RESUMEN
Sphingosine 1-phosphate (SPP) has been shown to inhibit chemotaxis of a variety of cells, in some cases through intracellular actions, while in others through receptor-mediated effects. Surprisingly, we found that low concentrations of SPP (10-100 nM) increased chemotaxis of HEK293 cells overexpressing the G protein-coupled SPP receptor EDG-1. In agreement with previous findings in human breast cancer cells (Wang, F., Nohara, K., Olivera, O., Thompson, E. W., and Spiegel, S. (1999) Exp. Cell Res. 247, 17-28), SPP, at micromolar concentrations, inhibited chemotaxis of both vector- and EDG-1-overexpressing HEK293 cells. Nanomolar concentrations of SPP also induced a marked increase in chemotaxis of human umbilical vein endothelial cells (HUVEC) and bovine aortic endothelial cells (BAEC), which express the SPP receptors EDG-1 and EDG-3, while higher concentrations of SPP were less effective. Treatment with pertussis toxin, which ADP-ribosylates and inactivates G(i)-coupled receptors, blocked SPP-induced chemotaxis. Checkerboard analysis indicated that SPP stimulates both chemotaxis and chemokinesis. Taken together, these data suggest that SPP stimulates cell migration by binding to EDG-1. Similar to SPP, sphinganine 1-phosphate (dihydro-SPP), which also binds to this family of SPP receptors, enhanced chemotaxis; whereas, another structurally related lysophospholipid, lysophosphatidic acid, did not compete with SPP for binding nor did it have significant effects on chemotaxis of endothelial cells. Furthermore, SPP increased proliferation of HUVEC and BAEC in a pertussis toxin-sensitive manner. SPP and dihydro-SPP also stimulated tube formation of BAEC grown on collagen gels (in vitro angiogenesis), and potentiated tube formation induced by basic fibroblast growth factor. Pertussis toxin treatment blocked SPP-, but not bFGF-stimulated in vitro angiogenesis. Our results suggest that SPP may play a role in angiogenesis through binding to endothelial cell G(i)-coupled SPP receptors.
Asunto(s)
Quimiotaxis/fisiología , Proteínas de Unión al ADN/fisiología , Endotelio Vascular/fisiología , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/fisiología , Proteínas I-kappa B , Proteínas Inmediatas-Precoces/fisiología , Lisofosfolípidos , Neovascularización Fisiológica/fisiología , Receptores de Superficie Celular/fisiología , Receptores Acoplados a Proteínas G , Esfingosina/análogos & derivados , Animales , Aorta , Bovinos , División Celular/efectos de los fármacos , Línea Celular , Células Cultivadas , Quimiotaxis/efectos de los fármacos , ADN/biosíntesis , Proteínas de Unión al ADN/genética , Relación Dosis-Respuesta a Droga , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Factor 2 de Crecimiento de Fibroblastos/farmacología , Humanos , Proteínas Inmediatas-Precoces/genética , Cinética , Inhibidor NF-kappaB alfa , Neovascularización Fisiológica/efectos de los fármacos , Receptores Lisofosfolípidos , Proteínas Recombinantes/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Esfingosina/farmacocinética , Esfingosina/farmacología , Transfección , Venas UmbilicalesRESUMEN
Hyperplasia of vascular smooth muscle cells (VSMCs) occurs during HIV infection, part of a spectrum of HIV-mediated cardiovascular and microvascular pathologies. These changes are not due to direct viral infection but may involve the receptor-mediated action of viral proteins, such as the envelope protein gp120. We sought to identify gp120 receptors which might mediate the vascular smooth muscle cell hyperplasia present in HIV infection. A homology between neuropeptide Y (NPY) and the previously identified receptor-active V2-region of gp120 defined by an octapeptide sequence (Peptide T) related to VIP was noted. Since NPY is mitogenic for VSMCs we therefore determined whether gp120 shares this activity. Rat aortic VSMCs were treated for 24 h with human (h)NPY and gp120 in the presence of 0.5% serum to measure [3H]thymidine incorporation, an index of cell proliferation. NPY increased [3H]thymidine incorporation by 80% after a 24-h treatment in a bimodal fashion, with peak effects at 10(-10) M and 10(-8) M. Gp120 was an even more potent mitogen for VSMCs with peak activity occurring at 10(-12) M. Peptide T was equipotent with gp120, and slightly less efficacious, suggesting that this domain may mediate gp120 effects on VSMCs. When combined, gp120 and NPY acted to antagonize one another, lowering DNA synthesis to basal levels. The profile of pharmacologic inhibition supports a role for NPY receptors since antagonists of Y1 and Y2 subtypes substantially or completely inhibited gp120-mediated VSMC proliferation. This is the first demonstration of the proliferative effects of HIV viral protein gp120 on VSMCs. The effect appears to be mediated via gp120 sequences related to VIP, peptide T, and NPY. These ligands may be competitive inhibitors of binding or gp120 processing. Novel treatments may emerge based upon VIP and NPY receptor antagonists if further work substantiates a role for gp120 in the vascular abnormalities of AIDS.
