergent processes in each phase of the condition.

Topics: Age Factors; Animals; Cytoplasmic Dyneins; Gene Expression Profiling; Gene Expression Regulation; Genes; Hypertension; Hypothalamus; Intracellular Signaling Peptides and Proteins; Mice; Neuropeptide Y; Neuropeptides; Oligonucleotide Array Sequence Analysis; Orexins; Oxidative Stress; Polymerase Chain Reaction; Pro-Opiomelanocortin; Quantitative Trait Loci; Receptors, G-Protein-Coupled

Neuropeptide Y (NPY) is a cotransmitter with norepinephrine (NE) and ATP in sympathetic nerves. There is evidence for increased activity of the sympathetic nervous system and the renin-angiotensin system (RAS), as well as a role for NPY in the development of hypertension in experimental animal models and in humans. Angiotensin II (ANG II) is known to facilitate sympathetic neurotransmission, an effect greater in spontaneously hypertensive rats (SHR) than normotensive Wistar-Kyoto (WKY) rats. A newly discovered product of the RAS is angiotensin-(1-7) [ANG-(1-7)]. There is evidence suggesting that ANG-(1-7) opposes the actions of ANG II, resulting in hypotensive effects. The objective of this study was to investigate the role of ANG-(1-7) on the nerve-stimulated overflow of NE and NPY from the mesenteric arterial bed of SHR and the mechanisms involved in mediating any effects produced. ANG-(1-7) (0.001, 0.01, 0.1 microM) decreased nerve-stimulated NE and NPY overflow, as well as perfusion pressure in preparations obtained from SHR. This effect was greater in preparations of SHR than WKY controls. In addition, ANG-(1-7) decreased NE overflow to a greater extent than NPY overflow. Administration of the Mas receptor antagonist, D-Ala(7) ANG-(1-7), attenuated the decrease in both NE and NPY overflow due to ANG-(1-7) administration. However, the angiotensin type 2 receptor antagonist, PD-123391, attenuated the effect of ANG-(1-7) on NE overflow without affecting the decrease in NPY overflow. Moreover, in the presence of N(G)-nitro-L-arginine methyl ester, ANG-(1-7) decreased NPY overflow, but not NE overflow. ANG-(1-7) decreases the nerve-stimulated overflow of NE and NPY in preparations of SHR, whereas ANG II enhances it. Therefore, ANG-(1-7) may counteract the effects of ANG II by acting on ANG type 2 and Mas receptors.

Topics: Angiotensin I; Animals; Antihypertensive Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Electric Stimulation; Hypertension; Imidazoles; Male; Mesenteric Arteries; Neuropeptide Y; NG-Nitroarginine Methyl Ester; Norepinephrine; Peptide Fragments; Pyridines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Angiotensin, Type 2; Sympathetic Nervous System; Synaptic Transmission

Hypertension is an independent determinant of cardiovascular risk, a phenotype that usually has a strong genetic component. Neuropeptide Y (NPY) plays an important role in BP homeostasis. The aim of this study was to investigate the possible influence of NPY polymorphisms on hypertension in a South Indian population. A total of 252 subjects (132 controls and 120 hypertensives) were analysed for T1128C, G1258A and A7735G polymorphisms in the NPY gene. Body mass index (BMI), pulse, SBP and DBP were assessed. Direct sequencing of PCR products was adopted for genotyping. All three polymorphisms were found to be in Hardy-Weinberg equilibrium. Additive, dominant and recessive models were tested using multivariate regression analysis. The results of our study reveal a significant association between T1128C and hypertension even after adjusting for age, sex and BMI. The adjusted OR (95% confidence interval) for the recessive model was 0.56 (0.33-0.95). The other two polymorphic sites (G1258A and A7735G) are not associated with hypertension. The Pro7 allele of the T1128C polymorphic site-containing haplotype (CGA) is associated with hypertension (P=0.049), but the combined haplotypes did not show any evidence of haplotype-phenotype association (global P=0.129). These data support the hypothesis that hypertension is influenced by the NPY T1128C polymorphism.

Topics: Adult; Female; Genetic Predisposition to Disease; Humans; Hypertension; India; Male; Middle Aged; Neuropeptide Y; Polymorphism, Single Nucleotide

Resistant hypertension is always fount to be accompanied with obstructive sleep apnea syndrome (OSAS). Previous studies assumed inflammation participated in OSAS and hypertension. The fact that tumor necrosis factor a (TNF-alpha) was related to OSAS, while neuropeptide Y (NPY) was related to hypertension, was widely reported separately. To investigate the involvement of TNF-alpha and NPY simultaneously in hypertension accompanied with OSAS, 417 subjects who underwent the polymonograph and blood pressure measurement were consecutively selected. Plasma TNF-alpha and NPY levels were determined in normotensive with OSAS (n = 113), hypertensive without OSAS (n = 73), hypertensive with OSAS (n = 134), and those of controls (n = 97), respectively. A significant increase of plasma TNF-alpha and NPY were both observed in hypertensive subjects with or without OSAS, the highest level of TNF-alpha and NPY were in hypertension with the OSAS group. TNK-alpha, NPY, and neck circumference contributed to OSAS and hypertension as risk factors in the logistic regression model. Neck circumference was impacted by apnea/hyponea index, mean diastolic blood pressure, and TNF-alpha level, which was indicated via the multiple linear model. The present study indicated a positive interplay between plasma TNF-alpha, NPY, hypertension, and OSAS in the Han population of Xinjiang. Although there is evidence that inflammation plays a role in the pathophysiology of hypertension and OSAS, clear evidence is still lacking, and raises the dilemma of the hen and the egg. Further studies are needed to clarify the role of inflammation in the pathogenesis of hypertension with OSAS, in which neck size should be considered as a linked independent factor.

Topics: Adult; Case-Control Studies; Female; Humans; Hypertension; Inflammation Mediators; Male; Middle Aged; Neck; Neuropeptide Y; Risk Factors; Sleep Apnea, Obstructive; Tumor Necrosis Factor-alpha

To explore the potential role of neuropeptide Y (NPY) in the pathophysiological process of hypertension caused by obstructive sleep apnea syndrome (OSAS).. The concentration of serum NPY were measured with radioimmunoassay (RIA) in 417 subjects (97 normotensive controls without OSAS, 113 cases of normotensive with OSAS, 73 cases of hypertensive without OSAS and 134 cases of hypertensive with OSAS. Further, the mean NPY level were compared in four groups and the possible effective factors on NPY were discussed.. (1) The concentration of NPY in four groups were (50.5 +/- 37.2) pmol/L in normal controls, (76.0 +/- 39.9) pmol/L in normotensive with OSAS group, (66.9 +/- 36.2) pmol/L in hypertensive without OSAS group and (86.8 +/- 36.8) pmol/L in hypertensive with OSAS group. Whether the patients with OSAS combined with hypertension or not, the concentration of NPY in the serum raised remarkably compared with those without OSAS and hypertension, the highest level of serum NPY was detected in OSAS combined with hypertension group. (2) Pearson correlation analysis indicated that both SBP and DBP related to the serum NPY significantly in non-OSAS group (AHI <10), while the BMI, abdominal circumference, AHI as well as the lowest level of SaO2 correlated to NPY besides SBP in OSAS group with (AHI > or =10). (3) Multiple linear regression model showed that the abdominal circumference and AHI were contributing factors to SBP, while neck circumference and BMI were contributing factors to DBP. The level of NPY in the serum were significantly affected by AHI and BMI, in which the former one had greater influence.. The increased level of serum NPY may play weakly potential roles in the pathophysiological process of hypertension caused by OSAS.

Topics: Adult; Blood Pressure; Case-Control Studies; Female; Humans; Hypertension; Male; Middle Aged; Neuropeptide Y; Obesity; Sleep Apnea, Obstructive

We asked whether naturally occurring genetic variation at the human NPY1R locus alters autonomic traits that might predispose individuals to cardiovascular disease.. Neuropeptide Y (NPY) interacts with the Y(1) receptor, NPY1R, to control adrenergic activity and blood pressure (BP).. We searched for polymorphism at NPY1R by systematic resequencing in ethnically diverse people. There were 376 twins/siblings who were evaluated for heritable autonomic traits: baroreflex function and pressor response to environmental stress.. The common NPY1R variant A+1050G in the 3'-untranslated region (3'-UTR) predicted baroreceptor slope (p = 0.014-0.047) and BP change to cold stress (p = 0.0091-0.016), with minor allele homozygotes displaying blunted slope and exaggerated pressor response. In 936 individuals with the most extreme BPs in the population, not only 3'-UTR A+1050G (p = 1.2 x 10(-4)) but also promoter A-585T (p = 0.001) affected both systolic BP and diastolic BP, in interactive fashion (p = 0.007), with combined homozygotes showing the highest diastolic BP (>20 mm Hg). The 3'-UTR variant +1050G decreased expression of a transfected luciferase reporter/NPY1R 3'-UTR plasmid; promoter variant A-585 also decreased expression of an NPY1R promoter/luciferase reporter. Thus, alleles that increased BP in vivo (3'-UTR +1050G, promoter A-585) also decreased NPY1R expression in cella. Computational alignment showed that A+1050G disrupted a microRNA motif.. Our results indicate that naturally occurring genetic variation at the NPY1R locus has implications for heritable autonomic control of the circulation, and ultimately, for systemic hypertension. The findings suggest novel pathophysiological links between the NPY1R locus, autonomic activity, and blood pressure, and suggest new strategies to approach the mechanism, diagnosis, and treatment of systemic hypertension.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Autonomic Nervous System; Baroreflex; beta-Galactosidase; Blood Pressure; Cold Temperature; Escherichia coli; Female; Gene Expression Regulation; Haplotypes; Humans; Hypertension; Linkage Disequilibrium; Luciferases; Male; Middle Aged; Neuropeptide Y; Phenotype; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Receptors, Neuropeptide Y; Stress, Physiological; Transfection; Young Adult

The sympathetic nervous system and renin-angiotensin system are both thought to contribute to the development and maintenance of hypertension in experimental models such as the spontaneously hypertensive rat (SHR). We demonstrated that periarterial nerve stimulation (NS) increased the perfusion pressure (PP) and neuropeptide Y (NPY) overflow from perfused mesenteric arterial beds of SHRs at 4-6, 10-12, and 18-20 wk of age, which correspond to prehypertensive, developing hypertensive, and maintained hypertensive stages, respectively, in the SHR. NS also increased PP and NPY overflow from mesenteric beds of Wistar-Kyoto (WKY) normotensive rats. NS-induced increases in PP and NPY were greater in vessels obtained from SHRs of all three ages compared with WKY rats. ANG II produced a greater increase in PP in preparations taken from SHRs than WKY rats. ANG II also resulted in a greater increase in basal NPY overflow from 10- to 12-wk-old and 18- to 20-wk-old SHRs than age-matched WKY rats. ANG II enhanced the NS-induced overflow of NPY from SHR preparations more than WKY controls at all ages studied. The enhancement of NS-induced NPY overflow by ANG II was blocked by the AT1 receptor antagonist EMD-66684 and the angiotensin type 2 receptor antagonist PD-123319. In contrast, ANG II greatly enhanced norepinephrine overflow in the presence of PD-123319. Both captopril and EMD-66684 decreased neurotransmitter overflow from SHR mesenteric beds; therefore, we conclude that an endogenous renin-angiotensin system is active in this preparation. It is concluded that the ANG II-induced enhancement of sympathetic nerve stimulation may contribute to the development and maintenance of hypertension in the SHR.

Topics: Adrenergic alpha-2 Receptor Antagonists; Adrenergic alpha-Antagonists; Age Factors; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin II Type 2 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Arginine; Blood Pressure; Captopril; Disease Models, Animal; Electric Stimulation; Hypertension; Imidazoles; Mesenteric Arteries; Neuropeptide Y; Prazosin; Pyridines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Angiotensin, Type 2; Receptors, Adrenergic, alpha-2; Receptors, Neuropeptide Y; Splanchnic Circulation; Sympathetic Nervous System

Current evidence suggests that hyperactivity of the sympathetic nervous system and endothelial dysfunction are important factors in the development and maintenance of hypertension. Under normal conditions the endothelial mediator nitric oxide (NO) negatively modulates the activity of the norepinephrine portion of sympathetic neurotransmission, thereby placing a "brake" on the vasoconstrictor ability of this transmitter. This property of NO is diminished in the isolated, perfused mesenteric arterial bed taken from the spontaneously hypertensive rat (SHR), resulting in greater nerve-stimulated norepinephrine and lower neuropeptide Y (NPY) overflow from this mesenteric preparation compared with that of the normotensive Wistar-Kyoto rat (WKY). We hypothesized that increased oxidative stress in the SHR contributes to the dysfunction in the NO modulation of sympathetic neurotransmission. Here we demonstrate that the antioxidant N-acetylcysteine reduced nerve-stimulated norepinephrine and increased NPY overflow in the mesenteric arterial bed taken from the SHR. Furthermore, this property of N-acetylcysteine was prevented by inhibiting nitric oxide synthase with N(omega)-nitro-l-arginine methyl ester, demonstrating that the effect of N-acetylcysteine was due to the preservation of NO from oxidation. Despite a reduction in norepinephrine overflow, the nerve-stimulated perfusion pressure response in the SHR mesenteric bed was not altered by the inclusion of N-acetylcysteine. Studies including the Y(1) antagonist BIBO 3304 with N-acetylcysteine demonstrated that this preservation of the perfusion pressure response was due to elevated NPY overflow. These results demonstrate that the reduction in the bioavailability of NO as a result of elevated oxidative stress contributes to the increase in norepinephrine overflow from the SHR mesenteric sympathetic neuroeffector junction.

Topics: Acetylcysteine; Animals; Antioxidants; Arginine; Blood Pressure; Disease Models, Animal; Electric Stimulation; Enzyme Inhibitors; Hypertension; Male; Mesenteric Arteries; Neuropeptide Y; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Norepinephrine; Oxidative Stress; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Neuropeptide Y; Splanchnic Circulation; Superoxides; Sympathetic Nervous System

Neuropeptide Y (NPY) plays a central in energy homeostasis and potentially in the development of obesity-related comorbidities, like type II diabetes. As the PreproNPY Leu7Pro polymorphism probably changes the intracellular processing of the synthesized preproNPY peptide, we assessed the hypothesis that PreproNPY Leu7Pro polymorphism is a risk factor for type II diabetes, impaired glucose tolerance and hypertension.. Blood pressure recordings and oral glucose tolerance test were performed in the hypertensive (n=515) and control cohorts (n=525) of our well-defined Oulu Project Elucidating Risk of Atherosclerosis (OPERA) study. The prevalence of type II diabetes was 9% (n=93). The genotypes, insulin and glucose metabolism indexes and plasma ghrelin of the subjects were determined.. Pro7 allele frequencies were 5.9, 5.3 and 11.3% in the total cohort, in subjects without and with type II diabetes, respectively. The PreproNPY Pro7 carrier status was a significant risk factor for type II diabetes, and the effect remained significant after adjustment for age, sex, waist circumference and study group (odds ratio=3.02, confidence interval: 1.67-5.44 and P<0.001). Pro7 carriers were more insulin resistant and showed lower ghrelin levels compared to non-carriers.. The PreproNPY Pro7 allele is associated with an increased risk for type II diabetes. The risk seems to be associated with a higher insulin resistance among Pro7 carriers whereas low ghrelin concentrations in Pro7 carriers are possibly a consequence of high insulin levels.

Topics: Adult; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Female; Gene Frequency; Genotype; Ghrelin; Humans; Hypertension; Insulin; Insulin Secretion; Leucine; Male; Middle Aged; Neuropeptide Y; Peptide Hormones; Polymorphism, Genetic; Proline; Protein Precursors; Risk Factors

The Gi pathway augments renal vasoconstriction induced by angiotensin II in spontaneously hypertensive but not normotensive Wistar-Kyoto rats. Because the Gi-coupled pancreatic polypeptide (PP)-fold peptide receptors Y1 and Y2 are expressed in kidneys and are activated by endogenous PP-fold peptides, we tested the hypothesis that these receptors regulate angiotensin II-induced renal vasoconstriction in kidneys from hypertensive but not normotensive rats. A selective Y1-receptor agonist [(Leu31,Pro34)-neuropeptide Y; 6 to 10 nmol/L] greatly potentiated angiotensin II-induced changes in perfusion pressure in isolated, perfused kidneys from hypertensive but not normotensive rats. A selective Y2-receptor agonist (peptide YY(3-36); 6 nM) only slightly potentiated angiotensin II-induced renal vasoconstriction and only in kidneys from hypertensive rats. Neither the Y1-receptor nor the Y2-receptor agonist increased basal perfusion pressure. BIBP3226 (1 micromol/L, highly selective Y1-receptor antagonist) and BIIE0246 (1 micromol/L, highly selective Y2-receptor antagonist) completely abolished potentiation by (Leu31,Pro34)-neuropeptide Y and peptide YY(3-36), respectively. Y1-receptor and Y2-receptor mRNA and protein levels were expressed in renal microvessels and whole kidneys, but the abundance was similar in kidneys from hypertensive and normotensive rats. Both Y1-receptor-induced and Y2-receptor-induced potentiation of angiotensin II-mediated renal vasoconstriction was completely abolished by pretreatment with pertussis toxin (30 microg/kg IV, blocks Gi proteins). These data indicate that, in kidneys from genetically hypertensive but not normotensive rats, Y1-receptor activation markedly enhances angiotensin II-mediated renal vasoconstriction by a mechanism involving Gi. Although Y2 receptors can also potentiate angiotensin II-mediated renal vasoconstriction via Gi, the effect is modest compared with Y1 receptors. These findings may have important implications for the etiology of genetic hypertension.

Topics: Angiotensin II; Animals; Blood Vessels; Blotting, Western; Hypertension; In Vitro Techniques; Kidney; Male; Neuropeptide Y; Peptide Fragments; Peptide YY; Perfusion; Pressure; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, G-Protein-Coupled; Receptors, Gastrointestinal Hormone; Receptors, Neuropeptide; Receptors, Neuropeptide Y; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Vasoconstriction

1. The present study addressed the role of neuropeptide (NPY) Y2 receptors in neurogenic contraction of mesenteric resistance arteries from female spontaneously hypertensive rats (SHR). Arteries were suspended in microvascular myographs, electrical field stimulation (EFS) was performed, and protein evaluated by Western blotting and immunohistochemistry. 2. In vasopressin-activated endothelium-intact arteries, NPY and fragments with selectivity for Y1 receptors, [Leu31,Pro34]NPY, Y2 receptors, NPY(13-36), and rat pancreatic polypeptide evoked more pronounced contractions in segments from SHR than in Wistar Kyoto (WKY) arteries, even in the presence of the Y1 receptor antagonist, BIBP3226 (0.3 microM, (R)-N(2)-(diphenacetyl)-N-[(4-hydroxyphenyl)methyl]D-arginineamide). 3. In the presence of prazosin and during vasopressin activation, EFS-evoked contractions were larger in arteries from SHR compared to WKY. EFS contractions were enhanced by the Y2 receptor selective antagonist BIIE0246TF (0.5 microM, (S)-N2-[[1-[2-[4-[(R,S)-5,11-dihydro-6(6h)-oxodibenz[b,e]azepin-11-y1]-1-piperazinyl]-2-oxoethyl]cyclo-pentyl-N-[2-[1,2-dihydro-3,5 (4H)-dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl]ethyl]-argininamide), reduced by BIBP3226, and abolished by the combination of BIBP3226 and BIIE0246TF. 4. Immunoblotting showed NPY Y1 and Y2 receptor expression to be similar in arteries from WKY and SHR, although a specific Y2 receptor band at 80 kDa was detected only in arteries from WKY. 5. Immunoreaction for NPY was enhanced in arteries from SHR. In contrast to arteries from WKY, BIIE0246TF increased NPY immunoreactivity in EFS-stimulated arteries from SHR. 6. The present results suggest that postjunctional neuropeptide Y1 and Y2 receptors contribute to neurogenic contraction of mesenteric small arteries. Moreover, both enhanced NPY content and altered neuropeptide Y1 and Y2 receptor activation apparently contribute to the enhanced neurogenic contraction of arteries from SHR.

Topics: Animals; Arginine; Benzazepines; Blood Pressure; Blotting, Western; Electric Stimulation; Female; Hypertension; Immunohistochemistry; Mesenteric Arteries; Neuropeptide Y; Peripheral Vascular Diseases; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Neuropeptide Y; Vasoconstriction; Vasodilation

Neuropeptide Y is a potent inhibitory neurotransmitter expressed in the central neurons that control blood pressure. NO also serves as an inhibitory neurotransmitter, and its deficit causes sympathetic overactivity, which then contributes to hypertension. This study tested the hypothesis that neuropeptide Y functions as a central neurotransmitter to lower blood pressure, therefore its increased signaling ameliorates hypertension induced by NO deficiency. Conscious neuropeptide Y transgenic male rats, overexpressing the peptide under its natural promoter, and nontransgenic littermates (controls) were used in this study. Neuropeptide Y, Y1 receptor antagonist BIBP3226, or vehicle (saline) were administered continuously for 14 days into the cerebral lateral ventricle in unrestrained animals using osmotic pumps. Blood pressure was measured by radiotelemetry. Compared with control animals, transgenic overexpression of neuropeptide Y significantly ameliorated (by 9.7+/-1.5 mm Hg) NO deficiency hypertension (induced by administration of N(omega)-nitro-L-arginine methyl ester in the drinking water). This hypotensive effect of neuropeptide Y upregulation was associated with reduced proteinuria and cardiac hypertrophy and fibrosis. Central administration of neuropeptide Y in nontransgenic rats also reduced (by 10.2+/-1.6 mm Hg) the NO deficiency hypertension, whereas a neuropeptide Y1 receptor antagonist centrally administered in the transgenic subjects during NO deficiency hypertension completely attenuated the depressor effect of neuropeptide Y upregulation. Thus, acting at the level of the central nervous system distinctively via a Y1 receptor-mediated mechanism, endogenous neuropeptide Y exerted a potent antihypertensive function, and its enhanced signaling ameliorated NO deficiency hypertension.