Asunto(s)
Enfermedades Cardiovasculares/etiología , Proteína gp120 de Envoltorio del VIH/toxicidad , Infecciones por VIH/complicaciones , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/patología , Receptores de Neuropéptido Y/efectos de los fármacos , Receptores de Neuropéptido Y/fisiología , Secuencia de Aminoácidos , Animales , Enfermedades Cardiovasculares/patología , División Celular/efectos de los fármacos , Células Cultivadas , VIH/genética , VIH/patogenicidad , Proteína gp120 de Envoltorio del VIH/genética , Humanos , Hiperplasia , Mitógenos/farmacología , Datos de Secuencia Molecular , Neuropéptido Y/genética , Neuropéptido Y/farmacología , Neuropéptido Y/fisiología , Péptido T/genética , Péptido T/toxicidad , Ratas , Homología de Secuencia de Aminoácido , Péptido Intestinal Vasoactivo/genética , Péptido Intestinal Vasoactivo/farmacología , Péptido Intestinal Vasoactivo/fisiologíaRESUMEN
Neuropeptide Y (1-36), NPY, is a sympathetic vasoconstrictor whose activities in blood vessels is determined by the presence of vasoconstrictive Y1 receptors and the enzyme dipeptidyl peptidase IV (DPPIV), which converts NPY to non-vasoconstrictive peptides. While the role of the NPY system has been established during cold water stress, its role in hypotensive conditions has not; yet, exogenous NPY improves hemodynamics and survival in rats with endotoxic shock. We used a new selective non-peptidergic Y1 receptor antagonist, BIBP-3226, to determine the role of the endogenous NPY/Y1 system in endotoxic shock (induced by i.v. injection of 10 mg/kg of Escherichia coli lipopolysaccharide 0127:B8, LPS) and hemorrhagic shock (bleeding of 15 ml/kg over 1.5 min). Conscious rats received a bolus of BIBP-3226 or the vehicle 5 min before endotoxin challenge or induction of hemorrhage, followed by continuous infusion. Mean arterial pressure (MAP) at 5 min after LPS administration dropped in the control group by 15%, compared to 36% in the BIBP-3226-treated group (p < 0.01). Similarly, the hemorrhage-induced drop in MAP in the control group was 32% at 5 min, compared to 53% in the BIBP-treated rats (p < 0.01). Plasma NPY levels were unchanged in the endotoxic shock group, but were significantly elevated in the hemorrhagic shock group. BIBP-3226 pretreatment abrogated the increased plasma NPY levels after hemorrhagic shock. Endogenous NPY contributes to blood pressure recovery during endotoxic and hemorrhagic shock.
Asunto(s)
Neuropéptido Y/fisiología , Choque Hemorrágico/fisiopatología , Choque Séptico/fisiopatología , Vasoconstricción/fisiología , Animales , Arginina/análogos & derivados , Arginina/farmacología , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Modelos Animales de Enfermedad , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Lipopolisacáridos/toxicidad , Masculino , Neuropéptido Y/sangre , Ratas , Ratas Wistar , Receptores de Neuropéptido Y/antagonistas & inhibidores , Receptores de Neuropéptido Y/fisiología , Choque Hemorrágico/etiología , Choque Séptico/etiología , Vasoconstricción/efectos de los fármacosRESUMEN
We have previously reported that neuropeptide Y (NPY), a sympathetic cotransmitter and vasoconstrictor, is mitogenic for vascular smooth muscle cells (VSMCs), and now report on the mechanisms mediating these effects. In rat aortic A10 cell line, NPY's potency was greater than that of norepinephrine, and efficacy similar to that of platelet-derived growth factor, but less than that of the full serum, in stimulating cell proliferation; this effect was optimal in cell 60-80% cell density. At lower cell density and serum content, NPY stimulated DNA fragmentation/apoptosis. In rat aortic primary VSMCs (RASMCs), mitogenic effect of NPY was bimodal with the first peak at 1 pM, a decline at 1 nM, and a second peak at 10-100 nM; peptide YY had similar but less efficacious effects. The first NPY's peak was mimicked by Y2 agonists, and blocked by Y2 antagonist (T4-[NPY(33-36]4), and the second mimicked by Y1 agonist and partially blocked by Y1 antagonist, BIBP3226, suggesting a multireceptor mode of action. In A10 and in RASMCs, the expression of NPY receptors, Y1, Y2 and Y5, using RT-PCR was undetectable in quiescent cells but detected after pre-treatment with NPY. The receptor induction was NPY dose-dependent and also affected by incubation time and presence of serum. The NPY mitogenic effects were attenuated by calcium channel blockers, particularly verapamil. In primary cultures of rat coronary endothelial cells (where NPY is also mitogenic), NPY stimulated mitogen-activated protein kinase (MAPK) activity. Thus, the growth-promoting effects of NPY in vascular cells occur at concentrations lower than vasoconstrictive, and appear to be mediated by inducible Y1, Y2, and Y5 receptors, calcium entry and possibly MAPK activation.
Asunto(s)
Desarrollo de Músculos , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/crecimiento & desarrollo , Neuropéptido Y/farmacología , Neuropéptido Y/fisiología , Receptores de Neuropéptido Y/fisiología , Animales , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Secuencia de Bases , Calcio/metabolismo , Bloqueadores de los Canales de Calcio/farmacología , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , División Celular/efectos de los fármacos , División Celular/fisiología , Línea Celular , Células Cultivadas , Cartilla de ADN/genética , Expresión Génica/efectos de los fármacos , Mitógenos/farmacología , Músculo Liso Vascular/fisiología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Receptores de Neuropéptido Y/clasificación , Receptores de Neuropéptido Y/genética , Transducción de SeñalRESUMEN
Some evidences indicate that the female sex hormones protect against the development of cardiovascular diseases. Modulation of sympathetic activity may be one of the possibilities. We investigated the influence of treadmill stress on blood pressure (BP) and plasma neuropeptide Y (NPY), norepinephrine (NE) and epinephrine (E) concentrations in 11 normotensive, menstruating women in the follicular (HWf) and luteal (HWl) phases and in eight ovariectomized women, before (OVX) and after estrogen supplementation (OVXe). Both at rest and during exercise there were no differences in BP between HWf and HWl and between OVX and OVXe. During stress BP was significantly lower in HWf and HWl than in OVX but not in OVXe. NPY did not differ significantly between the groups of women either at rest or during activity. We did not observe differences in resting and stimulated NE and E between HWf and HWl and between OVX and OVXe. Neither resting nor activated NE and E differed between the groups, except higher stimulated NE in OVX than in HWf. These results suggest that the female sex hormones may modulate the BP response to dynamic exercise. Our data support evidence that this influence may be exerted by circulating catecholamines and not by NPY.