Topics: Animals; Animals, Genetically Modified; Blood Pressure; Central Nervous System; Dose-Response Relationship, Drug; Enzyme Inhibitors; Heart; Heart Rate; Hypertension; Male; Neuropeptide Y; NG-Nitroarginine Methyl Ester; Proteinuria; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Signal Transduction; Up-Regulation

The aims of this study were to compare and contrast the development of the cardiac baroreflex and endocrine responses to acute hypotensive stress in healthy newborn pony foals and lambs during the first two weeks of postnatal life.. Under general anaesthesia, seven Welsh pony foals and six Welsh Mountain lambs were catheterised with hind limb artery and vein catheters. Following post-surgical recovery, at 1 week and 2 weeks of age, blood pressures of the animals were raised and lowered acutely by intravenous infusion of phenylephrine and sodium nitroprusside, respectively. During hypotension, blood samples were taken for measurement of plasma hormones associated with activation of the stress axis.. Basal arterial blood pressure increased significantly (P<0.05) between week 1 and week 2 in the absence of any significant change in basal heart rate in foals and with a significant reduction in basal heart rate in lambs. In foals, the slope of the heart rate-blood pressure relationship decreased in response to acute hypertension, and it increased in response to acute hypotension, from week 1 to week 2 (all P<0.05). In contrast, in lambs, the slope of the heart rate-blood pressure relationship decreased with both acute hypertension and acute hypotension from week 1 to week 2 (all P<0.05). In foals, there were significant increases in plasma concentrations of noradrenaline, neuropeptide Y (NPY), vasopressin, adrenocorticotrophic hormone (ACTH) and cortisol in response to hypotension (P<0.05). In lambs, there were also significant increases in plasma concentrations of ACTH and cortisol during hypotension. Plasma concentrations of noradrenaline, NPY and vasopressin were not measured during hypotension in lambs. In foals, although the magnitude of the ACTH response to hypotension was smaller at week 2 than week 1, the increment in plasma cortisol was similar in the two age groups. In contrast, in lambs, the profile of both the ACTH and cortisol responses was similar at week 1 and week 2.. These data suggest that the increase in basal arterial blood pressure in the foal and the lamb during the first 2 weeks of postnatal life is accompanied by differential maturational changes in the vagal and sympathetic components of the cardiac baroreflex between the two species. These developmental cardiac baroreflex changes occur together with increased adrenocortical responsiveness to acute hypotensive stress, which appears comparatively more mature in lambs than in foals.

Topics: Adrenocorticotropic Hormone; Animals; Animals, Newborn; Arginine Vasopressin; Baroreflex; Endocrine System; Epinephrine; Heart; Heart Rate; Horses; Hydrocortisone; Hypertension; Hypotension; Neuropeptide Y; Nitroprusside; Norepinephrine; Phenylephrine; Sheep; Stress, Physiological

The secretory prohormone chromogranin A (CHGA) is overexpressed in essential hypertension, a complex trait with genetic predisposition, while its catecholamine release-inhibitory fragment catestatin is diminished, and low catestatin predicts augmented adrenergic pressor responses. These findings from studies on humans suggest a mechanism whereby diminished catestatin might increase the risk for hypertension. We generated Chga and humanized mice through transgenic insertion of a human CHGA haplotype in order to probe CHGA and catestatin in vivo. Chga mice displayed extreme phenotypic changes, including: (a) decreased chromaffin granule size and number; (b) elevated BP; (c) loss of diurnal BP variation; (d) increased left ventricular mass and cavity dimensions; (e) decreased adrenal catecholamine, neuropeptide Y (Npy), and ATP contents; (f) increased catecholamine/ATP ratio in the chromaffin granule; and (g) increased plasma catecholamine and Npy levels. Rescue of elevated BP to normalcy was achieved by either exogenous catestatin replacement or humanization of Chga mice. Loss of the physiological "brake" catestatin in Chga mice coupled with dysregulation of transmitter storage and release may act in concert to alter autonomic control of the circulation in vivo, eventuating in hypertension.

Topics: Animals; Blood Pressure; Chromaffin Granules; Chromogranin A; Chromogranins; Circadian Rhythm; Corticosterone; Epinephrine; Gene Targeting; Humans; Hypertension; Hypertrophy, Left Ventricular; Mice; Mice, Knockout; Mice, Transgenic; Microscopy, Electron; Neuropeptide Y; Norepinephrine; Renin

The aim of this study was to investigate age-related changes in the density of calcitonin gene-related peptide (CGRP)-containing nerve fibers in spontaneously hypertensive rats (SHR) and the effects of long-term inhibition of the renin-angiotensin system on these changes. The density of immunocytochemically stained nerve fibers in the mesenteric artery was quantified by computer-assisted image processing. An age-related decrease in the density of CGRP-like immunoreactive (LI)-containing nerve fivers but not neuropeptide Y (NPY)-LI-containing sympathetic nerve fibers was found in the mesenteric artery of SHR but not Wistar Kyoto rats (WKY). The density of NPY-LI-containing sympathetic nerve fibers was significantly greater in SHR than in WKY. SHR were treated for 7 weeks with angiotensin converting enzyme inhibitor (0.005% temocapril), angiotensin II type-1 (AT1) receptor antagonist (0.025% losartan) or vasodilator (0.01% hydralazine) in their drinking water. Each drug treatment significantly lowered the systolic blood pressure measured by tail-cuff method. Long-term treatment of SHR with temocapril and losartan significantly increased the density of CGRP-LI-containing nerve fibers in mesenteric arteries. However, the density after hydralazine treatment was similar to the level in non-treated SHR. The density of NPY-LI-containing nerve fibers was not increased by any of the drug treatments. These results suggest that long-term inhibition of the renin-angiotensin system in SHR prevents remodeling of CGRPergic nerve fibers and prevents the reduction of CGRPergic nerve function.

Topics: Aging; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Calcitonin Gene-Related Peptide; Cell Count; Hydralazine; Hypertension; Immunohistochemistry; Losartan; Male; Mesenteric Arteries; Nerve Fibers; Neuropeptide Y; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin-Angiotensin System; Sympathetic Nervous System; Thiazepines; Vasodilator Agents

To search for a method for increasing therapeutic effect on hypertension and study on the mechanism.. Seventy-five cases were randomly divided into the treatment group (n=45) treated by acupuncture plus medicine, and the control group (n=30) treated by medicine. Their blood pressure and plasma neuropeptide Y (NPY) before and after treatment were investigated.. Blood pressure and NPY content in both the two groups decreased significantly (P < 0.01), and the treatment group in decreasing blood pressure and NPY content was superior to the control group (P < 0.05).. Acupuncture and medicine have cooperation in treatment of hypertension, which is performed possibly through decreasing NPY.

Topics: Acupuncture Therapy; Blood Pressure; Blood Pressure Determination; Humans; Hypertension; Neuropeptide Y

To investigate the effect of plasma neuropeptide Y (NPY), neurotensin (NT) and their relationships on the diurnal rhythm of BP and target organ damage for essential hypertension.. Ambulatory BP monitoring (ABPM) for 24 hours was performed in ninety patients with essential hypertension and thirty healthy subjects. The patients were divided into two groups: 55 dippers and 35 non-dippers according to the ABPM results. Plasma NPY and NT levels in subjects were measured at 8:00, 16:00 and 2:00 o'clock by using radioimmunoassay method. Target organ functions were measured.. The plasma NPY level was higher and NT was lower in patients with hypertension those in normal controls (P < 0.001). Compared with dippers, non-dippers had a higher NPY and a lower NT plasma levels, especially appearing at 2:00 o'clock. The patients with left ventricular hypertrophy, stroke or kidney damage had a higher NPY and a lower NT levels compares with those without target organ damage.. The changes in plasma NPY and NT may contribute to disturbance of the diurnal rhythm of blood pressure in patients with essential hypertension, especially in those with target organ damages, which may serve as a pathophysiologic mechanism for target organ damages in hypertension.

Topics: Adult; Aged; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Circadian Rhythm; Female; Humans; Hypertension; Male; Middle Aged; Neuropeptide Y; Neurotensin

The neuropeptide Y (NPY) signal peptide polymorphism T1128C has been linked to several risk factors for cardiovascular disease. The aim of the present study was to evaluate the significance of this polymorphism for cardiovascular and cerebrovascular disease outcome.. In a prospective study cohort, 1032 hypertensive patients (174 myocardial infarction and 170 stroke patients and 688 matched controls) were analysed for the T1128C polymorphism in the NPY gene.. The dynamic allele specific hybridization (DASH) method was used for genotyping. Serum from the same participants was analysed for total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglycerides.. The frequency of the NPY T1128C polymorphism was 8.4% among patients with a myocardial infarction or stroke, as compared to 5.1% in the control group (P = 0.040). The difference remained significant after adjustment for the cardiovascular risk factors age, sex, smoking status, body mass index, systolic and diastolic blood pressure, presence of diabetes, total cholesterol, HDL, LDL and triglycerides.. The present study indicates that the NPY T1128C polymorphism is an independent predictor for myocardial infarction and stroke in a Swedish hypertensive population.

Topics: Female; Genotype; Humans; Hypertension; Male; Middle Aged; Neuropeptide Y; Phenotype; Polymorphism, Genetic; Predictive Value of Tests; Protein Sorting Signals; Risk Factors; Stroke; Sweden

Nitric oxide (NO) reacts with catecholamines resulting in their deactivation. In the present study with the use of the perfused mesenteric arterial bed as a model of the sympathetic neuroeffector junction, the NO synthase (NOS) inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME) resulted in the enhancement of the periarterial nerve stimulation-induced increase in perfusion pressure and norepinephrine overflow while decreasing neuropeptide Y (NPY) overflow. These changes were prevented by l-arginine, demonstrating that the effects of l-NAME were specific to the inhibition of NOS. From the fact that norepinephrine acts on prejunctional alpha(2)-adrenoceptors to inhibit the evoked release of sympathetic cotransmitters, we carried out experiments in the presence of the alpha(2)-adrenergic receptor antagonist yohimbine to investigate the possibility that the decrease in NPY observed in the presence of l-NAME was due to the increase in bioactive norepinephrine acting on its autoreceptor. Periarterial nerve stimulation in the presence of both l-NAME and yohimbine prevented the previously observed decrease in NPY, indicating that the cause of this decrease was, as predicted, due to alpha(2)-adrenoceptor activation. The periarterial nerve stimulation-induced increase of norepinephrine overflow was greater in the spontaneously hypertensive rat compared with normotensive rats. In contrast to what was observed in the isolated perfused mesenteric arterial bed obtained from normotensive animals, inhibition of NOS did not result in a further increase in the overflow of norepinephrine or in a subsequent decrease in NPY. These results demonstrate that, in addition to being a direct vasodilator, NO, by deactivating norepinephrine, can modulate sympathetic neurotransmission and that this modulation is altered in the spontaneously hypertensive rat.

Topics: Adrenergic alpha-2 Receptor Antagonists; Adrenergic alpha-Antagonists; Animals; Blood Pressure; Enzyme Inhibitors; Hypertension; Male; Neuropeptide Y; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Norepinephrine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Splanchnic Circulation; Synaptic Transmission; Yohimbine

Debate exists regarding the relative importance of neuropeptide Y (NPY) in the pathogenesis of genetic and non-genetic hypertension. NPY concentrations were compared in conduit, mesenteric and renal vasculatures and in hypothalamic and medullary regions of age-matched normotensive control, aortic banded and spontaneously hypertensive rats (SHRs). Lower NPY concentrations were measured in the pre-optic area of banded rats compared to controls and SHR. Renal vein NPY levels were reduced in banded animals, whereas renal artery levels were decreased in SHR. In mesenteric arteries, NPY concentration was selectively increased in SHR. These findings suggest that local hemodynamic alterations influence endogenous levels of this potent vasoconstrictor.

Topics: Animals; Aorta; Blood Pressure; Body Weight; Brain; Disease Models, Animal; Hypertension; Male; Muscle, Smooth, Vascular; Neuropeptide Y; Rats; Rats, Inbred F344; Rats, Inbred SHR

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.

Topics: Cholesterol, LDL; Female; Haplotypes; Humans; Hypertension; Logistic Models; Male; Neuropeptide Y; Obesity; Pedigree; Phenotype; Polymorphism, Single Nucleotide; Receptors, Adrenergic, beta-2

Topics: Cytosine; Humans; Hypertension; Neuropeptide Y; Polymorphism, Genetic; Protein Sorting Signals; Sweden; Thymine

To investigate the relations between left ventricular hypertrophy and systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), neuropeptide Y (NPY) during cardiac hypertrophy and regression.. Blood pressure and heart rate were recorded with polygraph channel biologic message system. NPY in plasma and myocardium were measured with Radioimmunoassay. Correlation coefficient were calculated with SPSS software.. There were positive correlations between SBP, DBP, MAP, NPY in the cardiac tissue and cardiac coefficient (LVW/BW). There was no correlations between cardiac coefficient and heart rate (HR), NPY in plasma.. Hypertension is one of cardiac hypertrophy factors, SBP correlate better with LVW/ BW than DBP. SBP, DBP, MAP, NPY in cardiac tissue has correlative tendency with LVW/BW.

Topics: Animals; Blood Pressure; Heart Rate; Hypertension; Hypertrophy, Left Ventricular; Male; Neuropeptide Y; Rats; Rats, Wistar

Overactivity of sympathetic nervous system may lead to hypertension. The aim of this study was to assess changes of plasma concentration of neuropeptide Y in patients with hypertension after exercise.. The study group consisted of 46 patients with hypertension; the control group consisted of 29 healthy individuals. Plasma concentrations of neuropeptide Y, aldosterone, catecholamines and plasma renin activity were assessed before and after exercise performed on the treadmill.. Plasma concentrations of aldosterone, catecholamines and plasma renin activity increased in both groups but plasma concentration of neuropeptide Y increased only in the hypertensive group (52.4 +/- 100.2 pg/ml vs 103.4 +/- 206.7 pg/ml, p < 0.05) but not in controls (51 +/- 36.3 pg/ml vs 70.8 +/- 134.9 pg/ml, p = NS).. The increase of plasma concentration of neuropeptide Y after exercise in hypertensive group, but not in controls, indicates sympathetic nervous system overactivity in the study group.

Topics: Aldosterone; Catecholamines; Exercise; Female; Humans; Hypertension; Male; Middle Aged; Neuropeptide Y; Renin; Severity of Illness Index

It has been reported that neuropeptides may play a role in the control of appetite and in the mechanism of hormone release. Neuropeptides such as beta-endorphin, neuropeptide Y (NPY), galanin and leptin may affect hormones release, on the other hand the hormonal status may modulate neuropeptide activity.. The material consisted of 90 obese women, 30 women with Anorexia Nervosa, and 30 healthy, lean women of control group. Plasma beta-endorphin, NPY, leptin, somatostatin and serum pituitary and gonadal hormones concentrations were measured with RIA methods.. We observed the highest plasma NPY levels in obese hypertensive and diabetic patients. After carbohydrate administration (OGTT) a marked increase of insulin, beta-endorphin and NPY was found. The blunted response of GH to GH-RH may be connected with increased somatostatin activity and hyperinsulinemia. The abnormal response of LH to opioid blockade may be a result of disturbed opioid and NPY activities in obese patients. However in patients with anorexia nervosa, plasma leptin and NPY concentrations were low. The disturbances in beta-endorphin release are also observed.. The neuroendocrine disturbances in obesity and in anorexia nervosa are opposite. The feedback mechanism between leptin and NPY is disturbed in both in obesity and in anorexia nervosa. An abnormal activity of neuropeptides may lead to disturbed control of appetite and hormonal dysregulation in eating disorders.

Topics: Adult; Anorexia Nervosa; Appetite; beta-Endorphin; Diabetes Mellitus; Feedback, Physiological; Female; Glucose Tolerance Test; Human Growth Hormone; Humans; Hypertension; Leptin; Luteinizing Hormone; Neuropeptide Y; Neuropeptides; Obesity; Somatostatin

To determine whether neuropeptide Y (NPY)-related mechanisms become activated with progression of cardiac hypertrophy in vivo, protein mass and de novo protein synthesis (incorporation of [(14)C]Phe, 0.1 muCi ml(-1)) were assessed in cardiomyocytes, obtained from spontaneously hypertensive rats (SHRs) and normotensive Wistar Kyoto rats (8, 12, 16, 20, and 24 weeks of age), and cultured for 24 h. NPY (10(-8) M) increased protein mass of cardiomyocytes from 16-week-old SHRs by 9.2 +/- 2.1% (n = 8, P < 0.05). De novo protein synthesis was increased maximally in SHRs at 12, 16, and 20 weeks (P < 0.05, n = 8) in response to NPY by 12.6 +/- 2.1% (10(-6) M), 20.1 +/- 4.2% (10(-8) M), and 9.4 +/- 1.8% (10(-7) M), respectively. Peptide YY(3-36), (PYY(3-36)), which displays selectivity for NPY Y(2) and NPY Y(5) receptors, and the NPY Y(5)-selective agonist [D-Trp(34)]-NPY increased de novo protein synthesis maximally by 16.2 +/- 5.1% (10(-7) M; n = 4, P < 0.05) and 17.8 +/- 5.2% (10(-6) M; n = 7, P < 0.05), respectively, in SHRs at 16 weeks, whereas [Leu(31)Pro(34)]-NPY (< or =10(-6) M), which displays some activity at NPY Y(1) and NPY Y(4) receptors, did not. The NPY Y(1)-selective antagonist BVD-42 (2 x 10(-7) M) and the NPY Y(2)-selective antagonist BIIE0246 (2 x 10(-7) M) did not attenuate responses to NPY (10(-7) M) and PPY(3-36) (10(-7) M). These data indicate that hypertrophic responsiveness to NPY, mediated via NPY Y(5) receptors, is induced transiently in SHR cardiomyocytes subsequent to onset of cardiomyocyte hypertrophy in response to pressure overload.

Topics: Animals; Cardiomegaly; DNA; Female; Heart; Humans; Hypertension; Male; Muscle Proteins; Myocardium; Neuropeptide Y; Phenylalanine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Neuropeptide Y; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Time Factors; Transforming Growth Factor beta

Activation of alpha-2-adrenergic and neuropeptide Y (NPY) receptors in the nucleus tractus solitarii (NTS) induces hypotension and bradycardia. On the contrary, activation of angiotensin II (Ang II) receptors leads to hypertension. Acute changes in binding parameters of alpha-2-adrenergic, NPY and Ang II receptors were evaluated in the NTS and paraventricular hypothalamic nucleus (PVN) of rats after a hypertensive stimulus employing quantitative receptor autoradiography. Saturation experiments showed a decrease in the number (Bmax) of alpha-2-adrenergic binding sites in the NTS 6 hours after coarctation-induced hypertension. Furthermore, the affinity of NPY receptors was diminished as seen by the increase in the KD value of 125I-PYY. Tyrosine hydroxylase and NPY immunoreactivities were increased in the NTS and ventral medulla. Binding of 125I-Ang II was not changed in the NTS. Binding of all ligands analyzed was not altered in the PVN. The results suggest an acute down-regulation of alpha-2-adrenergic and NPY receptors involved with hypotension in response to hypertensive stimulus, which might be related to an increased availability of catecholamines and NPY in the NTS.

Topics: Animals; Antibodies; Aorta; Disease Models, Animal; Hypertension; Immunohistochemistry; Iodine Radioisotopes; Male; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Radioligand Assay; Rats; Rats, Wistar; Receptors, Adrenergic, alpha-2; Receptors, Angiotensin; Receptors, Neuropeptide Y; Solitary Nucleus; Tritium; Tyrosine 3-Monooxygenase

Topics: Animals; Calcitonin Gene-Related Peptide; Cardiomegaly; Endothelins; Hypertension; Motor Activity; Neuropeptide Y; Rats; Rats, Wistar

Neuropeptide Y (NPY), one of the most abundant neuropeptides found in the central nervous system (CNS), has been implicated in the regulation of many autonomic functions, including cardiovascular control and the central stress response. The present study represents a detailed investigation of the effects of acute and chronic restraint stress on the expression of the mRNA encoding the NPY precursor, prepro-NPY, in the CNS of normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) using in situ hybridization histochemistry. Basal (unstressed) levels of prepro-NPY mRNA expression were found to be significantly increased in the hypothalamic arcuate nucleus of SHR compared to WKY rats, with similar levels of prepro-NPY mRNA expression found in the remaining central nuclei. Following exposure to both acute and chronic restraint, significant changes in prepro-NPY mRNA expression were found in a variety of central regions in both strains, including the arcuate nucleus and hippocampus (both strains), medial amygdala and cortex (WKY only), and dentate gyrus, nucleus of the solitary tract and ventrolateral medulla (SHR only). A comparison of the temporal response to restraint revealed that significant differences between strains existed in regions such as the arcuate nucleus, hippocampus and dentate gyrus, providing further evidence that hypertensive rats apparently have an impaired neural stress response. The present study demonstrates that exposure to restraint results in significant changes in prepro-NPY mRNA expression in specific nuclei of both WKY and SHR that are components of not only the central circuitry regulating the stress response, but also the neural network modulating autonomic function.