Asunto(s)
Presión Sanguínea/fisiología , Epinefrina/sangre , Ejercicio Físico/fisiología , Hormonas Esteroides Gonadales/fisiología , Neuropéptido Y/sangre , Norepinefrina/sangre , Adulto , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/fisiopatología , Enfermedades Cardiovasculares/prevención & control , Terapia de Reemplazo de Estrógeno , Femenino , Humanos , Ciclo Menstrual/sangre , Ciclo Menstrual/fisiología , Ovariectomía , Estrés Fisiológico/sangre , Estrés Fisiológico/fisiopatologíaRESUMEN
BACKGROUND: Neuropeptide Y, an abundant neurohormone present with catecholamines in the adrenal medulla, is a potent non-adrenergic vasoconstrictor and a vascular growth factor. OBJECTIVE: To determine the mechanism of the release from, and possible role of neuropeptide Y in, pheochromocytomas, compared with those of catecholamines. METHODS: Plasma and tumour levels of neuropeptide Y-immunoreactivity (by, radioimmunoassay) and of noradrenaline and adrenaline (by a radioenzymatic method) in 29 patients (19 women and 10 men, aged 22-68 years) were measured during surgical removal of the tumour, during alpha-adrenergic and beta-adrenergic blockade. Arterial systemic blood samples were withdrawn before the ligation of the vessels supplying the tumour, during its surgical manipulations and after its removal, while haemodynamics was monitored. RESULTS: Plasma neuropeptide Y levels in 17 patients (58.6%, group I) significantly increased during manipulations of the pheochromocytoma and returned completely to normal after its removal. This response was independent of the plasma neuropeptide Y immunoreactivity manipulation and was correlated to increases in plasma noradrenaline (r = 0.638, P < 0.02) but not adrenaline levels. Manipulation-induced increases in plasma neuropeptide Y-immunoreactivity were associated with greater neuropeptide Y content in tumours (r = 0.508, P < 0.05) but neither plasma nor tumour levels of neuropeptide Y immunoreactivity were correlated to tumour mass. Plasma levels of neuropeptide Y immunoreactivity in the remaining 12 patients (41.4%, group II) remained unchanged throughout the experimental period, while levels of circulating catecholamine rose. In all, in spite of our attempt at complete adrenergic blockade, tumour manipulation elevated arterial blood pressure and these changes were significantly correlated to increases in levels of catecholamines in patients in both groups but also to plasma neuropeptide Y immunoreactivity in patients in group I. CONCLUSION: Pheochromocytomas exhibit different patterns of secretion. For about half of the patients either the secretion of neuropeptide Y is uncoupled from that of catecholamines or its secretion could be obscured by an increase in degradation of neuropeptide Y to inactive fragments undetectable by radioimmunoassay.
Asunto(s)
Catecolaminas/sangre , Neuropéptido Y/sangre , Feocromocitoma/sangre , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neuropéptido Y/inmunología , Feocromocitoma/cirugía , RadioinmunoensayoRESUMEN
Sympathetic nerves have long been suspected of trophic activity, but the nature of their angiogenic factor has not been determined. Neuropeptide Y (NPY), a sympathetic cotransmitter, is the most abundant peptide in the heart and the brain. It is released during nerve activation and ischemia and causes vasoconstriction and smooth muscle cell proliferation. Here we report the first evidence that NPY is angiogenic. At low physiological concentrations, in vitro, it promotes vessel sprouting and adhesion, migration, proliferation, and capillary tube formation by human endothelial cells. In vivo, in a murine angiogenic assay, NPY is angiogenic and is as potent as a basic fibroblast growth factor. The NPY action is specific and is mediated by Y1 and Y2 receptors. The expression of both receptors is upregulated during cell growth; however, Y2 appears to be the main NPY angiogenic receptor. Its upregulation parallels the NPY-induced capillary tube formation on reconstituted basement membrane (Matrigel); the Y2 agonist mimics the tube-forming activity of NPY, whereas the Y2 antagonist blocks it. Endothelium contains not only NPY receptors but also peptide itself, its mRNA, and the "NPY-converting enzyme" dipeptidyl peptidase IV (both protein and mRNA), which terminates the Y1 activity of NPY and cleaves the Tyr1-Pro2 from NPY to form an angiogenic Y2 agonist, NPY3-36. Endothelium is thus not only the site of action of NPY but also the origin of the autocrine NPY system, which, together with the sympathetic nerves, may be important in angiogenesis during tissue development and repair.
Asunto(s)
Endotelio Vascular/química , Neovascularización Fisiológica/efectos de los fármacos , Neuropéptido Y/fisiología , Sistema Nervioso Simpático/química , Animales , Aorta/efectos de los fármacos , Capilares , Colágeno/farmacología , Dipeptidil Peptidasa 4/biosíntesis , Dipeptidil Peptidasa 4/genética , Dipeptidil Peptidasa 4/fisiología , Combinación de Medicamentos , Factores de Crecimiento Endotelial/farmacología , Femenino , Factor 2 de Crecimiento de Fibroblastos/farmacología , Expresión Génica , Humanos , Laminina/farmacología , Linfocinas/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Neuropéptido Y/biosíntesis , Neuropéptido Y/genética , Neuropéptido Y/aislamiento & purificación , Neuropéptido Y/metabolismo , Neuropéptido Y/farmacología , Fragmentos de Péptidos/metabolismo , Fragmentos de Péptidos/farmacología , Reacción en Cadena de la Polimerasa , Proteoglicanos/farmacología , ARN Mensajero/biosíntesis , Ratas , Ratas Sprague-Dawley , Receptores de Neuropéptido Y/biosíntesis , Receptores de Neuropéptido Y/efectos de los fármacos , Receptores de Neuropéptido Y/genética , Receptores de Neuropéptido Y/fisiología , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial VascularAsunto(s)
Vasos Sanguíneos/fisiología , Neuropéptido Y/fisiología , Receptores de Neuropéptido Y/fisiología , Sistema Nervioso Simpático/fisiología , Vasoconstricción/fisiología , Animales , Plaquetas/fisiología , Vasos Sanguíneos/inervación , Endotelio Vascular/fisiología , Sustancias de Crecimiento , Humanos , Modelos Neurológicos , Neuropéptido Y/farmacología , Vasoconstricción/efectos de los fármacos , VasoconstrictoresRESUMEN
Neuropeptide-Y (NPY) is a sympathetic cotransmitter, which causes vasoconstriction, decreases coronary blood flow and decreases cardiac output. Circulating immunoreactive NPY (ir-NPY) levels increase with exercise, in patients admitted to the coronary care unit, and during thoracic surgery, and may play a role in postoperative hemodynamics. We studied changes in ir-NPY, epinephrine (E) and norepinephrine (NE) arterial plasma levels, and their correlation to simultaneous hemodynamic measurements at 8 perioperative time points in 13 patients undergoing open heart surgery. Changes in circulating ir-NPY negatively correlated with changes in systemic vascular resistance index (SVRI), mean arterial pressure (MAP) and mean pulmonary arterial pressure (MPAP) (P < 0.05), suggesting that the hemodynamic changes were the cause of the changes in ir-NPY levels, inducing overflow of NPY into the circulation via sympathetic activation. Changes in NE and E levels positively correlated with changes in heart rate (HR), SVRI and MPAP. Changes in E levels also positively correlated with changes in stroke volume index (SVI), central venous pressure (CVP) and cardiac index (CI). NE levels correlated well with E levels, but catecholamine levels did not correlate with ir-NPY levels. These results suggest, that the elevation in circulating NPY levels previously noted in patients with heart failure and acute myocardial infarction may reflect changes in NPY overflow and/or clearance secondary to increased sympathetic activity and to hemodynamic changes.