Topics: Animals; Brain; Hypertension; Male; Neuropeptide Y; Protein Precursors; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reference Values; Restraint, Physical; RNA, Messenger; Time Factors

To investigate the changes and its clinical significance of plasma neuropeptide Y (NPY) concentration in patients with pregnancy induced hypertension (PIH).. Plasma NPY levels were detected by radioimmunoassay in 30 patients with PIH, 20 normal non-pregnant women and 23 normal pregnant women. The PIH group was subdivided into mild, moderate and Severe subgroups, and the NPY concentration was also measured in these subgroups respectively at admission and one week after delivery.. The plasma NPY levels in patients with PIH [(164.16 +/- 68.32) ng/L] were significantly higher than those of normal non-pregnant women and normal pregnancies [(86.60 +/- 20.65) ng/L, (82.42 +/- 12.46) ng/L, P < 0.01, respectively]. There was significant difference among plasma NPY levels among the patients with mild, moderate, and severe PIH at admission (P < 0.01). At one week after delivery the concentrations of plasma NPY were significantly decreased in the moderate and severe subgroups compared with the value measured at admission (P < 0.01). Moreover, the NPY levels in patients with severe PIH after delivery were still higher than those of normal non-pregnant women.. The results suggested that the level of NPY in plasma is increased in women with PIH. Elevated plasma NPY levels may play a key role in the development of PIH.

Topics: Adult; Female; Humans; Hypertension; Neuropeptide Y; Pregnancy; Pregnancy Complications, Cardiovascular

We have compared the interaction between gender and strain (normotensive Wistar Kyoto vs. spontaneously hypertensive rats) in the regulation of cardiovascular and renal Y1 and Y5-receptor-mediated responses to neuropeptide Y. Anaesthetized rats received intravenous infusions of 0.3-10 microg/kg per min neuropeptide Y (45 min each) or vehicle. Enhancements of mean arterial pressure, renovascular resistance, diuresis and natriuresis were measured. Parallel group comparisons were performed on male normotensive, female normotensive, male hypertensive and female hypertensive rats. Gender and strain significantly affected the cardiovascular and renal neuropeptide Y responses. While neuropeptide Y elevated mean arterial pressure and renovascular resistance in all four groups, the extent of the alterations differed up to two- to threefold between genders and/or strains. Neuropeptide Y-induced diuresis and natriuresis were similar in male and female normotensive rats, desensitized in male but augmented in female hypertensive rats. We conclude that previously reported cardiovascular and renal neuropeptide Y responses are regulated by gender and the presence of hypertension. However, at least for renal function alterations in female hypertensive vs. male normotensive rats cannot be predicted from those in male hypertensive and female normotensive rats.

Topics: Animals; Blood Pressure; Female; Heart Rate; Hypertension; Male; Natriuresis; Neuropeptide Y; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Neuropeptide Y; Sex Factors

Neuropeptide Y (NPY), noradrenaline (NA) and adenosine 5'-triphosphate (ATP) are important co-transmitters in the sympathetic nervous system, which has a central role in cardiovascular control. In order to evaluate if hypertension is associated with alterations in vascular responses to sympathetic co-transmitters we studied the effects of intra-arterial infusion of NPY, NA and ATP on forearm blood flow. Blood flow was measured by venous occlusion plethysmography in six hypertensive (mean arterial blood pressure (MAP) 113 +/- 4 mmHg) and six matched normotensive subjects (MAP 97 +/- 3 mmHg). NPY and NA significantly reduced forearm blood flow, while a powerful increase was seen with ATP. Forearm vascular resistance, calculated as MAP divided by forearm blood flow, was significantly increased by NPY and NA and strongly reduced by ATP. There was no difference between hypertensive and normotensive subjects in response to either transmitter. In conclusion, vascular reactivity to intra-arterial administration of NPY, NA and ATP seems to be intact in hypertensive patients without metabolic aberrations.

Topics: Adenosine Triphosphate; Forearm; Humans; Hypertension; Injections, Intra-Arterial; Male; Middle Aged; Neuropeptide Y; Norepinephrine; Plethysmography; Reference Values; Regional Blood Flow; Vasoconstrictor Agents

Catecholamines, neuropeptide Y (NPY) and angiotensin II (Ang II) are known to participate in the central control of blood pressure. However, the modulation of these neurotransmitter receptors in response to a hypertensive stimulus is not appropriately established. The purpose of the present study was to examine binding parameters of alpha(2)-adrenergic, NPY and Ang II receptors in the nucleus tractus solitarii (NTS) and paraventricular hypothalamic nucleus (PVN) following a hypertensive stimulus in the aortic-coarcted rat by means of quantitative receptor autoradiography. No changes were seen in binding parameters of alpha(2)-adrenergic and NPY receptors in the NTS of the hypertensive rat compared to control. However, an increased affinity (54%) of noradrenaline competing for 3H-PAC was seen in the PVN. Moreover, an increased binding (49%) of 125I-PYY was also observed in the PVN. The affinity of Ang II for 125I-Sar(1)Ile(8)-Ang II binding sites was also increased (57%) in the NTS of the hypertensive rat. No changes in the binding parameters of radioactive Ang II were observed in the PVN. The results suggest that systems involved with hypertension like Ang II in the NTS and catecholamines in the PVN might collaborate in the development/maintenance of high blood pressure in the aortic-coarcted rat.

Topics: Adrenergic Agents; Animals; Aortic Coarctation; Autoradiography; Binding Sites; Binding, Competitive; Blood Pressure; Disease Models, Animal; Evaluation Studies as Topic; Hypertension; Male; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Radiography; Rats; Rats, Wistar; Receptors, Angiotensin; Solitary Nucleus

We hypothesized that hypothalamic NPYergic mechanisms mediate the blood pressure lowering effect of caloric restriction in hypertensive rats. Aortic coarctation-induced (AC) hypertensive rats (n=25) were assigned to either an ad libitum fed control group (AL) or food restricted group (FR; 60% of AL consumption) for 3 weeks. Rats were instrumented chronically with vascular catheters and bilateral guide cannulae directed at the paraventricular hypothalamic nuclei (PVN). Blood pressure (BP) and heart rate (HR) responses to bilateral PVN microinjection of saline (200 nl) or the putative NPY receptor antagonists [D-Trp32]NPY(1-36) (3.3 micrograms/200 nl) and [D-Tyr27,36 Thr32]NPY(27-36) (D-NPY(27-36); 3.3 micrograms/200 nl) were determined. The FR rats were then refed and cardiovascular responses to PVN injections of NPY receptor antagonists were again determined. FR rats had significantly reduced resting BP (159+/-4 vs. 129+/-4 mmHg) and HR (360+/-11 vs. 326+/-9 bpm) compared to AL controls. Refeeding restored BP and HR of FR rats to levels similar to AL (BP=153+/-4 mmHg, HR=359+/-11 bpm). PVN administration of [D-Trp32]NPY produced foraging behavior and concurrent increases in BP and HR in FR, AL and Re-fed rats. The behavioral activation suggests that [D-Trp32]NPY(1-36) produced activation of NPY receptors. In contrast, D-NPY (27-36) did not produce any behavioral response or affect BP or HR in AL or Re-fed rats. In FR rats, D-NPY (27-36) produced significant increases in BP (peak=15+/-3 mmHg) which partially reversed the effect of FR on BP. Thus, in FR rats with reduced BP, PVN administration of an NPY receptor antagonist increases BP. NPY blockade in the PVN accounted for about 50% of the BP effect of food restriction, thus other mechanisms are likely to be involved. These findings are consistent with the hypothesis that NPYergic mechanisms may contribute to the reduction of BP produced by food restriction.

Topics: Animals; Aortic Coarctation; Behavior, Animal; Blood Pressure; Body Weight; Energy Intake; Energy Metabolism; Heart Rate; Hypertension; Male; Microinjections; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Peptide Fragments; Rats; Rats, Sprague-Dawley

Neuropeptide Y (NPY) is found in autonomic neurones and participates in regulation of autonomic functions. To investigate the role of NPY in the stress response in normo- and hypertensive rats, activation of brainstem and arcuate nucleus (ARC) NPY neurones and levels of NPY mRNA in the ARC were measured in response to restraint stress in adult spontaneously hypertensive rats (SHRs) and two strains of normotensive rats. Controls from each strain were not restrained. Sections of the brain were prepared for Fos immunohistochemistry and NPY in-situ hybridization to identify activated NPY neurones in the nucleus of the tractus solitarii (NTS), ventrolateral medulla (VLM), and ARC. NPY mRNA levels were quantified in the ARC. In the NTS and VLM of restrained rats, approximately 33% and 75%, respectively, of NPY neurones were activated. No differences among strains were found. In the ARC, about 36% of neurones activated by restraint contained NPY mRNA with no differences found among strains. In unrestrained rats, NPY mRNA levels were significantly elevated in SHRs compared to the normotensive rats. Restraint led to significant decreases in mRNA levels in all strains and mRNA levels among strains were no longer different from one another. These data show that NPY likely participates as a neurotransmitter in the autonomic pathways utilized during stress and originating in the NTS, VLM, and ARC. On the other hand, the decreased gene expression of NPY in the ARC in response to restraint stress argues against a role for activation of autonomic pathways or the hypothalamo-pituitary-adrenal (HPA) axis by NPY from the ARC of stressed rats. The elevated NPY gene expression in resting SHRs compared to normotensive rats is abrogated after restraint, suggesting that this gene is differentially regulated in SHRs compared to normotensive rats.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Brain Stem; Hypertension; Immunohistochemistry; In Situ Hybridization; Neurons; Neuropeptide Y; Proto-Oncogene Proteins c-fos; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Restraint, Physical; Stress, Physiological

Topics: Adenosine Triphosphate; Animals; Arteries; Calcium; Calcium Channels; Catecholamines; Electric Stimulation; Hypertension; Neuroeffector Junction; Neuropeptide Y; Norepinephrine; PC12 Cells; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Chronic cold stress (4 degrees C) produced a sustained increase in mean arterial pressure in both normotensive and borderline hypertensive rats (BHR). The high blood pressure in BHRs was significantly reversed by a neuropeptide Y (NPY) Y1 receptor antagonist suggesting that NPY is involved in mediating stress-induced hypertension. Corresponding increases in adrenal NPY messenger RNA and NPY immunoreactivity were found during the stress; furthermore, chronic cold stress also potentiated the pressor response of rats to a subsequent acute stress test in which NPY has been shown to play a role. These results suggest that chronic cold stress-induced hypertension is mediated by elevated NPY release and vascular tone as a result of increased NPY gene expression and storage.

Topics: Adrenal Glands; Animals; Blood Pressure; Cold Temperature; Gene Expression; Heart Rate; Hypertension; Male; Neuropeptide Y; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Stress, Physiological

Inhibition of the renin-angiotensin system has been shown to improve symptoms and prognosis in heart failure. We compared the effects of inhibition of angiotensin-converting enzyme or blockade of angiotensin II type 1 (AT1) receptors in a model with renin-induced hypertension that is known to exhibit similar changes in sympathetic activation and beta-adrenergic desensitization, as observed in heart failure. Treatment with captopril (100 mg/kg of feed) or the AT1-antagonist Bay 10-6734 (100 mg/kg of feed) was performed in transgenic rats harboring the mouse renin 2d gene [TG(mREN2)27]. Neuropeptide Y and angiotensin II levels, adenylyl cyclase activity, beta-adrenergic receptors, G(salpha), and G(ialpha) were investigated. TG(mREN2)27 showed a depletion of myocardial neuropeptide Y stores and an increase in myocardial angiotensin II concentrations. Isoprenaline- and guanylylimidodiphosphate-stimulated adenylyl cyclase activities and beta-adrenergic receptor density were reduced, whereas the catalyst and G(salpha)-function were unchanged. G(ialpha) protein and mRNA concentrations were increased. All alterations were normalized by both treatments. Systolic left ventricular pressures, plasma atrial natriuretic peptide, and myocardial steady state atrial natriuretic peptide mRNA concentrations and heart weights were similarly reduced by both treatments. Sympathetic neuroeffector defects are similarly reversed by angiotensin-converting enzyme inhibition or AT1 antagonism. The data support the concept that pharmacological interventions in the myocardial renin-angiotensin system significantly reverse local sympathetic neuroeffector defects. This could be important for the beneficial effects of these agents.

Topics: Adenylyl Cyclases; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Genetically Modified; Atrial Natriuretic Factor; Blood Pressure; GTP-Binding Proteins; Heart; Hypertension; Myocardium; Neuropeptide Y; Organ Size; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Adrenergic, beta; Signal Transduction

Hypertension often occurs with fluid overload. The most common mechanism is considered to be mediated by increased cardiac output. Hemodialysis (HD) patients frequently have large amounts of fluid overload. Neuropeptide Y (NPY) is activated by stress and contributes to hypertension and heart failure. We speculated that NPY may be released by the stress of fluid overload and, by its vasoconstrictor effect, may contribute to hypertension and heart failure. Plasma levels of NPY and other vasoconstrictors were studied in 20 HD patients with varying degrees of fluid overload, and the relationship of NPY plasma levels to blood pressure was analyzed. The plasma concentrations of NPY correlated with the degree of fluid overload (r = 0.89; P < 0.0001) and the mean arterial blood pressure (r = 0.85; P < 0.0001). Seven patients had fluid overload of greater than 6% of body weight. They had higher blood pressures and higher plasma concentrations of NPY than 13 HD patients with less than 5% of fluid retention (systolic blood pressure, 179+/-8.2 v 145+/-3.7 mm Hg, P = 0.007; NPY, 61+/-4.6 v 26.8+/-2.7 pmol/L, P < 0.001). In stepwise multiple regression analysis, NPY alone explained blood pressure elevation when analyzed with fluid overload and angiotensin II, renin, noradrenaline, and adrenaline levels. We hypothesized that fluid overload in dialysis patients is a stress-inducing state that activates the sympathetic nervous system and releases the vasoconstrictor NPY. The resulting inappropriate vasoconstriction may contribute to volume-induced hypertension and heart failure in a vicious cycle. We conclude that determination of plasma NPY levels may be useful as a marker of the clinical threat of overhydration.

Topics: Adult; Aged; Aged, 80 and over; Blood Pressure; Female; Humans; Hypertension; Male; Middle Aged; Neuropeptide Y; Norepinephrine; Renal Dialysis; Water-Electrolyte Imbalance

The nucleus tractus solitarii (NTS) in the dorsomedial medulla comprises a wide range of neuropeptides and biogenic amines. Several of them are related to mechanisms of central blood pressure control. Angiotensin II (Ang II), neuropeptide Y (NPY) and noradrenaline (NA) are found in the NTS cells, as well as their receptors. Based on this observation we have evaluated the modulatory effect of these peptide receptors on alpha 2-adrenoceptors in the NTS. Using quantitative receptor radioautography, we observed that NPY and Ang II receptors decreased the affinity of alpha 2-adrenoceptors for their agonists in the NTS of the rat. Cardiovascular experiments agreed with the in vitro data. Coinjection of a threshold dose of Ang II or of the NPY agonists together with an ED50 dose of adrenergic agonists such as NA, adrenaline and clonidine counteracted the depressor effect produced by the alpha 2-agonist in the NTS. The results provide evidence for the existence of an antagonistic interaction between Ang II AT1 receptors and NPY receptor subtypes with the alpha 2-adrenoceptors in the NTS. This receptor interaction may reduce the transduction over the alpha 2-adrenoceptors which can be important in central cardiovascular regulation and in the development of hypertension.

Topics: Angiotensin II; Animals; Autoradiography; Blood Pressure; Clonidine; Epinephrine; Hypertension; Neuropeptide Y; Norepinephrine; Rats; Receptors, Adrenergic; Receptors, Angiotensin; Receptors, Neuropeptide Y; Solitary Nucleus

Elevated bladder smooth muscle cell (BSMC) nerve growth factor (NGF) secretion and related neuroplasticity are associated with hyperactive voiding in spontaneously hypertensive rats (SHRs: hypertensive, behaviorally hyperactive), compared with control Wistar-Kyotos (WKYs). We used two inbred strains (WKHT: hypertensive; WKHA: hyperactive) to further investigate this phenomenon. WKHA BSMCs secreted higher basal levels of NGF than WKHT BSMCs. Antagonists did inhibit NGF output in WKHA but not WKHT cultures. Thus augmented basal secretion of NGF cosegregates with a hyperactive phenotype, whereas a lack of regulatory inhibition of NGF output cosegregates with a hypertensive phenotype. Bladder norepinephrine content paralleled NGF content, with WKHTs > SHRs > WKHAs > WKYs, providing evidence that a lack of inhibition is the greatest contributor to elevated bladder NGF and noradrenergic innervation. Protein kinase C (PKC) agonists affected NGF production differentially depending on strain, suggesting that altered PKC signaling may contribute to strain differences in NGF secretion. Finally, 6-h voiding frequency differed between the strains, with SHRs > WKHTs = WKHAs > WKYs. Thus aspects of both the hypertensive and hyperactive phenotypes may be associated with elevated SHR bladder NGF and hyperactive voiding.

Topics: Animals; Cells, Cultured; Colforsin; Hypertension; Isoproterenol; Nerve Growth Factors; Neuronal Plasticity; Neuropeptide Y; Phenylephrine; Platelet-Derived Growth Factor; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Species Specificity; Tetradecanoylphorbol Acetate; Urinary Bladder; Urination; Urination Disorders

To study the effects of the selective neuropeptide Y (NPY) Y1 receptor antagonist BIBP 3226 in spontaneously hypertensive rats (SHR) in order to elucidate whether NPY function may be altered in the SHR and whether the NPY Y1 receptor plays a specific role in the maintenance of high blood pressure in this genetic form of hypertension.. Pithed and conscious SHR were studied after intravenous administration of 0.125-1 mg/kg BIBP 3226. The cardiovascular effects were evaluated under baseline conditions, under acute stress and after exogenous administration of 20 microg/kg NPY. The potentiating effects of NPY on pressor responses to phenylephrine and tyramine were studied in the SHR.. Intravenous administration of 0.125-1 mg/kg BIBP 3226 dose-dependently inhibited the pressor response to exogenous NPY in pithed SHR. At higher doses BIBP 3226 had an effect duration of 20-40 min. In the pithed SHR, a 0.5 mg/kg bolus injection of BIBP 3226 shifted the pressor response curve for exogenous NPY significantly to the right It also inhibited significantly the potentiating effects of NPY on pressor responses to phenylephrine and tyramine. In conscious SHR, 0.125-1 mg/kg BIBP 3226 did not reduce the basal blood pressure. In combination with a hypotensive dose of prazosin, administration of 0.5 mg/kg BIBP 3226 had no added effects lowering the basal blood pressure. A stressful stimulus, namely an air jet, caused a brief increase in blood pressure and heart rate in the conscious SHR. In this model, 0.5 mg/kg BIBP inhibited the heart rate response slightly but had no effect on the blood pressure response.. Our results demonstrate that, although the selective NPY Y1 receptor antagonist BIBP 3226 may shift the pressor response to exogenous NPY potently, it does not influence basal blood pressure significantly in the SHR.

Topics: Animals; Arginine; Blood Pressure; Electric Stimulation; Heart Rate; Hypertension; Male; Neuropeptide Y; Peripheral Nerves; Phenylephrine; Prazosin; Rats; Rats, Inbred SHR; Receptors, Neuropeptide Y; Stress, Physiological; Tyramine

The regulation by neuropeptide Y of alpha2-adrenoceptors in the nucleus tractus solitarii was evaluated in the adult normotensive Wistar Kyoto rat and the adult spontaneously hypertensive rat. The microinjection of a submaximal dose of l-noradrenaline (800 pmol in 50 nl) alone into the nucleus tractus solitarii produced a significant reduction in the mean arterial blood pressure in either strain. The threshold dose (1 pmol in 50 nl) of neuropeptide Y(1-36) for the vasodepressor response in the Wistar Kyoto rat was five times higher than that (0.2 pmol in 50 nl) in the spontaneously hypertensive rat. Furthermore, neuropeptide Y(1-36) at 0.2 pmol in 50 nl could significantly counteract the vasodepressor response to l-noradrenaline (800 pmol in 50 nl) in the spontaneously hypertensive rat, but not in the Wistar Kyoto rat, in which 1 pmol in 50 nl of neuropeptide Y(1-36) must be employed to counteract the vasodepressor response to l-noradrenaline (800 pmol in 50 nl), although the vasodepressor responses are of a similar magnitude. The in situ hybridization and quantitative receptor autoradiographical experiments showed that the alpha2A-adrenoceptor messenger RNA levels and the B(max) value of the alpha2-adrenoceptor agonist [3H]p-aminoclonidine binding sites measured in the nucleus tractus solitarii of the spontaneously hypertensive rat were substantially lower than those in the Wistar Kyoto rat. The quantitative receptor autoradiographical results were consistent with the cardiovascular results and showed that in the spontaneously hypertensive rat, neuropeptide Y(1-36) at 1 nM led to a significant increase in the K(d) value of [3H]p-aminoclonidine binding sites. In the Wistar Kyoto rat, neuropeptide Y(1-36) produced this effect only at 10 nM. The present study provides evidence for an increase of the potency of neuropeptide Y(1-36) to antagonistically modulate alpha2-adrenoceptors in the nucleus tractus solitarii of the spontaneously hypertensive rat. This enhanced antagonistic action may partly be related to a reduction in the number of alpha2A-adrenoceptors in the nucleus tractus solitarii of the spontaneously hypertensive rat, since a decrease has been observed in the alpha2A-adrenoceptor messenger RNA levels and the alpha2-adrenoceptor binding sites in the spontaneously hypertensive rat. This increased potency of neuropeptide Y(1-36) to antagonize alpha2-adrenoceptor function in the nucleus tractus solitarii of the spontaneously hypertensive rat may cont

Topics: Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-2 Receptor Antagonists; Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Autoradiography; Blood Pressure; Heart Rate; Hypertension; In Situ Hybridization; Male; Neuropeptide Y; Norepinephrine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Messenger; Solitary Nucleus

Neuropeptide Y (NPY), noradrenaline (NA) and ATP are cotransmitters of the sympathetic nervous system and exert vasocontractile effects. The aim of this study was to determine the role of these sympathetic co-transmitters in human hypertension. Subcutaneous vessels from 12 patients with essential hypertension and 12 matched controls were studied in vitro. Vascular contractile responses to NPY, NA, alpha,beta-methylene ATP (alpha,beta-mATP) and potassium were studied in isolated arteries and veins (diameter 0.1-1.1 mm) with intact endothelium. The dilatory effect of acetylcholine was used to test the endothelial function. There was no difference in potency (pD2) or contractile response to NPY, NA or alpha,beta-mATP between hypertensive and control arteries. In veins, however, the contractile response to NPY was significantly reduced in hypertensives and the responses to NA were unchanged. Furthermore, the sensitivity (pD2) to alpha,beta-mATP was significantly reduced in veins from hypertensives. There was no difference in the dilatory response to acetylcholine between the hypertensives and the controls, neither in the arteries nor in the veins, indicating that the observed changes in vascular reactivity to NPY, NA and alpha,beta-mATP were not endothelium-dependent. In conclusion, the postjunctional contractile effect of NPY and sensitivity (pD2) to alpha,beta-mATP, co-transmitters of the peripheral sympathetic nervous system, are attenuated in veins in essential hypertension.

Topics: Acetylcholine; Adenosine Triphosphate; Aged; Aged, 80 and over; Female; Humans; Hypertension; In Vitro Techniques; Male; Middle Aged; Neuropeptide Y; Neurotransmitter Agents; Norepinephrine; Sympathetic Nervous System; Vasoconstriction; Vasoconstrictor Agents; Veins

Hemorrheological and humoral abnormalities and excessive platelet activity can predict the development of cardiovascular complications in patients with essential hypertension. A study was conducted to assess the influence of gender on these factors and the interrelations between changes in hemorrheology and the sympatho-adrenal system in 54 patients (18 women, 36 men) with essential hypertension (aged 39.6 +/- 9.7 years) and 25 healthy volunteers (10 women, 15 men; aged 36.0 +/- 7.2 years). A decrease in erythrocyte deformability (p < 0.01) was found in the hypertensive men compared with the hypertensive women. Hematocrit (p < 0.01), blood viscosity at the shear rates of 0.3 s-1 (p < 0.01) and 6 s-1 (p < 0.01), plasma viscosity (p < 0.01), erythrocyte aggregation (p < 0.01), and neuropeptide Y (p < 0.02) concentrations were higher in the hypertensive men than in the hypertensive women. A positive correlation between blood fibrinogen and serotonin was found in the pooled hypertensive group and in the hypertensive men (p < 0.01) and between blood viscosity (shear rate 6 s-1) and neuropeptide Y in the pooled hypertensive group (p < 0.01). Neuropeptide Y correlated with filtration time of 1 mL blood in the hypertensive men (p < 0.05) and in the pooled normotensive group (p < 0.01) and with beta-thromboglobulin in the hypertensive women (p < 0.001). A positive correlation was also found in the hypertensive men between erythrocyte and platelet aggregation (p < 0.01) and between beta-thromboglobulin and adrenaline (p < 0.01). Hemorrheological and humoral abnormalities are more pronounced in men than in women with essential hypertension and may contribute to the increased incidence of cardiovascular events in men.

Topics: Adult; beta-Thromboglobulin; Epinephrine; Erythrocyte Aggregation; Female; Fibrinogen; Hematocrit; Humans; Hypertension; Male; Middle Aged; Neuropeptide Y; Norepinephrine; Platelet Aggregation; Rheology; Serotonin; Sex Factors

Our previous studies show that neuropeptide Y (NPY) is involved in mediating sympathetic nerve stimulation-induced vasoconstriction. Insulin hypoglycemia is known to produce increased sympathetic output and elevated arterial pressure. The present study examined the role of NPY in the hypertensive response to insulin by examining the effects of insulin on NPY gene expression, tissue content and release. Subcutaneous injection of insulin produced an immediate increase in plasma NPY immunoreactivity (NPYir) and delayed increases in adrenal and neuronal NPY mRNA and adrenal NPYir in rats. These results suggest that NPY may play a role in insulin-induced hypertension.

Topics: Adrenal Medulla; Animals; Denervation; Gene Expression Regulation; Hypertension; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Neuropeptide Y; Nicotine; Nicotinic Agonists; Rats; Rats, Sprague-Dawley; Stress, Physiological; Superior Cervical Ganglion

The effect of anti-hypertensive drug amlodipine on regression of cardiovascular hypertrophy due to hypertension was studied by using cultured smooth muscle cells derived from arteries of spontaneously hypertensive rats (SHR) and measuring [3H]-TdR and [3H]-Leucine binding. 48 h after adding amlodipine, [3H]-TdR binding in arterial smooth muscle cells from SHR in vitro was reduced by 50.5% and [3H]-Leucine binding was reduced by 56.2% as compared with neuropeptide Y (NPY)-treated group. However, there was no significant change in cell number. The results showed that amlodipine could effectively inhibit increase of DNA and protein synthesis of vascular smooth muscle cell (VSMC) due to NPY. It indicates that amlodipine is of great significance on regression of genesis and development of cardiovascular hypertrophy due to hypertension.

Topics: Amlodipine; Animals; Aorta, Thoracic; Calcium Channel Blockers; Cell Division; Cells, Cultured; Hypertension; Muscle, Smooth, Vascular; Neuropeptide Y; Rats; Rats, Inbred SHR

The effects of repeated sensory stimulation (electro-acupuncture) and physical exercise (running) on open-field behaviour and on hippocampal concentrations of neuropeptide Y, neurokinin A, substance P, galanin and vasoactive intestinal peptide (VIP)-like immunoreactivities were studied in WKY (wistar-Kyoto) and SHR (spontaneously hypertensive) rats. Significantly higher concentrations of substance P-like immunoreactivity, neurokinin A-like immunoreactivity and neuropeptide Y-like immunoreactivity were found in the hippocampus immediately after 3 weeks of treatment (electro-acupuncture and running), but not 1 week after the last (tenth) changes in neuropeptide concentrations were similar in the two rat strains. Open-field behaviour was significantly reduced during the treatment period in both strains. There were significant negative correlations between behaviour and neuropeptide concentrations in SHR rats, suggesting interdependency with sympathetic activity. It is proposed that the effects of electro-acupuncture and physical exercise in rats are related to increases in neuropeptide Y, neurokinin A and substance P in the hippocampus.

Topics: Animals; Depression; Electric Stimulation; Electroacupuncture; Exploratory Behavior; Galanin; Hippocampus; Hypertension; Male; Neurokinin A; Neuropeptide Y; Neuropeptides; Physical Exertion; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Substance P; Vasoactive Intestinal Peptide

Neurones containing neuropeptide Y (NPY) may participate in central cardiovascular control by tonically influencing barosensitive neurones within the nucleus tractus solitarius. The present study has employed both in situ hybridisation histochemistry and receptor autoradiography, to visualise the expression of prepro-NPY mRNA in the forebrain and to determine the NPY receptor subtype(s) in the brainstem, respectively. Prepro-NPY gene expression was visualised in the hypothalamus, cortex, dentate gyrus and lateral reticular thalamus from age-matched spontaneously hypertensive rats (SHR) and normotensive Don Ryu rats (DRY) and Wistar Kyoto rats (WKY). Quantitative densitometry revealed an increase in the NPY transcript in the arcuate nucleus of SHR rats compared to their normotensive counterparts. Autoradiography using [125I]Bolton-Hunter-NPY (BH-NPY, 15 pM) demonstrated NPY binding sites in the area postrema, the commissural nucleus tractus solitarius (cNTS) and the inferior olivary complex. NPY (1 microM) and peptide YY (1 microM), but not [Leu31,Pro34]NPY (10-100 nM), fully inhibited the binding of [125I]BH-NPY. These results indicate that NPY receptors of the Y2 subtype predominate in the dorsal vagal complex. Unilateral nodose ganglionectomy resulted in a partial loss of NPY binding sites in the commissural NTS, but not the area postrema, suggesting that a proportion of binding sites (Y2 subtype) are present on central vagal terminals. While all three rat strains appear to have the same relative proportions of NPY receptor subtypes in the brainstem, the relevance of the differential NPY gene expression in the arcuate nucleus regarding central cardiovascular control mechanisms and/or the pathogenesis of hypertension remains to be elucidated.

Topics: Animals; Autoradiography; Base Sequence; Brain; Gene Expression; Hypertension; In Situ Hybridization; Iodine Radioisotopes; Male; Molecular Sequence Data; Neurons; Neuropeptide Y; Nodose Ganglion; Oligonucleotide Probes; Oligonucleotides, Antisense; Protein Precursors; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Inbred WKY; Receptors, Neuropeptide Y; Reference Values; Solitary Nucleus

Tissue concentration of norepinephrine and neuropeptide-Y immunoreactivity (NPY-IR) were measured in the urinary bladder, urethra, prostate and corpus cavernosum of the spontaneously hypertensive rat, as well as the normotensive Wistar-Kyoto rat. The results showed significantly increased tissue norepinephrine concentrations in the urinary bladder, urethra and prostate of the spontaneously hypertensive rat when compared to those of the normotensive rat (hypertensive, n = 18: 18.3 +/- 2.1, 14.9 +/- 1.7, 22.6 +/- 2.3 vs. normotensive, n = 18: 11.2 +/- 1.9, 10.4 +/- 1.3, 16.7 +/- 2.4 nmol/g tissue, respectively, P < 0.05 in each case). No difference was noted in the cavernosal tissue (hypertensive, n = 18: 11.3 +/- 1.6 vs. normotensive, n = 18: 10.1 +/- 1.8 nmol/g tissue, P > 0.01). Correspondingly, tissue NPY-IR was significantly increased in the bladder, urethra and prostate tissue of the spontaneously hypertensive rat (hypertensive, n = 18: 39.7 +/- 5.6, 25.3 +/- 3.4, 31.5 +/- 2.8 vs. normotensive, n = 18: 27.4 +/- 3.1, 18.6 +/- 2.7, 24.2 +/- 3.2 pmol/g tissue, respectively, P < 0.05 in each case). Again, no significant difference was observed in the cavernosal tissue (hypertensive, n = 18: 15.9 +/- 2.2 vs. normotensive, n = 18: 14.8 +/- 2.6 pmol/g tissue, P > 0.01). It is therefore concluded that increased tissue concentration of norepinephrine and NPY-IR were present in the urinary bladder, urethra and prostate of the spontaneously hypertensive rat. The significance of such biochemical findings needs further investigation but may suggest increased sympathetic innervation or activity. On the contrary, no corresponding changes were observed in the corpus cavernosum of the hypertensive rat.

Topics: Animals; Autonomic Nervous System; Hypertension; Immunohistochemistry; Male; Nerve Fibers; Neuropeptide Y; Norepinephrine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Urogenital System

To assess the effects of long-term pressure overload on sympathetic presynaptic components in the left ventricle, young adult male rats were subjected to surgical constriction of the suprarenal abdominal aorta. At 4 and 8 wk postsurgery, but not at 1 wk, left ventricular sympathetic activity, measured by the net fractional norepinephrine (NE) decrease after alpha-methyl-p-tyrosine methyl ester administration, was elevated in the aortic-banded rats. However, left ventricular NE was reduced only at 8 wk. Scatchard analysis of saturation binding of [3H]nisoxetine, a specific ligand for NE uptake sites, determined that left ventricular NE transporter sites were also reduced at 8 wk, suggesting a relationship between a reduced number of uptake sites and loss of NE stores. In contrast, aortic constriction did not reduce neuropeptide Y (NPY), tyrosine hydroxylase, dopamine beta-hydroxylase, nervegrowth factor, and low-affinity nerve growth factor receptors at any time point. Thus long-term pressure overload can cause a selective reduction in ventricular NE stores without a reduction in NPY, a colocalized sympathetic neurotransmitter.

Topics: Animals; Aorta, Abdominal; Binding Sites; Carrier Proteins; Fluoxetine; Hypertension; Ligation; Male; Methyltyrosines; Myocardium; Neuropeptide Y; Norepinephrine; Norepinephrine Plasma Membrane Transport Proteins; Presynaptic Terminals; Rats; Rats, Sprague-Dawley; Sympathetic Nervous System; Symporters; Time Factors; Ventricular Function, Left

Cardiac function was evaluated in rest and after exercise on a cycloergometer in 20 patients with essential hypertension (EH) aged 14 to 19 years and 12 age-matched healthy volunteers. Selected parameters of ECHO examination and mitral flow were assessed, including SV, CO, CI, %SF, EF, LIVDd, IVSd, LVPWd, LVMI, total peripheral vascular resistance, ESS, velocity of wave E. A and E/A index. In all cases, serum ET1 and NPY levels were measured in rest and after exercise, before and after 6-month enalapril therapy. The ETI serum level in hypertensive patients did not differ from controls, while the NPY level was significantly higher in hypertensives. Exercise did not affect the ETI serum concentration, however, it did increase the NPY level. Enalapril therapy had no effect on serum peptide concentrations. Correlation of the ETI serum level with ECHO parameters, including CO, Cl, SV, LIVDd, LVPWd, %SF, TPRI and wave E velocity, as well as correlation of NPY concentration with LIVDd, LVPWd, LVMI, ESS and wave E and A velocity may suggest that these peptides influence left ventricle function and structure disturbances in children with EH.

Topics: Adolescent; Adult; Electrocardiography; Endothelin-1; Ergometry; Female; Heart Ventricles; Humans; Hypertension; Male; Neuropeptide Y

To investigate the hypotheses that Kyoto spontaneously hypertensive rats (SHR) possess more sympathetic neurons than do normotensive Wistar-Kyoto (WKY) animals due to reduced perinatal cell death and that this is due to increased availability of the sympathetic survival neurotrophin, nerve growth factor.. Total cell counts of neuron numbers were performed in neonatal and adult SHR and WKY rat superior cervical ganglia and correlated with counts of apoptotic cells. The values for sympathetic neuron numbers were compared with those for a spinal sensory ganglion. Immunocytochemistry was used to obtain more information about the phenotypes of neurons counted.. Adult SHR sympathetic ganglia contained about 25% more sympathetic neurons than did those of WKY animals. Similar elevation of numbers was found both for neurons containing and for those devoid of neuropeptide Y. In neonatal animals, in contrast, there was no strain difference in sympathetic cell numbers but the number of apoptotic cells was reduced in SHR. Spinal sensory neuron numbers in adult SHR were elevated to a similar extent as were sympathetic neurons, but biochemical and morphometric data suggested that this change does not involve cells that are sensitive to nerve growth factor.. Although our results support the view that there is reduced developmental cell death both in sympathetic and in sensory systems, they also suggest that this is unlikely to be due to a simple excess of nerve growth factor during development.

Topics: Age Factors; Animals; Cell Count; Cell Death; Female; Hypertension; Neurons, Afferent; Neuropeptide Y; Pregnancy; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Spinal Cord; Sympathetic Nervous System; Tyrosine 3-Monooxygenase

This study was designed to assess the role of renin and of the sympathoadrenal system in the maintenance of the hypertension induced by chronic nitric oxide synthase (NOS) inhibition in rats kept on a normal (RS) or a low-sodium (LS) diet. With the administration of NG-nitro-L-arginine methyl ester (L-NAME) in drinking water (0.4 milligrams) for 6 wk, mean intra-arterial blood pressure rose to a similar extent to 201 mmHg in the RS and 184 mmHg in the LS animals. Simultaneously, plasma norepinephrine was increased to 838 and 527 pg/ml and epinephrine to 2,041 and 1,341 pg/ml in RS and LS, respectively. Plasma neuropeptide Y levels did not change. Plasma renin activity rose to 21 ng.ml-1.h-1 in RS but remained at 44 ng.ml-1.h-1 in the LS. Both losartan (10 mg/kg) and phentolamine (0.1 mg/kg) intravenous bolus injections reduced blood pressure considerably in the L-NAME hypertensive animals. Whole brain NOS activity was reduced by 84%. Hypertension induced by chronic NOS inhibition in LS as well as in RS fed rats seems to be sustained by an interaction of several mechanisms, including the activation of the sympathetic nervous system and the renin-angiotensin system.

Topics: Amino Acid Oxidoreductases; Analysis of Variance; Animals; Antihypertensive Agents; Arginine; Biphenyl Compounds; Blood Pressure; Brain; Creatinine; Diet, Sodium-Restricted; Epinephrine; Heart Rate; Hypertension; Imidazoles; Kidney; Losartan; Male; Neuropeptide Y; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Norepinephrine; Phentolamine; Rats; Rats, Wistar; Reference Values; Renin; Renin-Angiotensin System; Sympathetic Nervous System; Tetrazoles; Weight Gain

The C-terminal NPY fragment (13-36)[NPY-(13-36)], a Y2 receptor agonist, elicits vasopressor responses upon central administration. The cardiovascular responses of NPY-(13-36) together with the distribution of NPY receptor subtypes within the nucleus tractus solitarius (nTS) have therefore been studied in spontaneously hypertensive rats (SHR). NPY-(13-36) was injected intracerebro-ventricularly in different doses (7.5 to 3000 pmol) in awake, unrestrained rats to evaluate the cardiovascular effects. NPY receptor subtypes were studied by autoradiography using [125I]peptide YY ([125I]PYY) as a radioligand and by masking the NPY Y1 and Y2 receptor subtypes with unlabelled [Leu31,Pro43]NPY and NPY-(13-36) respectively. In both male SHR and age-matched male normotensive Wistar-Kyoto rats (WKY) NPY-(13-36) injections elicited vasopressor effects. In WKY this effect was dose-dependent and became significant at doses from 75 pmol, whereas in the SHR the vasopressor effect had a longer duration than in the WKY and became significant at lower doses (25 pmol) but associated with the development of an early ceiling effect. The heart rate was unaffected in both groups of rats. Total specific [125I]PYY binding in the nTS was 25% higher in SHR than in WKY rats. By masking the Y1 and Y2 receptor subtypes respectively it could be shown that this difference was due to an increase in Y2 receptor binding within the nTS. The present results give evidence for an increased potency but not an increased efficacy of NPY-(13-36) in inducing a pressor response in the SHR associated with a longer duration as compared with the WKY rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Pressure; Dose-Response Relationship, Drug; Heart Rate; Hypertension; Injections, Spinal; Male; Neuropeptide Y; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Neuropeptide Y; Solitary Nucleus; Time Factors

Considerable evidence indicates an enhanced sympathetic innervation of resistance arterial smooth muscle in the spontaneously hypertensive rat (SHR) compared with its normotensive Wistar-Kyoto (WKY) control. In addition to sympathetic hyperinnervation, an increased vascular innervation by neuropeptide Y-containing fibers, which are known to exert a vasoconstrictive and trophic action in vascular smooth muscle, has also been described. In addition to genetic hypertension, the SHR expresses hyperactive behavior and hyperreactivity to stress. To determine whether the enhanced neuropeptide Y-immunoreactive vascular innervation is specifically associated with hypertension and/or these behavioral abnormalities, four genetically related, inbred rat strains were used: SHR, which are hypertensive and hyperactive; WKY rats, which are neither hypertensive nor hyperactive; WKHA, which are hyperactive but normotensive; and WKHT, which are hypertensive but not hyperactive. The present study demonstrated that whereas the hypertensive strains (SHR and WKHT) exhibited smooth muscle hypertrophy in both superior mesenteric and caudal arteries in adulthood (10 months) but not at a prehypertensive age (1 month), both arteries exhibited significantly increased neuropeptide Y-immunoreactive innervation at both ages. It was further observed that the mesenteric artery in WKHA, a normotensive strain, had significant smooth muscle hypertrophy at 10 months; however, neuropeptide Y innervation in this artery was no different from that of WKY controls. The findings indicate that there is a cosegregation of neuropeptide Y hyperinnervation of the vasculature with the hypertensive phenotype, evident as early as 1 month of life in the hypertensive strains, and this should be considered further as a contributory factor in genetic hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arteries; Behavior, Animal; Hypertension; Hypertrophy; Male; Muscle, Smooth, Vascular; Nerve Fibers; Neuropeptide Y; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Inbred WKY; Species Specificity

To investigate the pathophysiological role of platelet neuropeptide Y (NPY) in hypertension.. The content of NPY in plasma and platelets from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKR) were measured by radioimmunoassay.. There was no difference in NPY concentration between SHR plasma and WKR plasma (2.1 +/- 1.0 vs 1.8 + 1.0 microgram.L-1), but higher amounts of NPY in SHR platelets than in WKR platelets (32 +/- 6 vs 22 +/- 9 micrograms.L-1, P < 0.05). The platelet aggregation and the release of NPY from platelets induced by thrombin and collagen were increased in SHR; ADP did not cause NPY release from platelets, although it produced severe aggregation in both SHR and WKR.. The content of NPY in platelets and thrombin- and collagen-induced NPY release from platelets are higher in SHR than in WKR.

Topics: Animals; Blood Platelets; Hypertension; Male; Neuropeptide Y; Platelet Aggregation; Radioimmunoassay; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Modest increases in urinary bladder pressure result in acute hypertensive episodes in humans with spinal cord lesions above T5. The underlying mechanisms of this condition, referred to as autonomic dysreflexia, are not well understood. The aim of this study was to characterize the contribution of alpha- and beta-adrenoceptors as well as circulating neuropeptide-Y (NPY) to the pressor response to bladder distension in conscious cervical spinal rats. Rats were chronically instrumented with arterial and venous catheters. After 2-3 days, a complete spinal transection (C7) was performed, and the urinary bladder was catheterized: 24 h later, mean arterial pressure (MAP) responses to 5 min bladder distensions (+40) were measured under control conditions and after administration of specific autonomic antagonists. To assess the contribution of alpha and beta adrenergic mechanisms the alpha antagonist prazosin (0.45 mg/kg i.v.) and beta antagonist, propranolol (4 mg/kg i.v.), were administered individually or together. Blood samples were taken before, during and after bladder distension for determination of plasma NPY by radioimmunoassay. The pressor response to bladder distension was approximately 30 mmHg under control conditions. The response was attenuated (-38%), but not abolished, by prazosin. A similar attenuation (-41%) was observed with propranolol. There were no changes in plasma NPY in response to bladder distension. Finally, the pressor response was completely abolished by combined alpha- and beta-adrenergic blockade. These results suggest that autonomic dysreflexia is mediated exclusively by adrenergic receptors in the spinal rat. Moreover, both alpha and beta adrenergic receptors contribute to the pressor response induced by bladder distension in the conscious cervical spinal rat.

Topics: Animals; Autonomic Nervous System Diseases; Blood Pressure; Ganglionic Blockers; Heart Rate; Hexamethonium; Hypertension; Male; Neuropeptide Y; Prazosin; Propranolol; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta; Spinal Cord Injuries; Sympathetic Nervous System; Urinary Bladder; Urinary Catheterization

We describe a 29-year-old woman with persistent arterial hypertension which resolved following complete excision of a capillary haemangioblastoma from within the spinal cord at the cervico-medullary junction. Immunohistochemical staining was positive for neuropeptide Y in capillary walls and nerves in the tumour. This raises the possibility of an association between neuropeptide Y and the central control of blood pressure in man.

Topics: Adult; Brain Stem; Cerebellar Neoplasms; Female; Hemangioblastoma; Humans; Hypertension; Immunohistochemistry; Neuropeptide Y

Vascular tissues from spontaneously hypertensive rats (SHR) exhibit increased nerve growth factor (NGF) levels and increased density of sympathetic innervation compared with those from normotensive Wistar-Kyoto (WKY) rats. The present study asked whether basal NGF secretion or secretion elicited by agents analogous to sympathetic neurotransmitters differ in cultured vascular smooth muscle cells (VSMCs) from SHR and WKY rats. VSMCs were maintained in serum-free medium (SFM) for 72 h and then treated and sampled at 4, 6, 8, and 24 h. Conditioned medium was assayed for NGF using a two-site enzyme-linked immunoassay. NGF secretion by SHR (19.2 +/- 4.6 pg.well-1.48 h-1) and WKY VSMCs (16.7 +/- 5.4 pg.we..-1.48 h-1) was similar in cultures grown in serum-containing medium, whereas SHR VSMCs maintained in SFM secrete more NGF than WKY VSMCs (9.1 +/- 1.9 vs. 2.9 +/- 0.4 pg.well-1.24 h-1, respectively). Treatment of cultures with phenylephrine (0.1-10 microM), neuropeptide Y (1-1,000 nM), or alpha beta-methyleneadenosine 5'-triphosphate (10 and 100 microM) had no effect on NGF secretion by WKY VSMCs, while increasing NGF secretion by SHR VSMCs. Treatment with isoproterenol (0.1-10 microM) decreased NGF secretion by WKY VSMCs but not SHR VSMCs. These data indicate that the regulation of NGF secretion by sympathetic neurotransmitter receptors is different for cultured VSMCs from SHR and WKY rats. If similar differences exist in vivo, they could account for the alterations in NGF levels and sympathetic innervation that are observed.

Topics: Animals; Blood; Cell Division; Cells, Cultured; Culture Media, Serum-Free; Hypertension; In Vitro Techniques; Muscle, Smooth, Vascular; Nerve Growth Factors; Neuropeptide Y; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Adrenergic; Receptors, Purinergic

Neuropeptide-Y (NPY) is a peptide proposed to modulate the effect of the sympathetic nervous system on blood pressure control and contribute to the development of essential hypertension. To assess the possible influence of gender on its role, we evaluated plasma NPY, noradrenaline (NA) and adrenaline (A) concentrations in men and women with essential hypertension. No difference in NPY concentration was found between genders, but NPY concentration was elevated in both hypertensive men and women. NA levels were similar in all investigated hyper- and normotensives, while A was increased only in hypertensive men. These results suggest various patterns of sympatho-adrenal activity in gender subgroups of patients with essential hypertension.

Topics: Adult; Age Factors; Blood Pressure; Epinephrine; Evaluation Studies as Topic; Female; Humans; Hypertension; Male; Middle Aged; Neuropeptide Y; Norepinephrine; Sex Factors; Statistics as Topic

In the present study, we investigated serum and myocardial neuropeptide Y concentrations as measures of sympathetic activity as well as myocardial beta-adrenoceptors and beta-adrenoceptor-stimulated adenylyl cyclase activity in spontaneously hypertensive rats (SHR). SHR and control rats at 10 weeks of age were kept on oral treatment with captopril, nitrendipine, or both for 20 weeks. Treatment only slightly reduced but did not normalize blood pressure and cardiac hypertrophy in SHR. The elevated serum concentration of neuropeptide Y, the reduced number of beta-adrenoceptors, and the depressed beta-adrenoceptor-stimulated adenylyl cyclase activity were partly normalized compared with the values observed in control rats. We conclude that antihypertensive treatment, at doses that failed to normalize systolic pressure and to reverse cardiac hypertrophy completely, is able to reduce sympathetic activity in SHR, thereby resensitizing the depressed beta-adrenoceptor-adenylyl cyclase system.

Topics: Adenylyl Cyclases; Animals; Captopril; Cardiomegaly; Hypertension; Male; Myocardium; Neuropeptide Y; Nitrendipine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Wistar; Receptors, Adrenergic, beta; Sympathetic Nervous System

The possible involvement of prejunctional alpha 2-adrenergic autoinhibition in hypertension is still controversial. The aim of this study was to determine the functional integrity of this regulatory mechanism in conscious DOCA-salt hypertensive rats, a model characterized by an increased sympathetic tone and reactivity. Basal and hemorrhage-induced increases in catecholamine and immunoreactive neuropeptide Y (NPY) levels were compared between control and yohimbine (alpha 2-adrenergic receptor antagonist) pretreated normotensive and DOCA-salt hypertensive rats. DOCA-salt hypertensive rats had higher basal norepinephrine levels (NE), as well as increased NE and epinephrine (EPI) responses to a 15-mL/kg hemorrhage as compared to control normotensive rats. In normotensive animals, yohimbine (0.5 mg/kg, intravenous [iv]) doubled plasma NE, EPI, and NPY levels in basal conditions and in response to the hemorrhage. In contrast, the same treatment had smaller or no effect on basal NE levels and on the hemorrhage-induced responses in DOCA-salt hypertensive rats, although basal EPI levels were increased in this group. These results therefore suggest a decreased function of the prejunctional alpha 2-adrenergic autoinhibitory mechanism at the level of sympathetic nerve terminals and adrenal medulla during sympathetic hyperactivity in DOCA-salt hypertension. This dysfunction could in part explain the hyperactivity and hyperreactivity of the sympathetic nervous system observed in this model, and thus contribute to the elevation of blood pressure in DOCA-salt hypertension.

Topics: Adrenal Medulla; Animals; Blood Pressure; Body Weight; Desoxycorticosterone; Epinephrine; Hemorrhage; Hypertension; Male; Neuropeptide Y; Norepinephrine; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-2; Sodium Chloride; Sympathetic Nervous System; Yohimbine

Pheochromocytoma is a unique type of hypertension caused by excessive production of catecholamines by the chromaffin tumor. Pheochromocytoma, a potentially life-threatening disease, is a rare cause of hypertension. The incidence varies from 0.1 to 0.8% of hypertensive population. The author's experience is based on 138 patients treated in one institution from 1956 to 1995. Hormonal activity of pheochromocytoma varies considerably, influencing the pattern, of blood pressure and the clinical symptoms. It is emphasized that different other humoral mechanisms may play a role in the pathophysiology of this type of endocrine hypertension. Biochemical tests and non-invasive localizing methods are essential for the definite diagnosis of pheochromocytoma. A great progress has been made in this respect during the last three decades. Surgical removal of the tumor is the only definite therapy with low morbidity and mortality.

Topics: Atrial Natriuretic Factor; Catecholamines; Humans; Hypertension; Neuropeptide Y; Pheochromocytoma; Renin

The aim of the study was to investigate endothelin-1 (ET-1) and neuropeptide Y (NPY) plasma concentrations in renal venous blood of hypertensive patients with unilateral renal artery stenosis (URAS). The study was performed in 22 patients with URAS and 18 patients diagnosed as essentially hypertensive. In each subject renal arteriography and renal vein catheterisation was performed. Blood samples for ET-1, NPY and plasma renin activity (PRA) were withdrawn from renal veins and vena cava inferior, and for ET-1 and NPY from the aorta. Patients with URAS were divided in two subgroups according to the renal vein renin ratio. Both in nine patients with URAS and ratio > 1.5 and in 13 patients with URAS and ratio < 1.5, ET-1 and NPY plasma concentrations evaluated in renal venous blood of the ischaemic kidney were not different from those assessed in the contralateral side, in vena cava inferior and in the aorta. In essential hypertension, the mean ET-1 and NPY plasma concentrations of both renal veins were not different from the ET-1 and NPY plasma values assessed in renal vein of stenosed and contralateral side, vena cava and aorta of patients with URAS with and without activation of the renin system. Our study indicates that chronic ischaemia does not affect ET-1 and NPY plasma concentrations in renal venous blood of hypertensive URAS patients both with and without activation of the renin system.

Topics: Adult; Endothelins; Female; Humans; Hypertension; Male; Middle Aged; Neuropeptide Y; Renal Artery Obstruction; Renal Veins

To comprehend the relationship between the distribution of perivascular neuropeptides and remodified structure of arterioles in hypertension, we applied the technique of sheeting from pia matter of spontaneously hypertensive rats (SHR) to reveal branches at all levels of the vascular network so as to make an overall and stereoscopic observation of the vasculature. In addition, immunohistochemical technique and image analyser were applied to analyse qualitatively and quantitatively neuropeptide Y(NPY)-containing innervation in the vasculature. Findings revealed that the surface density of NPY-containing innervation and integral luminous density of positive reaction particle for anti-NPY in middle cerebral artery and its branches -small arteries and arterioles of SHR were significantly increased as compared with findings in Wistar Kyoto. The results reveal that an increase in density of NPY-containing innervation of cerebral small arteries and arterioles intensifies action of nutritive adjustment of vascular smooth muscle and is clearly related with increase of contractive excitability of artery, hypertrophy of artery, smooth muscle cells and the development of hypertension.

Topics: Animals; Arterioles; Cerebral Arteries; Hypertension; Image Processing, Computer-Assisted; Neuropeptide Y; Rats; Rats, Inbred SHR; Rats, Inbred WKY

An analogue of the 10 C-terminal amino acids of neuropeptide Y (NPY) containing three D-isomeric substitutions (27-36-D) has been synthesized and its cardiovascular activity studied in Sprague-Dawley (SD) and spontaneously hypertensive (SHR) rats. Intravenous administration of 1000 nmol/kg 27-36-D decreases MAP in SHR (-59.9 +/- 5.0 mmHg) and SD rats (-44.4 +/- 4.7 mmHg). The hypotension produced by 1000 nmol/kg 27-36-D diminished by 71.2% following pretreatment with the histamine receptor antagonist diphenhydramine, although histamine depletion with compound 48/80 does not significantly alter this hypotension. These data suggest that NPY (27-36)-D produces a profound and sustained hypotension in two strains of rat which is partially attributable to activity at histamine receptors.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Diphenhydramine; Dose-Response Relationship, Drug; Histamine H1 Antagonists; Hypertension; Male; Neuropeptide Y; Peptide Fragments; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Receptors, Histamine

Endothelin-1 (ET-1) may play an important role in the development and maintenance of hypertensive states. In patients with essential hypertension, ET-1 plasma concentration increases or remains unchanged. The aim of the present study was to investigate ET-1 plasma concentration in patients with mild-to-moderate essential hypertension and its interrelationship with catecholamines, neuropeptide Y and atrial natriuretic peptide (ANP).. The study included 37 patients (mean age 38.2 +/- 1.6 years) with mild-to-moderate essential hypertension. The control group consisted of 21 healthy volunteers (mean age 35.6 +/- 1.4 years). ET-1, neuropeptide Y and ANP were determined by radioimmunoassay methods and catecholamine plasma concentration was determined radioenzymatically.. Our study shows that plasma ET-1 and neuropeptide Y levels are elevated in patients with essential hypertension compared with a control group. No correlation was found in either of the groups between plasma ET-1 level and plasma neuropeptide Y, catecholamine or ANP concentrations.. Our results suggest that ET-1 is relevant in the development and maintenance of elevated blood pressure.

Topics: Adult; Atrial Natriuretic Factor; Catecholamines; Endothelins; Female; Humans; Hypertension; Male; Neuropeptide Y

There is evidence for an altered endothelial function in established hypertension but little is known about endothelial function in borderline hypertension. It has also been suggested that the early stages of hypertension are characterized by an increased sympathetic drive.. To investigate whether alterations in endothelin, neuropeptide Y (NPY) and calcitonin gene-related peptide (CGRP) are already present in the borderline hypertensive stage.. A case-control study of age-matched men recruited from a population screening programme.. Seventy-five men with stable borderline hypertension [diastolic blood pressure (DBP), 85-94 mmHg] and 75 age- and sex-matched normotensive controls (DBP < or = 80 mmHg) were investigated. Plasma samples were drawn in a standardized fashion, and extracted and analysed using competitive radio immunoassays.. Basal concentrations of NPY and CGRP were similar in the two groups (28.4 versus 26.7 pmol/l and 24.2 versus 21.7 pmol/l, respectively). Basal concentrations of endothelin were significantly higher in the borderline hypertensive group (2.0 versus 1.5 pmol/l, P < 0.0001).. These results suggest that a disturbed endothelial function, represented by endothelin, could be involved in the early hypertensive processes. They also suggest that these changes could be present before the basal sympathetic/parasympathetic drive alters, warranting further research into this area.

Topics: Adult; Calcitonin; Endothelins; Humans; Hypertension; Male; Neuropeptide Y; Radioimmunoassay

1. This study examined neuropeptide Y (NPY) concentrations in brain regions and peripheral tissues of young (3-4 months) and old (17-18 months) normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). 2. Neuropeptide Y-like immunoreactivity (NPY-LI) was determined in kidney, adrenal, heart ventricles, atria and four brain regions, cerebral cortex, hypothalamus, ventrolateral medulla (VLM) and dorsomedial medulla containing the nucleus tractus solitarius (NTS), by radio-immunoassay following acid extraction. 3. Significant age-related increases in organ weights were observed in atria, ventricle and kidney of both WKY and SHR (P < 0.01). In order to take into account tissue hypertrophy, NPY-LI data were analysed as pmol/g tissue as well as total pmol/tissue. 4. At each age, similar NPY-LI concentrations were observed in WKY and SHR in all brain regions. A significant age-induced decrease in NPY-LI concentration and total NPY content was found in the hypothalamus of both WKY and SHR (P < 0.01). 5. In the cardiac ventricle, decreases were observed in NPY-LI concentration with ageing, and in SHR relative to WKY; however, no differences were observed in total NPY-LI content. A significant age-related increase in adrenal NPY-LI concentration was observed. No age- or strain-related alterations in atrial or renal NPY-LI were detected, with the exception of an increase in total kidney NPY-LI in WKY with ageing. 6. Thus in the periphery, few changes in NPY-LI were observed with genetic hypertension or with ageing.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenal Glands; Aging; Animals; Brain Chemistry; Hypertension; Kidney; Myocardium; Neuropeptide Y; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Neuropeptide Y (NPY) has been recently characterised as a circulating vasoconstrictor peptide which is co-stored with noradrenaline (NA) in sympathetic neurons. We measured NPY by radioimmunoassay and NA by HPLC in plasma of ten healthy volunteers (23-27 years of age) during bicycle ergometry and found a rapid increase of both NPY and NA during exercise. NPY rose from 1.3 +/- 0.5 to 9.6 +/- 7.8 pmol/l and NA from 1.3 +/- 0.3 to 10.8 +/- 5.6 mnol/l (mean +/- SD). Following maximal exercise NA disappeared more rapidly from plasma than NPY. Compared with these healthy volunteers, plasma NPY was found to be elevated in 23 children and adolescents aged 9-18 years with borderline primary hypertension (NPY 3.1 +/- 1.7 pmol/l, P < 0.01). Basal NPY was also elevated when compared with 21 age-matched pediatric controls (P < 0.05). The bicycle ergometry protocol performed in 23 patients separated ten adolescents with normal basal and exercise blood pressure from 13 with high BP also during ergometry. In the latter group, NPY rose to 11.9 +/- 7.3 pmol/l and NA to 12.3 +/- 8.6 nmol/l during exercise. Treatment of the hypertensive patients with the beta-adrenergic blocker atenolol (50 mg per day) lowered basal and exercise BP. Heart rate fell during atenolol treatment from 92 +/- 19 to 72 +/- 15 beats/min. Treatment did not alter plasma concentrations under basal conditions and during exercise (NPY from 2.8 +/- 2.1 to 11.7 +/- 5.3 pmol/l and NA from 2.0 +/- 0.8 to 15.6 +/- 14.1 nmol/l).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Atenolol; Blood Pressure; Child; Chromatography, High Pressure Liquid; Exercise Test; Female; Heart Rate; Humans; Hypertension; Male; Neuropeptide Y; Osmolar Concentration; Reference Values; Sodium

Neuropeptide Y (NPY) is a sympathetic cotransmitter and a platelet-derived factor which causes vasoconstriction, potentiation of norepinephrine (NE) action, and vascular mitogenic effects. Reciprocally, NE markedly enhances the actions of NPY. We studied vasopressor effects of NPY and sources of peptide release during the development of hypertension in spontaneously hypertensive rats (SHR). Conscious SHR (4 and 16 weeks old) had higher resting plasma levels of NE and epinephrine than age-matched Wistar-Kyoto (WKY) rats, but similar NPY immunoreactivity (NPY-ir) levels in platelet-poor plasmas (PPP). In both strains, NPY-ir levels in PPP were higher in 4-week-old than in older rats. However, at all ages (4-24 weeks) SHR had markedly elevated NPY-ir content in platelet-rich-plasmas than WKY rats, although levels declined with age and hypertension. In the superior mesenteric artery, NPY-ir content (per mg) was significantly higher in 4-week-old but lower in 16-week-old SHR than in WKY rats, suggesting greater sympatho-neural NPY stores and release (leading to depletion) during the development of hypertension. Four-week-old SHR also tended to have higher NPY-ir content in the adrenal medullae and coeliac ganglia but a lower content in the kidney than WKY rats; these differences disappeared with age. Pressor responsiveness to alpha-agonists and NPY were similar in both strains at 4 weeks. While unchanged by age in WKY rats, adrenergic and NPY-mediated vasopressor responses became augmented in 16- to 24-week-old SHR (compared with WKY rats); this hyperresponsiveness was not completely abolished by ganglionic blockade and not observed with vasopressin.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenal Medulla; Adrenergic alpha-Agonists; Animals; Blood Platelets; Catecholamines; Hypertension; Male; Neuropeptide Y; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sympathetic Nervous System

Pheochromocytoma is often associated with paroxysmal hypertension. We report a 49-year-old woman with pheochromocytoma whose blood pressure (BP) was elevated regularly only at night. Plasma norepinephrine (NE) and neuropeptide Y (NPY) concentrations increased in parallel with the elevation of BP. After resection of the adrenal tumor, these circadian changes disappeared. Plasma NE and NPY, especially the former, from the tumor were considered to be the cause of this unusual fluctuation in BP.

Topics: Adrenal Gland Neoplasms; Blood Pressure; Circadian Rhythm; Female; Humans; Hypertension; Middle Aged; Neuropeptide Y; Norepinephrine; Pheochromocytoma

Recent evidence supports the view that the sympathetic system actively participates in the development of hypertension. Because norepinephrine, contained within central neurons involved in cardiovascular sympathetic regulation, is known to coexist with neuropeptide Y, it is possible that a functional interaction between neuropeptide Y and norepinephrine exists within the brain. In an effort to clarify whether or not central catecholamine systems are modulated by neuropeptide Y in hypertensive situations, the paraventricular nucleus of spontaneously hypertensive rats was exposed to neuropeptide Y (10(-9) M), and levels of norepinephrine were sampled by microdialysis. Norepinephrine levels in spontaneously hypertensive rats were significantly increased and did not change after exposure to neuropeptide Y, in sharp contrast to the decreases seen in Wistar-Kyoto controls. To ascertain whether these alterations in norepinephrine control were specific to the model used, a similar series of experiments was carried out in the paraventricular nucleus of aortic-banded rats. These studies supported the previous findings. Norepinephrine levels in aortic-banded rats were markedly elevated when compared with sham-operated controls and demonstrated no change after exposure to neuropeptide Y, whereas decreases of > 50% were seen in sham-operated controls. These results support the view that mechanisms normally involving neuropeptide Y as a neuromodulator in the paraventricular nucleus are altered in hypertensive situations. It is suggested that hypertension may precipitate changes in mechanisms involving brain neuropeptide Y and increased sympathetic activity.

Topics: Animals; Aorta; Dialysis; Hypertension; Ligation; Male; Neuropeptide Y; Norepinephrine; Paraventricular Hypothalamic Nucleus; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley

1. Eleven untreated men with mild to moderate primary hypertension and 10 normotensive control subjects were studied at rest and during a mental stress test (Stroop colour word conflict test), which has previously been used in studies of hypertensive patients with regard to non-invasive cardiovascular variables and venous plasma catecholamine concentrations. 2. Heart rate, central cardiovascular pressures, cardiac output (thermodilution) and forearm blood flow (strain gauge plethysmography) were determined. Systemic and forearm vascular resistances were calculated. Arterial and venous plasma adrenaline and noradrenaline concentrations were measured by h.p.l.c., and arterial noradrenaline spillover and noradrenaline overflow from the forearm were assessed by isotope methodology ([3H]noradrenaline). Neuropeptide Y-like immunoreactivity was measured by radioimmunoassay. 3. In hypertensive patients heart rate, arterial blood pressure, cardiac output and forearm blood flow increased by 28%, 13%, 37% and 115%, respectively, and forearm and systemic vascular resistances decreased by 48% and 21%, respectively (P < 0.001 for all responses), during stress. These responses were not different from those of the control group. 4. Arterial noradrenaline spillover rose by 63% and noradrenaline overflow from the forearm rose by 150% in the hypertensive patients in response to mental stress (P < 0.001); no significant group differences could be demonstrated. However, the forearm noradrenaline overflow response to stress tended to be greater in the hypertensive group (P = 0.11). Arterial adrenaline concentrations doubled in both groups (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenal Glands; Adult; Cardiac Output; Cardiovascular System; Epinephrine; Forearm; Heart Rate; Humans; Hypertension; Male; Middle Aged; Neuropeptide Y; Norepinephrine; Stress, Psychological; Sympathetic Nervous System; Vascular Resistance

Innervation by noradrenergic (NA) and neuropeptide Y-immunoreactive (NPY-IR) nerves to the pancreatic islets and the arteries supplying the islets was studied by immunocytochemistry in 6- and 20-week-old spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Since both the NA and NPY-IR nerves follow the intra- and interlobular small arteries and innervate the islets, we examined mainly the innervation of intra- and interlobular small arteries by these nerves. The NA nerve density of the intralobular small arteries supplying the islets was significantly more extensive in 6-week-old SHR than in age-matched WKY (7.11 +/- 1.78 vs. 4.04 +/- 0.71 x 10(-2) micron/micron2, P < 0.001), and the NPY-IR nerve density of the intralobular small arteries was significantly more extensive in SHR than in WKY at 6 weeks of age (7.68 +/- 2.28 vs. 5.69 +/- 0.91 x 10(-2) micron/micron2, P < 0.05). The interlobular small arteries branching off the intralobular small arteries in SHR were also more innervated by NA (P < 0.05) and NPY-IR nerves (P < 0.001) than by those in WKY at 6 weeks of age. At 20 weeks of age, the NA and NPY-IR nerve densities of the intra- and interlobular small arteries were higher in SHR than in WKY, and showed an increase with age in both strains. In addition, the islet innervation by these nerves in cross-section appeared denser in SHR than in WKY.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arteries; Blood Pressure; Body Weight; Fluorescent Antibody Technique; Hypertension; Immunohistochemistry; Insulin; Insulin Secretion; Islets of Langerhans; Male; Neuropeptide Y; Norepinephrine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sympathetic Nervous System

To investigate the cardiovascular effect of alpha-trinositol (D-myo-inositol-1,2,6-trisphosphate; PP56) in spontaneously hypertensive rats (SHR) and in normotensive Wistar-Kyoto (WKY) rats. alpha-Trinositol, a representative of a new group of pharmacological agents, is an inositol phosphate which seems to bind to a single population of binding sites, inhibiting, for example, agonist-induced vasoconstriction. In particular, alpha-trinositol seems to inhibit agonist-induced (e.g. neuropeptide Y-induced) elevations in intracellular Ca2+ levels in vascular smooth muscle cells.. alpha-Trinositol was administered as a bolus injection (2-40 mg/kg body weight), followed by a continuous infusion (20-400 mg/kg body weight per h) for 40 min in freely moving SHR and WKY rats.. Acute intravenous bolus administration of alpha-trinositol reduced systolic and diastolic blood pressure, as well as heart rate, in a dose-dependent manner in SHR and WKY rats. After completion of the 40-min infusion the reduction in blood pressure was more pronounced in the SHR than in the WKY control rats. Heart rate did not change in the SHR, whereas it was significantly increased at the highest dosage (400 mg/kg) in the WKY rats. At this dosage, three out of eight SHR died from cardiac arrhythmias after completing the infusion. The lowest dose of alpha-trinositol administered (2 mg/kg bolus followed by 20 mg/kg per h infusion over 40 min) significantly inhibited the increase in mean arterial pressure induced by neuropeptide Y (2 micrograms/kg per min for 10 min) by approximately 30% in both the SHR and WKY rats. Furthermore, alpha-trinositol treatment completely inhibited the potentiation induced by neuropeptide Y (0.1 micrograms/min for 30 min) of the blood pressure responses to intravenous bolus injections of noradrenaline (20 ng), tyramine (40 micrograms) or angiotensin II (10 ng).. Our results demonstrate that alpha-trinositol antagonizes the direct postsynaptic pressor response to exogenous neuropeptide Y, as well as the potentiating effects of neuropeptide Y on other vasoconstrictors in SHR and WKY rats. However, in the SHR alpha-trinositol lowered basal blood pressure only in the dose range which was non-specific for neuropeptide Y inhibition. Thus, the present study indicates that neuropeptide Y is involved only slightly in the maintenance of high blood pressure in SHR.

Topics: Animals; Blood Pressure; Dose-Response Relationship, Drug; Heart Rate; Hypertension; Inositol Phosphates; Male; Neuropeptide Y; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Muscle nerve sympathetic activity (MSA) was recorded during wakefulness in 11 patients with obstructive sleep apnea (OSA) and in 9 sex- and age-matched healthy control subjects. Plasma levels of norepinephrine (NE) and neuropeptide Y were analyzed. Five patients had established hypertension (resting supine systolic BP/diastolic BP > or = 160/95 mm Hg). The investigation was performed after a minimum of 3 weeks' washout period of antihypertensive medication. Muscle sympathetic activity during supine rest was higher in patients compared with controls (p < 0.01) with no difference between normotensive and hypertensive patients. However, systolic, but not diastolic, BP was positively related to resting MSA (n = 20, p < 0.01). There was no significant correlation between body mass index and MSA. Resting MSA was unrelated to disease severity expressed as apnea frequency or minimum SaO2 during the overnight recording. Both the arterial and venous plasma norepinephrine was higher in patients compared with controls (p < 0.05). Plasma levels of NE correlated to resting MSA (p < 0.01) in the whole study group (patients and controls) but not within the respective subgroups. No significant correlation, however, was found between plasma NE (arterial and venous) and BP. Plasma neuropeptide Y-like immunoreactivity was similar in patients and controls. However, one patient with hypertension had approximately twice this level in repeated samples. It is concluded that neurogenic sympathetic activity as well as circulating plasma NE is increased in patients with OSA. This increased sympathetic activity during awake supine rest may reflect a pathophysiologic adaptation to hypoxia and hemodynamic changes occurring at repetitive apneas during sleep. The correlation between MSA and systolic BP implies that this mechanism may be directly or indirectly involved in the development of cardiovascular complications in OSA.

Topics: Adult; Blood Pressure; Humans; Hypertension; Leg; Male; Middle Aged; Muscles; Neuropeptide Y; Norepinephrine; Prospective Studies; Sleep Apnea Syndromes; Sympathetic Fibers, Postganglionic; Sympathetic Nervous System; Wakefulness

Recent advances in molecular biology have allowed the study of the candidate genes for essential hypertension. To identify the genes responsible for basal blood pressure in the spontaneously hypertensive rat strain, the rat model of genetic hypertension, we performed a cosegregation analysis between the genotype and blood pressure in a set of male F2 progeny obtained from SHR and Wistar-Kyoto rats, a reference normotensive strain. Our investigation revealed that a locus on the chromosome 4 cosegregates with the blood pressure in SHR, especially at neuropeptide Y locus. The degree of cosegregation with all values of blood pressure without sodium loading was moderate but consistent. We propose that neuropeptide Y locus on chromosome 4 is a new candidate for the hypertensive effect in original SHR.

Topics: Animals; Base Sequence; Chromosome Mapping; DNA, Single-Stranded; Female; Genotype; Hypertension; Male; Molecular Sequence Data; Neuropeptide Y; Rats; Rats, Inbred SHR; Rats, Inbred WKY

To investigate the pathological role of platelet neuropeptide Y (NPY) in genetically hypertensive rats, we measured the platelet content and plasma concentration of immunoreactive (ir)-NPY in hypertensive and normotensive rats and examined the aggregating ability of rat platelets and the NPY releasing reaction in each of these rat types. In addition, we purified platelet NPY and determined its amino acid sequence.. To characterize immunoreactive NPY in rat platelets, rat platelet NPY was purified to homogeneity and the purified peptide was analysed by gas-phase sequencer. Platelet content and plasma concentration of NPY was measured by a sensitive radioimmunoassay for NPY. Aggregating ability was examined by a turbidimetric method; aggregation was recorded for 5 min and the maximum aggregation was read.. Rat platelet NPY was purified and the amino acid sequence was determined to be YPSKPDNPGEDAPAEDMARYYSALRHYINLITRQRY. The platelet content of ir-NPY in 5-, 10-, and 15-week-old spontaneously hypertensive rats (SHR) was higher than that in Wistar-Kyoto (WKY) rats of the same age. The platelet content of ir-NPY in 10-week-old stroke prone-SHR was also higher than that in 10-week-old WKY rats. No differences were observed between any of the pairs in any WKY rats, SHR or stroke-prone SHR group with regard to the plasma concentration of ir-NPY. Ir-NPY was not released from rat platelets when adenosine diphosphate was used for aggregation. However, NPY was released from the platelets when they were aggregated by collagen and, furthermore, in this case the amount of NPY released from platelets was greater in SHR than in WKY rats.. That the platelet content of NPY in SHR (and stroke-prone SHR) was higher than that in WKY rats seems to be an important genetic characteristic of SHR. As NPY is a potent vasoconstrictor, it may be involved in the progression of vascular lesions.

Topics: Amino Acid Sequence; Animals; Blood Platelets; Hypertension; Molecular Sequence Data; Neuropeptide Y; Platelet Aggregation; Radioimmunoassay; Rats; Rats, Inbred SHR; Rats, Inbred WKY

To investigate the modification of plasma and tissue neuropeptide Y-like immunoreactivity (NPY-li) concentrations, in relation to blood pressure and plasma catecholamine levels, during the development of deoxycorticosterone acetate (DOCA)-salt hypertension.. Mean arterial pressure (MAP), heart rate, tissue and plasma NPY-li levels, and aortic norepinephrine and epinephrine plasma levels were measured in conscious DOCA-salt hypertensive rats treated for 1, 2 and 3 weeks, and in their respective normotensive controls.. Both norepinephrine and NPY-li plasma levels increased significantly in parallel with blood pressure during DOCA-salt treatment, so that MAP was significantly correlated with plasma norepinephrine and NPY-li levels in hypertensive rats. Plasma NPY-li levels were also correlated with norepinephrine levels only in hypertensive rats, but were correlated with epinephrine levels only in normotensive animals. Tissue NPY-li content was lower in the mesenteric artery and heart ventricles after 1-3 weeks of DOCA-salt treatment, but the content in the adrenal gland was not significantly different from that in normotensive rats.. In DOCA-salt hypertensive rats, increased plasma NPY-li levels originate primarily from the sympathetic nerves, since those levels were correlated exclusively with circulating norepinephrine levels and they were associated with a reduction in NPY-li content of the heart and mesenteric artery. It is thus possible that the enhanced release of NPY-li from sympathetic nerves could contribute to the rise in blood pressure and to the maintenance of hypertension in this experimental model.

Topics: Animals; Blood Pressure; Desoxycorticosterone; Hypertension; Male; Neuropeptide Y; Norepinephrine; Radioimmunoassay; Rats; Rats, Inbred Strains; Sodium, Dietary; Sympathetic Nervous System

1. We investigated the usefulness of neuropeptide Y as a plasma marker for phaeochromocytoma, ganglioneuroblastoma and neuroblastoma using a simple and highly sensitive r.i.a. for human neuropeptide Y. 2. Plasma immunoreactive neuropeptide Y concentrations were measured without extraction in plasma samples (100 microliters) from patients with various diseases. 3. The plasma immunoreactive neuropeptide Y concentration in patients with phaeochromocytoma (172.3 +/- 132.4 pmol/l, mean +/- SD, n = 23) was significantly higher than that in healthy adult subjects (40.1 +/- 10.1 pmol/l, n = 40, P < 0.0001). The plasma immunoreactive neuropeptide Y concentrations in patients with ganglioneuroblastoma (590.7 +/- 563.6 pmol/l, n = 6) and patients with neuroblastoma (566.9 +/- 524.4 pmol/l, n = 15) were significantly higher than those in control children (1-9 years old, 82.2 +/- 39.9 pmol/l, n = 72, P < 0.0001). 4. The plasma immunoreactive neuropeptide Y concentration in patients with essential hypertension (34.0 +/- 3.7 pmol/l, n = 18) was within the normal range, but in patients with chronic renal failure undergoing maintenance haemodialysis (192.1 +/- 68.0 pmol/l, n = 25) and in non-dialysed patients with chronic renal failure (85.1 +/- 23.1 pmol/l, n = 7) it was significantly higher than that in healthy adult subjects (P < 0.0001). 5. Eighty-seven per cent of the patients with phaeochromocytoma, 67% of the patients with ganglioneuroblastoma and 80% of the patients with neuroblastoma showed plasma immunoreactive neuropeptide Y concentrations higher than the upper limits in the control subjects [62 pmol/l (adult) and 160 pmol/l (children)].(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adrenal Gland Neoplasms; Adult; Aged; Biomarkers, Tumor; Child; Child, Preschool; Female; Ganglioneuroma; Humans; Hypertension; Infant; Kidney Failure, Chronic; Male; Middle Aged; Neuroblastoma; Neuropeptide Y; Pheochromocytoma; Radioimmunoassay

Neuropeptide Y is a co-transmitter with noradrenaline in sympathetic neurons supplying arteries and veins with potent contractile effects. To investigate the role of neuropeptide Y in hypertension, we measured the circulating levels of neuropeptide Y and noradrenaline in patients with severe hypertension.. Samples were collected from patients with untreated, severe hypertension (diastolic blood pressure > 120 mmHg) and in age- and sex-matched controls. After treatment with beta-adrenoceptor blockers, diuretics, angiotensin converting enzyme inhibitors of calcium antagonists, samples were taken from the patients during 12 months.. The circulating levels of neuropeptide Y-like immunoreactivity (NPY-LI) were measured with a radioimmunoassay using a rabbit antiserum. Catecholamines were measured using high-performance liquid chromatography and electrochemical detection.. There was a significantly higher level of NPY-LI in the patients when they were compared with the controls. However, there was no correlation either in the controls or in the hypertensives between systolic blood pressure, diastolic blood pressure and NPY-LI or noradrenaline. The increased level of NPY-LI in plasma remained elevated for up to 12 months despite reduction in blood pressure to acceptable levels. The noradrenaline level was not increased before treatment, after 2-4 weeks or after 2-12 months treatment.. The high level of NPY-LI may represent a marker for higher activity of the sympathetic nervous system which is not controlled by the treatment of blood pressure to normotension.

Topics: Acute Disease; Adult; Age Factors; Antihypertensive Agents; Blood Pressure; Case-Control Studies; Epinephrine; Female; Follow-Up Studies; Humans; Hypertension; Male; Middle Aged; Neuropeptide Y; Norepinephrine

Neuropeptide Y (NPY) has a wide and specific distribution in the central nervous system, and is colocalized with catecholamines in specific neuronal systems. In this study, in order to investigate the regulatory mechanisms of NPY and presynaptic alpha 2-adrenergic receptors on central noradrenergic transmission in hypertension, we have examined the effects of NPY and the alpha 2-agonist, UK 14,304, on (3H)-noradrenaline (NA) release from hypothalamic slices of spontaneously hypertensive rats (SHR). Electrical stimulation (1 Hz)-evoked (3H)-NA release was significantly greater in the hypothalamic slices of SHR than in those of Wistar Kyoto rats (WKY). NPY and the alpha 2-agonist, UK 14,304, inhibited the stimulation-evoked (3H)-NA release in a dose-related manner. The inhibitory effects of NPY and UK 14,304 on NA release were significantly attenuated in SHR compared with WKY. These results suggest that NPY and alpha 2-adrenoceptors might be involved in the regulation of central sympathetic nervous activity in hypertension.

Topics: Adrenergic alpha-Agonists; Animals; Brimonidine Tartrate; Electric Stimulation; Hypertension; Hypothalamus; In Vitro Techniques; Male; Neuropeptide Y; Norepinephrine; Quinoxalines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Adrenergic, alpha; Synaptic Transmission

1. Family and population studies have reported that blood pressure has a heritability of 30-50%, but simple genetic models do not readily explain the patterns of inheritance of hypertension. 2. Restriction fragment length polymorphisms were used to study allele frequencies of a selection of candidate genes that may be important in determining the genetic component of hypertension. These included the genes for renin, haptoglobin, neuropeptide Y and cardiac myosin beta heavy chain. 3. There was no significant association between alleles at any of these loci and the presence of hypertension in this population, suggesting that the contribution of variation at these loci to the genetic component of the variance in hypertension may be quite small.

Topics: Alleles; Cardiomyopathy, Hypertrophic; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 14; Chromosomes, Human, Pair 7; DNA; DNA Probes; Female; Genetic Linkage; Haptoglobins; Humans; Hypertension; Male; Middle Aged; Myosins; Neuropeptide Y; Nucleic Acid Hybridization; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Renin

The possible cardiovascular and biochemical interactions between the imidazoline ligand rilmenidine, a novel antihypertensive agent, and neuropeptide Y (NPY) were examined in spontaneously hypertensive rats (SHR). Rilmenidine (25-225 micrograms/kg) and NPY (1.7-15 micrograms/kg) both produced a significant, dose-dependent reduction in blood pressure (BP) after intracisternal (i.c.) administration in conscious SHR. When submaximal doses of rilmenidine (25 micrograms/kg) and NPY (1.7 micrograms/kg) were coadministered i.c., the resultant hypotension and bradycardia was less than either individual response and significantly less than the sum of their individual responses, suggesting the existence of an inhibitory interaction between these agents. To determine whether this interaction was evident at the second-messenger level, the effect of these agents on cyclic AMP levels was investigated in slices from the medulla oblongata of SHR. NPY (10(-6) and 10(-7) M) significantly inhibited forskolin-stimulated cyclic AMP production. Rilmenidine (10(-8)-10(-5) M) itself had no significant effect on forskolin-stimulated cyclic AMP levels in this system, but rilmenidine (10(-6) M) attenuated the inhibitory effect of NPY (10(-6) M) on cyclic AMP production. Thus, an inhibitory interaction between rilmenidine and NPY was observed at the hemodynamic and second-messenger level in the SHR.

Topics: Adenylyl Cyclases; Adrenergic alpha-Agonists; Animals; Colforsin; Cyclic AMP; Dose-Response Relationship, Drug; Hemodynamics; Hypertension; In Vitro Techniques; Male; Medulla Oblongata; Neuropeptide Y; Oxazoles; Rats; Rats, Inbred SHR; Rilmenidine

Animal experimental evidence suggests that neuropeptide Y (NPY) is coreleased with norepinephrine (NE) from sympathetic nerve endings and is involved in nonadrenergic neurogenic vascular control of skeletal muscle. We wished to determine whether these findings may be extended to humans. Forearm blood flow (venous occlusion plethysmography) and the regional overflows of NE and NPY-like immunoreactivity (NPY-LI) were studied at rest and during sympathetic nerve activation by lower body negative pressure (LBNP; -10 mm Hg, 10 min) in 10 hypertensive men before and after local alpha-adrenergic blockade by a dose of phenoxybenzamine (60 micrograms x 100 ml-1 x min-1 for 60 min), which most markedly attenuated responses to exogenous NE; propranolol (10 micrograms x 100 ml-1 x min-1) was present throughout. Phenoxybenzamine increased forearm blood flow at rest (11.5 +/- 1.0 vs. 3.9 +/- 0.3 ml x 100 ml-1 x min-1; p less than 0.001). LBNP-evoked reduction of forearm blood flow (37 +/- 2%, p less than 0.001) was attenuated (p less than 0.001) but not abolished (18 +/- 2%, p less than 0.001) by phenoxybenzamine. LBNP increased the overflow of NE from 5.0 +/- 1.7 to 8.2 +/- 3.0 pmol x 100 ml-1 x min-1 (p less than 0.05) and that of NPY-LI from -9.0 +/- 4.4 to 8.0 +/- 4.9 fmol x 100 ml-1 x min-1 (p less than 0.05) after phenoxybenzamine; effects on the evoked overflows of NE and NPY-LI before phenoxybenzamine were slight. Prejunctional inhibitory alpha-adrenoceptors may thus modulate NPY release as well.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Pressure; Epinephrine; Forearm; Heart Rate; Hemodynamics; Humans; Hypertension; Lower Body Negative Pressure; Male; Middle Aged; Neuropeptide Y; Norepinephrine; Phenoxybenzamine; Propranolol; Regional Blood Flow; Vascular Resistance

The mechanisms of hypertension during primary hyperaldosteronism and Cushing's syndrome are not completely understood. An enhanced vascular sensitivity to noradrenaline has been described in both situations. Neuropeptide Y (NPY) induces direct vasoconstriction and potentiates the action of noradrenaline. Sodium retention and dexamethasone have been shown to increase circulating NPY levels in animals and the expression of NPY in neuroendocrine cells. In order to determine if NPY could be involved in the enhanced vascular sensitivity to noradrenaline associated with adrenocortical hyperactivity, we measured plasma NPY in patients with Cushing's syndrome (n = 26) and primary hyperaldosteronism (n = 15) and compared it with that of hypertensive patients with pheochromocytomas (n = 13) or essential hypertension (n = 51) and with normotensive controls (n = 47). The concentration of NPY-Like immunoreactivity (NPY-Li) (mean +/- S.E.) in controls was 39.6 +/- 3.0 pg/ml. Elevated concentrations were found in 77% of the samples collected from pheochromocytoma patients (1180.4 +/- 394.0 pg/ml). NPY-Li levels in patients with essential hypertension (35.0 +/- 2.6 pg/ml), primary hyperaldosteronism (31.3 +/- 3.9 pg/ml) and Cushing's syndrome (33.1 +/- 4.8 pg/ml) were not different from that of controls. NPY-Li levels in hypertensive and normotensive patients with Cushing's syndrome were similar (38.5 +/- 7.5 vs 24.2 +/- 3.7 pg/ml). No correlation was found between the NPY-Li level and the mean blood pressure at the time of sampling. Our results suggest that NPY is unlikely to be involved in the pathogenesis of hypertension associated with primary hyperaldosteronism and Cushing's syndrome.

Topics: Adolescent; Adrenal Gland Neoplasms; Adult; Aged; Blood Pressure; Cushing Syndrome; Female; Humans; Hyperaldosteronism; Hypertension; Male; Middle Aged; Neuropeptide Y; Pheochromocytoma

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.

Topics: Animals; Denervation; Dogs; Hypertension; Neuropeptide Y; Norepinephrine; Research Design; Yohimbine

The release of catecholamines and their coneurotransmitter neuropeptide Y (NPY) 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 NPY-like immunoreactivity (NPY-LI) levels in plasma (evaluated by RIA) has been found. This dissociation could be explained by 1) a transient release of NPY during the first weeks after surgery, 2) a depletion of neuronal NPY due to the permanent sympathetic stimulation, or 3) an insufficient increase in sympathetic tone. To test these hypotheses, we investigated the time courses of catecholamine and NPY-LI levels in arterial plasma during the first five weeks after sinoaortic denervation and responses to yohimbine (an alpha 2 antagonist which enhances transmitter release). Resting NPY-LI 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 NPY-LI levels (1.5-fold), whereas a lower dose (0.05 mg/kg i.v.) induced a two fold elevation of catecholamine levels without changing NPY-LI concentrations. In sinoaortically denervated dogs, yohimbine elicited elevation of both catecholamines and NPY-LI whatever the dose used. Thus, neurogenic arterial hypertension in dogs seems to involve catecholamines but not NPY. Moreover, the present work suggests that a high level of sympathetic stimulation is required for a co-release of catecholamines and NPY.

Topics: Animals; Blood Pressure; Catecholamines; Denervation; Dogs; Female; Heart Rate; Hypertension; Male; Neuropeptide Y; Radioimmunoassay; Sinoatrial Node; Sympathetic Nervous System; Yohimbine

Neuropeptide Y (NPY) is coreleased with noradrenaline (NA) from sympathetic nerve endings. In vitro data suggest that NPY is coreleased during high stimulation frequencies. The present study investigates plasma levels of catecholamines and neuropeptide Y (NPY) during changes in sympathetic nervous activity in conscious dogs. Increase in sympathetic tone: arterial hypertension elicited by sinoaortic denervation induced an increase (X 2) in plasma noradrenaline (NA) but no change in NPY levels. High (0.5 mg/kg i.v.) but not low (0.05 mg/kg i.v.) doses of yohimbine rose plasma NPY concentrations. Decrease in sympathetic tone: clonidine (10 micrograms/kg i.v.) but not beta-blocking agents (propranolol or atenolol: 1 mg/kg i.v.) reduced plasma NPY levels. These results show that NPY is correleased in vivo from sympathetic nerve endings during marked and rapid increases in sympathetic tone. They suggest a lack of relationship between NA and NPY release. Alpha 2-adrenoceptors are involved in the presynaptic control of NPY release from sympathetic tone. Finally, some antihypertensive drugs (clonidine but not beta-blocking agents) are able to decrease plasma NPY levels.

Topics: Animals; Clinical Protocols; Clonidine; Dogs; Hypertension; Neuropeptide Y; Norepinephrine; Propranolol; Receptors, Adrenergic, alpha; Sympathetic Nervous System; Yohimbine

Perivascular innervation in cerebral arteries of spontaneously hypertensive rats and of normotensive Wistar-Kyoto rats was studied. Adrenergic nerve fibers and neuropeptide Y-containing nerve fibers, indicative of vasoconstrictor nerves, were denser in all cerebral arteries of spontaneously hypertensive rats than those of Wistar-Kyoto rats. In contrast, cholinergic nerve fibers and vasoactive intestinal polypeptide, substance P-containing nerve fibers, indicative of vasodilator nerves, remained unchanged in all cerebral arteries of spontaneously hypertensive rats, as compared with findings in the Wistar-Kyoto rats. Thus, not only adrenergic nerve fibers but also neuropeptide Y-containing nerve fibers may play an important role in preventing the disruption of the blood-brain barrier and the development of hypertensive encephalopathy in spontaneously hypertensive rats.

Topics: Adrenergic Fibers; Animals; Brain Diseases; Cerebral Arteries; Cholinergic Fibers; Hypertension; Immunohistochemistry; Male; Neuropeptide Y; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Substance P; Vasoactive Intestinal Peptide; Vasoconstriction; Vasodilation

The effects of various doses of intravenously (i.v.) infused (5-min duration, 0.1-3.2 nmol/kg/min) or bolus-injected (0.1-3.2 nmol/kg) porcine and/or rat/human neuropeptide Y (NPY) on mean arterial pressure (MAP), heart rate (HR), and plasma concentrations of porcine NPY-like immunoreactivity (pNPYir) were examined in conscious, unrestrained spontaneously hypertensive (SHR), Wistar-Kyoto (WKY), and Sprague-Dawley (SD) rats of various ages. When administered as an infusion to 12- to 17-week-old SHR, WKY, and SD rats, porcine NPY (pNPY) was more potent in increasing MAP in SHR than in either WKY or SD rats. Infusions of rat/human NPY instead of pNPY resulted in similar increases in potency in 12- to 17-week-old SHR as compared with WKY. This potency-associated hyperresponsiveness to infused pNPY was also observed when 36- to 41-week-old and 6-week-old SHR and WKY were examined, but infused NPY induced similar HR reductions in age-matched rats regardless of rat strain. Furthermore, doses of infused pNPY that elicited significantly greater pressor responses in SHR and WKY (0.32 nmol/kg/min in 12- to 17-week-old rats and 1.0 nmol/kg/min in 6-week-old rats) resulted in essentially identical plasma pNPYir concentrations in the two rat strains. In contrast, hyperresponsiveness to the MAP effects of bolus injections of pNPY in 12- to 17-week-old SHR was manifested as an increase in efficacy rather than potency, was associated with significantly smaller reductions in HR in SHR than in WKY and occurred at plasma pNPYir concentrations that were significantly larger than those required for infusion-associated hyperresponsiveness. These results are consistent with the hypothesis that NPY is an important contributor to the development and maintenance of essential hypertension.

Topics: Aging; Animals; Blood Pressure; Heart Rate; Humans; Hypertension; Iodine Radioisotopes; Neuropeptide Y; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Recombinant Proteins; Species Specificity; Swine

Topics: Animals; Blood Pressure; Drug Synergism; Hypertension; Inositol Phosphates; Male; Neuropeptide Y; Norepinephrine; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Circulating levels of neuropeptide Y (NPY)-like immunoreactivity (-LI), adrenaline and noradrenaline (NA) were analysed in 17 patients admitted to the emergency ward due to severe hypertension; blood pressure mean 204/127 mmHg. The levels of NPY-LI and NA were significantly higher (P less than 0.001) in the hypertensives as compared to a normotensive control group. HPLC analysis revealed that the plasma contained besides NPY-LI also several NPY-LI fragments of low hydrophobicity. Following 2 to 3 weeks treatment the blood pressure had decreased to a mean of 150/89 mmHg. However, circulating levels of NPY-LI (P less than 0.001) and NA (P less than 0.01) were still significantly higher than in controls in spite of the marked reduction in blood pressure. Simultaneous measurements of adrenaline did not reveal any significant changes and these values did not differ compared with those in the normotensive subjects. The findings suggest that peripheral markers of the sympathetic system (NPY-LI and NA) in severe hypertension is not directly related to the blood pressure level.

Topics: Aged; Blood Pressure; Chromatography, High Pressure Liquid; Epinephrine; Female; Humans; Hypertension; Male; Middle Aged; Neuropeptide Y; Norepinephrine

Sexual function was examined in spontaneously hypertensive rats (SHR) from 8 to 20 wk of age and compared with normotensive Wistar-Kyoto (WKY) and Long-Evans rats (LE). Blood pressures (evaluated indirectly) were elevated in SHR (185 +/- 2 and 195 +/- 3 mmHg at 16 and 19 wk of age, respectively) relative to WKY and LE (135-144 mmHg). SHR exhibited good copulatory behavior but displayed fewer erections (less than 20% of the number displayed by WKY or LE) in ex copula tests. At the conclusion of the study (20 wk of age), body weights were lowest in SHR, intermediate in WKY, and greatest in LE. Relative weights of testes were greater in SHR, whereas relative weights of accessory organs, pituitary and adrenal glands, and kidneys were equivalent across strains, as were circulating levels of aldosterone. Circulating levels of testosterone were higher in SHR and WKY than in LE. Neuropeptide Y (NPY) levels in the median preoptic and arcuate nuclei were significantly greater in SHR than in WKY or LE, whereas NPY levels in the medial preoptic area and the suprachiasmatic, hypothalamic dorsomedial, and hypothalamic paraventricular nuclei were equivalent in SHR and WKY, with both greater than LE. No strain differences were evident in the medial nucleus of the amygdala, the bed nucleus of the stria terminalis, the median eminence, the anterior hypothalamic nucleus, or the hypothalamic dorsomedial nucleus.

Topics: Aldosterone; Analysis of Variance; Animals; Blood Pressure; Body Weight; Brain Chemistry; Copulation; Genitalia, Male; Hypertension; Male; Neuropeptide Y; Organ Size; Organ Specificity; Penis; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sexual Behavior, Animal; Testosterone

The role of the endothelium in the effects of neuropeptide Y (NPY) and norepinephrine was investigated in mesenteric resistance arteries of the spontaneously hypertensive rat (SHR) and of the normotensive Wistar-Kyoto rat (WKY). Endothelium-dependent relaxation to acetylcholine (1 microM) was reduced in arteries of SHR compared with WKY. In the presence of the endothelium, the vessels of the two strains responded similarly to norepinephrine and NPY (100 nM) produced only a slight contraction. After removal of the endothelium, the response to norepinephrine was greater in WKY than in SHR. Furthermore, endothelium denudation enhanced markedly contraction elicited by NPY in WKY (up to 40% of the maximal effect of norepinephrine), but not in SHR. NPY potentiated the contractile response to low concentrations of norepinephrine (less than 300 nM) in both strains regardless whether the endothelium was intact or not. These results indicate that the contractile responses to NPY and to norepinephrine are inhibited by the endothelium in vessels of WKY, but not in those of the SHR. Furthermore, the potentiating effect of NPY occurs via an endothelium-independent mechanism in mesenteric arteries of both SHR and WKY. It is proposed that the differential responses between the two strains are related to abnormal function of the endothelium and to decreased responsiveness of smooth muscle cells in mesenteric resistance arteries of SHR compared to WKY.

Topics: Animals; Blood Pressure; Endothelium, Vascular; Hypertension; Male; Mesenteric Arteries; Neuropeptide Y; Norepinephrine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Species Specificity; Vascular Resistance; Vasoconstriction

Topics: Adrenergic beta-Antagonists; Animals; Calcitonin Gene-Related Peptide; Endothelium, Vascular; Hypertension; In Vitro Techniques; Mesenteric Arteries; Neuropeptide Y; Neuropeptides; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Inbred WKY; Receptors, Neurotransmitter; Synaptic Transmission

We describe the effects of neuropeptide Y (NPY) on [3H]norepinephrine (NE) release from hypothalamic slices of spontaneously hypertensive rats (SHR). The electrical stimulation (1 Hz)-evoked [3H]NE release was significantly greater in hypothalamic slices of SHR than in those of Wistar Kyoto rats (WKY). NPY inhibited the stimulation-evoked [3H]NE release in a dose-dependent manner. The inhibitory effect of NPY was significantly attenuated in SHR compared with WKY. The results may indicate that the less inhibitory effect of NPY on NE release induces increased sympathetic nerve activity in the hypothalamus of SHR.

Topics: Animals; Dose-Response Relationship, Drug; Electric Stimulation; Hypertension; Hypothalamus; Male; Neuropeptide Y; Norepinephrine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Synaptic Transmission

To investigate the relationship between insulin and sympathetic activity, plasma norepinephrine, neuropeptide Y, serum glucose and insulin concentrations were measured in ten age-, weight-, and sex-matched normotensive and untreated hypertensive subjects at fasting and 2 h following ingestion of a 75 g oral glucose dose. Hypertensives had higher fasting serum insulin (27 +/- 6 v 12 +/- 2 microU/mL; P = .02) and plasma norepinephrine (356 +/- 38 v 235 +/- 35 pg/mL; P = .03) concentrations than normotensives. Glucose load increased serum insulin (P less than .001) and plasma norepinephrine concentrations (P = .001) in both groups and hypertensives had still higher postglucose insulin (P = .003) and norepinephrine levels (P = .003) than normotensives. Fasting neuropeptide Y was higher in hypertensives than in normotensives (P = .03) and correlated with age in both groups (r = 0.7; r = 0.77). Postglucose serum insulin correlated positively with plasma norepinephrine (r = 0.75; P = .013) in normotensives, but these parameters correlated negatively in hypertensives (r = -0.7; P = .036). We hypothesize that elevated plasma norepinephrine and neuropeptide Y levels reflect an increased level of sympathetic nervous activity in hypertensives, which in turn may be responsible for the abnormal relationship between plasma NE and insulin levels.

Topics: Blood Glucose; Blood Pressure; Fasting; Female; Glucose; Humans; Hypertension; Insulin; Male; Middle Aged; Neuropeptide Y; Norepinephrine

1. The effect of neuropeptide Y (NPY) on cardiovascular function at three levels of the noradrenergic axis where the peptide is known to co-exist with noradrenaline (NA) and or adrenaline (A) was studied in normotensive Sprague-Dawley (SD), Wistar-Kyoto (WKY) or spontaneously hypertensive rats (SHR). 2. In the perfused mesenteric arterial bed, NPY and the structurally similar peptide intestinal polypeptide (PYY) decreased the periarterial nerve stimulation induced release of NA and potentiated the increase in perfusion pressure to nerve stimulation or exogenously applied agonists (e.g. angiotensin, vasopressin, phenylephrine). In contrast to NPY and PYY, C-terminal NPY fragments inhibited NA release and produced a parallel decrease in perfusion pressure thus supporting the concept of Y1 (post) and Y2 (pre) NPY receptors. 3. In the mesenteric artery of SHR the prejunctional inhibitory effect of NPY was attenuated while the postjunctional response was enhanced. 4. Following intrathecal (Int) injection of NPY, there was a decrease in blood pressure, total peripheral resistance (predominantly by a decrease in mesenteric vascular resistance) and renal nerve activity. The depressor effect of Int NPY was attenuated in the SHR. 5. Unilateral injections of NPY into the posterior hypothalamic nucleus increased blood pressure, hindquarter and renal vascular resistance and renal nerve activity. The pressor effect was enhanced in the SHR. 6. Periarterial nerve stimulation of the perfused mesenteric artery produced a frequency dependent vasodilation in beds pretreated with guanethidine and precontracted with methoxamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anterior Hypothalamic Nucleus; Calcitonin Gene-Related Peptide; Epinephrine; Hemodynamics; Hypertension; In Vitro Techniques; Injections, Spinal; Male; Microinjections; Neuroeffector Junction; Neuropeptide Y; Norepinephrine; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Inbred WKY; Splanchnic Circulation

We have used immunocytochemistry to quantitate neuronal neuropeptide Y in superior cervical ganglia of a strain of normotensive Wistar-Otago rats and a related genetically hypertensive strain over the age range 1-60 weeks. The numbers of neuropeptide Y-immunoreactive cells and total ganglionic cell numbers were both greater in ganglia of young normotensive than in those of hypertensive rats. Between 10 and 60 weeks of age, peptide immunoreactivity and total cell numbers both fell in normotensive rat ganglia but remained constant in ganglia from hypertensive rats. Densitometric analysis showed that the concentrations of neuropeptide Y were similar in neurons of age-matched individuals of both strains, but during aging there was a substantial decline in neuronal peptide content that was similar in both strains and that was not accompanied by any decline in neuronal immunoreactivity for tyrosine hydroxylase. Our results suggest that there is a developmental abnormality of neuropeptide Y in sympathetic neurons of this strain of genetically hypertensive rat and that, furthermore, the aging process is accompanied by a selective loss of neuronal neuropeptide Y that is independent of blood pressure status.

Topics: Aging; Animals; Hypertension; Neurons; Neuropeptide Y; Rats; Rats, Inbred Strains; Species Specificity; Sympathetic Nervous System

Substance P-like immunoreactivity (SPI) was investigated in the superior cervical ganglion of normotensive and genetically hypertensive (GH) Otago Wistar rats aged 1, 2, 8-10 and 50-60 weeks, by used of an indirect immunoperoxidase method. SPI was not seen in neuronal cell bodies but a subpopulation of ganglion cells was supplied by SP-positive terminals which closely invested the cell surface. This subpopulation showed no particular topographical distribution. The number of SP-positive terminal varicosities per unit area was several times higher in GH rats than in normotensive rats at all ages over 2-60 weeks. The proportion of neurons supplied by SP-positive terminals (sampled in 8-10 week-old rats) was also greater in GH than in normotensive rats. Decentralization of the ganglion or chronic capsaicin treatment removed all SP-immunoreactive terminals around the cell bodies, indicating that the SP-positive terminals are collaterals of thoracic sensory afferents. As SP has been reported to have an excitatory effect in sympathetic ganglia, intraganglionic release of SP might contribute to the development of hypertension in the GH strain.

Topics: Aging; Animals; Capsaicin; Ganglia, Sympathetic; Hypertension; Neurons, Afferent; Neuropeptide Y; Rats; Rats, Inbred Strains; Substance P

A high concentration of immunoreactive neuropeptide Y was observed in rat platelets using a specific and sensitive radioimmunoassay for neuropeptide Y. Three kinds of high performance liquid chromatography combined with radioimmunoassay for neuropeptide Y showed that immunoreactive neuropeptide Y in rat platelets is identical to rat authentic neuropeptide Y. To investigate the pathological role of platelet neuropeptide Y in genetic hypertensive rats, the platelet content and plasma concentration of neuropeptide Y were measured by a sensitive radioimmunoassay for rat neuropeptide Y in 5-, 10- and 15-wk old spontaneously hypertensive rat and age-matched Wistar Kyoto rat. Platelet content of immunoreactive neuropeptide Y in 5-, 10- and 15-wk old spontaneously hypertensive rat was higher than that in Wistar Kyoto rat at each age. No difference was observed in plasma concentration of immunoreactive neuropeptide Y between spontaneously hypertensive rat and Wistar Kyoto rat at each age.

Topics: Animals; Blood Platelets; Chromatography, High Pressure Liquid; Hypertension; Male; Neuropeptide Y; Radioimmunoassay; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Neuropeptide Y (NPY), a 36-residue peptide amide, has been shown by numerous studies to be a potent vasoconstrictor. In order to gain an appreciation of the structural requirements for this action, we have previously synthesized a number of fragments of NPY. It had been shown that sequential deletions from the N-terminus resulted in peptides with decreasing hypertensive activity. In the present study we present data supporting the unexpected finding of two fragments, NPY17-36 and NPT18-36 with substantial hypotensive action in vivo. This action was dose dependent (data not shown) and was also observed to a lesser extent with NPY19-36 but not NPY16-36 or NPY20-36. It was, however, slower in onset and of longer duration than the hypertensive action of NPY. These differing kinetics of action may suggest that NPY and NPY18-36 act through different mechanisms. Structural studies using circular dichroism were performed. While NPY was found to assume an ordered helical structure in both aqueous buffer and trifluoroethanol (TFE), 30% TFE in aqueous buffer was required to induce substantial helicity for NPY18-36. This structural investigation suggests that both NPY and NPY18-36 assume an ordered conformation upon reaching the lipid rich receptor environment.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Circular Dichroism; Hypertension; Male; Neuropeptide Y; Peptide Fragments; Protein Conformation; Rats; Rats, Inbred Strains; Structure-Activity Relationship

Neuropeptide Y (NPY) coexists with noradrenaline in postganglionic sympathetic neurons and with noradrenaline and adrenaline in the central nervous system. The possibility that NPY is released into the circulation during activation of the sympathoadrenal system was investigated in ten moderately hypertensive volunteers using three different stimuli. In healthy moderately hypertensive volunteers cold pressor test, head up tilt and graded bicycle exercise resulted in increased blood pressure, heart rate and plasma catecholamine concentrations. While there was a trend for plasma NPY-like immunoreactivity (NPY-LI) to increase during cold pressor test and head up tilt, NPY-LI concentration only increased significantly during bicycle exercise, the stimulus of greatest duration. These results suggest that plasma NPY-LI can be released into the circulation on sympathoadrenal activation in moderately hypertensive subjects and demonstrate that the pattern of release is similar to that previously observed in normotensive subjects.

Topics: Adrenal Glands; Adult; Blood Pressure; Cold Temperature; Epinephrine; Exercise Test; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Neuropeptide Y; Norepinephrine; Sympathetic Nervous System

The distribution and density of nerves containing vasoactive intestinal polypeptide, substance P, and neuropeptide Y around the cerebral and peripheral blood vessels of stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto rats (WKY) were studied using an indirect immunofluorescence technique. Neonatal sympathectomy of SHRSP with anti-nerve growth factor and guanethidine was also carried out to study the effect of sympathectomy on the distribution of these nerves. Vasoactive intestinal polypeptide nerve density was higher in the veins and superior mesenteric artery of SHRSP than of WKY and lower in the cerebral arteries of SHRSP than of WKY, but no difference was found in the muscular mesenteric arteries. Sympathectomy reduced the density of these nerves in all the peripheral vessels but had little effect on the cerebral arteries. Density of substance P nerves was similar between SHRSP and WKY in the peripheral vessels but higher in the cerebral arteries of WKY than of SHRSP. Sympathectomy reduced the density of these nerves in the peripheral vessels but increased the density in some cerebral arteries of SHRSP. Neuropeptide Y nerve density was higher in the peripheral blood vessels of SHRSP than of WKY, and no difference was found in the cerebral arteries. Sympathectomy almost completely removed these nerves in the peripheral vessels but had no effect on the cerebral arteries. We suggest that some of the differences in nerve density between SHRSP and WKY, especially those in the peripheral blood vessels, may be related to the development of hypertension in the SHRSP.

Topics: Animals; Blood Vessels; Cerebral Arteries; Hypertension; Male; Mesenteric Arteries; Neuropeptide Y; Neuropeptides; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Inbred WKY; Substance P; Vasoactive Intestinal Peptide

The effect of the intrathecal administration of neuropeptide Y (NPY) on blood pressure and heart rate of anesthetized normotensive and hypertensive rats was studied. Neuropeptide Y was observed to produce a decrease in the blood pressure of Sprague-Dawley, Wistar Kyoto (WKY), DOCA-salt, and DOCA-sham control rats. The maximum percent decrease in blood pressure of Sprague-Dawley rats was 12.8 and 15.2% in response to 0.1 and 1.0 nmol NPY, respectively. Similar changes in heart rate were observed. The depressor effect of intrathecal NPY was attenuated by prior treatment with yohimbine and propranolol but not prazosin. The depressor effect of intrathecal NPY observed in normotensive and DOCA-salt hypertensive rats was not seen in the spontaneously hypertensive rat (SHR). The studies extend to the spinal cord the list of regions and tissues where NPY can produce physiological effects. It is concluded that the effects of NPY are closely associated with sympathetic preganglionic neurons in the spinal cord that the depressor effect of NPY involves alpha 2 and beta adrenoceptors, and that a loss of the depressor effect of NPY may contribute to the development or maintenance of hypertension in the SHR.

Topics: Adrenergic alpha-Antagonists; Animals; Blood Pressure; Desoxycorticosterone; Heart Rate; Hypertension; Injections, Spinal; Male; Neuropeptide Y; Propranolol; Rats; Rats, Inbred Strains; Rats, Inbred WKY

The effect of neuropeptide Y on the contractile response to field stimulation was examined in isolated blood vessels. Exogenous neuropeptide Y at a concentration of 100 nmol/l significantly potentiated the response to field stimulation in rabbit ear artery and canine saphenous vein. Administration of neuropeptide Y antiserum to tissues not previously exposed to neuropeptide Y significantly reduced the response to field stimulation; greater effects were observed in the rabbit ear artery than in the canine saphenous vein. Furthermore, this antiserum depressed the response to field stimulation in caudal arteries from spontaneously hypertensive rats (SHR), but not in those from normotensive Wistar-Kyoto rats (WKY). The depression by the anti-neuropeptide Y antibody did not appear to be produced by a non-specific mechanism, since antiserum against either thyrotrophin-releasing factor or platelet-derived growth factor did not affect the response to field stimulation. It is concluded that endogenous neuropeptide Y can contribute to the vascular contractile response to field stimulation, and that this contribution may be enhanced in hypertensive animals.

Topics: Animals; Dogs; Electric Stimulation; Hypertension; Immunologic Techniques; In Vitro Techniques; Neuropeptide Y; Rabbits; Rats; Rats, Inbred SHR; Synaptic Transmission; Vasomotor System

In the present study, the mean arterial pressures (MAP) and heart rates (HR) were measured in Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) that had received a 10-day continuous subcutaneous infusion of either saline or the centrally acting alpha-adrenoceptor agonist clonidine (10 micrograms/kg/h). In separate groups of similarly treated rats, the concentrations of neurotensin (NT), vasoactive intestinal polypeptide (VIP), cholecystokinin octapeptide (CCK-8), calcitonin gene-related peptide (CGRP), and neuropeptide Y (NPY) were measured in the cortex (COR), hypothalamus (HYP), medulla oblongata/pons (MO/P), and cervical (CSC) and thoracic (TSC) spinal cord. In comparison to the WKY rats, the SHR had significantly lower neuropeptide concentrations within the COR (NPY, CCK-8), HYP (NT), MO/P (NPY, NT, and CCK-8), CSC (all neuropeptides), and TSC (NPY, NT, CCK-8, and VIP). The infusion of clonidine lowered the MAP of the WKY and SHR rats (-10 and -35 mm Hg, as compared with respective saline controls) and HR in the WKY rats (-45 beats/min). In general, the infusion of clonidine produced decreases in neuropeptide levels within the CNS of the WKY rather than the SHR strain. When there was a strain difference (i.e., SHR less than WKY), it was evident, particularly within the spinal cord, that clonidine reduced the levels of the neuropeptides in the WKY rats to those levels in the SHR. These findings suggest that the reduced neuropeptide concentrations of the SHR (particularly those within the CSC) and TSC may be a result of, rather than a causal factor in, hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Brain Chemistry; Clonidine; Female; Hypertension; Infusion Pumps; Infusions, Parenteral; Neuropeptide Y; Neuropeptides; Neurotensin; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sincalide; Spinal Cord

125I-Neuropeptide Y (125I-NPY) binding capacities were quantitated in the areas postrema of young (5 weeks) and adult (20 week SHR and compared with age-matched WKY rats using autoradiography. The maximum binding capacity (Bmax) was significantly higher in the area postrema of adult SHR, while no difference was seen at the age of 5 weeks. Our result supports the idea of a functional role for NPY receptors in the central control of blood pressure. NPY receptors in the area postrema may be involved in the perception of circulating NPY resulting in the alteration of the neuronal activity of the nucleus tractus solitarii.

Topics: Age Factors; Animals; Autoradiography; Blood Pressure; Cerebral Ventricles; Hypertension; Male; Neuropeptide Y; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Receptors, Neuropeptide Y; Receptors, Neurotransmitter

Although the majority of extraadrenal paragangliomas are nonfunctional, some of these tumors are associated with hormone production and clinical symptoms, notably hypertension. The authors have investigated 22 paragangliomas, five of which were diagnosed as clinically functional in a light microscopic immunocytochemical and electron microscopic study (nine cases). Histologically, all the paragangliomas exhibited similar features, with a "Zellballen" pattern of polygonal cells. All 22 cases were strongly immunoreactive to protein gene product 9.5 (PGP 9.5) antisera and moderately reactive to antineuron-specific enolase (NSE) sera. Ten cases (five functional) were focally immunoreactive to antichromogranin sera. Seven cases (four functional) were immunoreactive to neuropeptide Y and enkephalin antisera, and six (five functional) to tyrosine hydroxylase antisera. The clinically functional tumors expressed at least two of the antigens, enkephalin, neuropeptide Y, or tyrosine hydroxylase, whereas none of the 17 nonfunctional possessed more than one of these. Electron microscopic study revealed cells from all the nine cases studied to contain secretory granules. Granule sizes ranged from 100 to 280 nm and the morphologic examination of the secretory granules generally showed a dense core with a membrane-bound halo of variable size. Secretory granules were observed in the five functional cases and these were larger (220-280 nm) than those seen in the nonfunctional tumor cells (100-180 nm). Also, tumor cells from the functional cases contained numerous dilated mitochondrial profiles.

Topics: Adult; Biomarkers, Tumor; Cytoplasmic Granules; Enkephalins; Female; Humans; Hypertension; Immunoenzyme Techniques; Male; Microscopy, Electron; Neuropeptide Y; Neuropeptides; Paraganglioma, Extra-Adrenal; Phosphopyruvate Hydratase; Tyrosine 3-Monooxygenase; Ubiquitin Thiolesterase

A computer-assisted morphometrical and microdensitometrical analysis has been performed on cardiovascular noradrenaline (NA), adrenaline (A) and neuropeptide (Y (NPY) neurons in adult and 24-month-old male rats and on hypotensive (LL), normotensive (LN) and hypertensive (LH) male rats of the Lyon strain using the indirect immunoperoxidase procedures. It was found that in NPY/phenylethanolamine-N-methyltransferase (PNMT) costoring neurons of the CI area of the rostral medulla oblongata NPY-like immunoreactivity showed a more marked reduction than the PNMT immunoreactivity. Furthermore, within the parvocellular part of the paraventricular hypothalamic nucleus. NPY immunoreactive nerve terminal profiles were much more affected than the PNMT immunoreactive profiles during aging as revealed by a marked reduction in the number of profiles and by a marked reduction of absorbency values in the microdensitometrical analysis. Thus, in the NPY/PNMT costoring neurons of the A C1 group of the ventrolateral medulla projecting, for example, to the hypothalamus, the peptide transmission line may have a special vulnerability to the aging processes which may contribute to the development of hypertension in old people in view of a vasodepressor role of many central NPY/PNMT neurons. An extensive morphometrical and microdensitometrical analysis of the various catecholamine (CA) cell groups of the medulla oblongata of the LL, LN and LH rats of the Lyon strain was performed. In a comparison between LL and LH rats the A2 cell group of the LH strain showed a trend for an increase in the mean tyrosine hydroxylase (TH) immunoreactive cell body area and the C3 group showed a significant increase in the number of PNMT immunoreactive profiles.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aging; Animals; Catecholamines; Densitometry; Hypertension; Immunoenzyme Techniques; Male; Medulla Oblongata; Neurons; Neuropeptide Y; Phenylethanolamine N-Methyltransferase; Rats; Rats, Inbred Strains

To investigate the clinical usefulness of radio-immunoassay of neuropeptide Y (NPY), we measured plasma immunoreactive neuropeptide Y (IR-NPY) concentrations in normal subjects (n = 21), essential hypertensive patients (n = 33), patients with phaeochromocytoma (n = 7), patients with chronic renal disease with serum creatinine levels of less than 1.9 mg/dl (n = 5) and patients with chronic renal failure whose serum creatinine levels were greater than or equal to 1.9 mg/dl (n = 18, eight without haemodialysis and 10 undergoing maintenance haemodialysis), by radio-immunoassay. Plasma IR-NPY concentrations in patients with phaeochromocytoma (577 +/- 256 pg/ml, mean +/- s.d.) were significantly higher (P less than 0.001) than those in normal subjects (151 +/- 28 pg/ml), essential hypertensive patients (177 +/- 49 pg/ml) and patients with chronic renal disease with serum creatinine levels less than 1.9 mg/dl (198 +/- 71 pg/ml). Plasma IR-NPY concentrations in patients with chronic renal failure (without haemodialysis: 330 +/- 63 pg/ml; undergoing maintenance haemodialysis: 374 +/- 80 pg/ml) were also high. These results suggest that NPY is useful as one of the tumour markers of phaeochromocytomas. However, this study revealed that patients with chronic renal failure, without phaeochromocytoma also have increased plasma IR-NPY concentrations.

Topics: Adrenal Gland Neoplasms; Adult; Chromatography, Gel; Creatinine; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Neuropeptide Y; Pheochromocytoma; Radioimmunoassay; Renal Dialysis

The field stimulation induced release of 3H-norepinephrine (NE) from the isolated portal vein and endogenous NE from the isolated caudal artery and perfused mesenteric arterial bed of spontaneously hypertensive rats (SHR) and age-matched normotensive rats (Wistar-Kyoto or Sprague-Dawley) was studied. There was a significantly greater release of NE from all three preparations obtained from 10- to 12-week-old SHR compared to normotensive animals. In addition, there was a greater release of NE from the caudal artery of 5- to 6-week-old SHR compared to controls. No differences were seen in the evoked release of NE from portal vein or caudal artery obtained from renal or DOCA salt hypertensives compared to vessels obtained from sham controls. Neuropeptide Y (NPY) produced a concentration-dependent decrease in the field stimulation induced release of NE from the perfused mesenteric artery. Low concentrations of NPY decreased while higher concentrations potentiated the increase in perfusion pressure. The NPY induced inhibition of evoked NE release was not altered by alpha 1- or alpha 2-adrenoceptor antagonists while the alpha 1-adrenoceptor antagonist, prazosin, prevented the postjunctional response. These results are consistent with there being an alteration of NE release at the vascular neuroeffector junction in SHR which may contribute to the development or maintenance of hypertension. NPY exerts a modulatory role in noradrenergic transmission at the vascular neuroeffector junction.

Topics: Animals; Blood Vessels; Hypertension; Neuroeffector Junction; Neuropeptide Y; Norepinephrine; Perfusion; Pressure; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Inbred WKY

The distribution and concentrations of neuropeptide Y (NPY) in kidneys, renal arteries, heart, aorta, mesenteric artery and adrenal glands from aorta-ligated hypertensive rats were studied by immunocytochemistry and radioimmunoassay. Immunocytochemistry showed that in the hypertensive animals NPY-immunoreactive fibres were decreased in both kidney and renal artery, above and below the ligation, and in mesenteric arteries. The depletion of NPY-containing nerves in the kidney was more pronounced around the juxtaglomerular apparatus than in other areas of the organ. By radioimmunoassay, the concentrations of NPY immunoreactivity were significantly lower in the hypertensive animals when compared with the controls, (kidney: hypertensive 1.0 +/- 0.1; controls 2.0 +/- 0.2 pmol/g, mean +/- SEM; p less than 0.05 renal artery: hypertensive 5.0 +/- 0.8; controls 12.1 +/- 2.0; p less than 0.05 and mesenteric artery: hypertensive 8.6 +/- 1.9; 17.6 +/- 3.0; p less than 0.01). While there were no statistically significant changes in the levels of NPY immunoreactivity in the other areas studied, there was a general trend for the level to fall in the renal artery below the ligation (hypertensive 10.6 +/- 1.5; control 15.3 +/- 2.4; p greater than 0.05). It is of interest that changes were observed in the vasoconstrictor peptide NPY in this commonly used model of hypertension.

Topics: Adrenal Glands; Animals; Heart; Hypertension; Immunohistochemistry; Kidney; Mesenteric Arteries; Neuropeptide Y; Radioimmunoassay; Rats; Renal Artery

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.

Topics: Adrenalectomy; Animals; Desoxycorticosterone; Hypertension; Male; Methylprednisolone; Neuropeptide Y; Rats; Rats, Inbred Strains; Renin

In the periphery, neuropeptide Y is present in plasma, in the adrenal medulla as well as in sympathetic nerve endings and in the juxtaglomerular apparatus. The aim of the present study was to assess the effect of this peptide on renin secretion. Normotensive rats were adrenalectomized 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 initial surgery, 12 adrenalectomized and 8 sham-operated conscious rats were infused for 30 min with neuropeptide Y (0.1 micrograms/min) whereas 8 other adrenalectomized and 9 sham-operated conscious rats received under similar conditions the vehicle of neuropeptide Y (10 microliter/min). Neither before nor during the infusions was there a significant difference in blood pressure and heart rate between the 4 groups of animals. Plasma renin activity, measured at the end of the infusion, was 30.5 ng/ml/hr in the adrenalectomized group receiving vehicle and 6.3 ng/ml/hr in that infused with neuropeptide Y (p less than 0.001). This latter value did not differ from that found in sham-operated rats. These results suggest that neuropeptide Y may play an important role in regulating renin secretion.

Topics: Adrenalectomy; Animals; Blood Pressure; Hypertension; Male; Neuropeptide Y; Rats; Rats, Inbred WKY; Renin

The concentrations of neuropeptide Y immunoreactivity (NPY-ir) were measured in the cortex and cervical, thoracic and lumbar spinal cord of 8-, 18- and 31-week-old normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). This peptide was measured using a highly sensitive and specific radio-immunoassay (RIA) developed in our laboratory. The concentrations of NPY-ir in the cortex, cervical and thoracic spinal cord were significantly different between the two strains, with the levels being consistently lower in the SHR strain independent of age. While there was no obvious change in the levels of NPY-ir in the cortex with increasing age, there was a general trend for the levels to fall in all three spinal cord regions. The rate of decrease of NPY-ir in the thoracic spinal cord appeared greater in the SHR compared with the WKY rats. These biochemical differences observed in the cortex and thoracic spinal cord of SHR and WKY rats may be related to the behavioural and blood pressure differences observed in these strains.

Topics: Age Factors; Animals; Cerebral Cortex; Hypertension; Male; Neuropeptide Y; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Spinal Cord; Tissue Distribution

Topics: Animals; Antihypertensive Agents; Blood Pressure; Brain; Cardiovascular System; Carotid Arteries; Hypertension; Injections, Intra-Arterial; Nerve Tissue Proteins; Neuropeptide Y; Rats; Rats, Inbred Strains; Rats, Inbred WKY; Receptors, Adrenergic, alpha

Topics: Adult; Aged; Calcium; Epinephrine; Female; Humans; Hypertension; Hypertension, Renovascular; Male; Middle Aged; Nerve Tissue Proteins; Neuropeptide Y; Norepinephrine; Patient Compliance; Prostaglandins; Sodium; Sports; Sympathetic Nervous System

Topics: Animals; Hypertension; Medulla Oblongata; Nerve Tissue Proteins; Neuropeptide Y; Rats; Rats, Inbred Strains; Receptors, Adrenergic, alpha