Asunto(s)
Epinefrina/sangre , Hemodinámica , Neuropéptido Y/sangre , Norepinefrina/sangre , Presión Sanguínea , Femenino , Humanos , Masculino , Persona de Mediana Edad , Arteria Pulmonar/fisiologíaRESUMEN
The physiological role of neuropeptide Y (NPY), a sympathetic cotransmitter and vasoconstrictor, has not been determined yet. We used a specific nonpeptide antagonist to the NPY Y1 receptor [BIBP-3226; (R)-N2-(diphenacetyl)-N-[(4-hydroxyphenyl) methyl]-D-arginineamide] to study the involvement of NPY in stress-induced vasoconstriction in the mesenteric bed. In rats subjected to cold water stress (COLD), plasma NPY immunoreactivity levels increased progressively from 0.15 +/- 0.01 to 0.32 +/- 0.05 pmol/ml and remained elevated during recovery. Administration of BIBP-3226 (3 mg.kg-1.h-1 infusion) tended to decrease the stress-induced pressor response and significantly attenuated the post-COLD elevation of blood pressure. The COLD-induced fall in the superior mesenteric artery blood flow and the increase of up to 300% in the mesenteric vascular resistance were either reduced or eliminated by BIBP-3226. Conversely, the Y1 antagonist had no effect on the COLD-induced tachycardia. This study provides the first evidence of the physiological role of NPY. The peptide is released during stress and increases mesenteric vascular resistance via activation of its Y1 receptors. Specific Y1-receptor antagonists may therefore be of potential benefit in prevention or treatment of stress-induced vasospasm.
Asunto(s)
Arterias Mesentéricas/fisiología , Receptores de Neuropéptido Y/fisiología , Vasoconstricción/fisiología , Animales , Arginina/análogos & derivados , Arginina/farmacología , Presión Sanguínea/efectos de los fármacos , Frío , Hemodinámica , Masculino , Ratas , Ratas Wistar , Receptores de Neuropéptido Y/antagonistas & inhibidores , Flujo Sanguíneo Regional/efectos de los fármacos , Estrés Mecánico , Resistencia Vascular/efectos de los fármacosAsunto(s)
Neoplasias de las Glándulas Suprarrenales/sangre , Neoplasias de las Glándulas Suprarrenales/metabolismo , Biomarcadores de Tumor/sangre , Neuropéptido Y/sangre , Feocromocitoma/sangre , Feocromocitoma/metabolismo , Neoplasias de las Glándulas Suprarrenales/cirugía , Adulto , Anciano , Epinefrina/sangre , Epinefrina/orina , Femenino , Humanos , Masculino , Persona de Mediana Edad , Norepinefrina/sangre , Norepinefrina/orina , Feocromocitoma/cirugíaRESUMEN
Several lines of evidence suggest that NPY is a neurotransmitter and neurohormone intricately involved in stress responses of the body, and as such should be considered a "stress molecule." Thus, circulating plasma NPY levels are increased by stress particularly if it is severe or prolonged. Stress stimulates the release of NPY from the sympathetic nerves and the adrenal medulla (in some species also from platelets), and in addition, modulates NPY inactivation. Stress-induced plasma NPY levels may reach the concentrations that are vasoconstrictive per se in addition to potentiating the actions of catecholamines. Reciprocally, elevated circulating levels of catecholamines during stress appear to induce hypersensitivity of blood vessels to NPY. Consequently, the peptide may be responsible for stress-induced regional vasoconstriction (splanchnic, coronary, and cerebral) but also may exert other actions that may be a part of the stress response: facilitate platelet aggregation, leukocyte adhesion, and macrophage activation. NPY release and actions appear to be up-regulated by testosterone and down-regulated by estrogens; therefore, NPY may be of particular importance to stress-induced cardiovascular events in men. In addition to acute vasoconstrictive effects, NPY exerts chronic actions and stimulates vascular smooth muscle proliferation and vascular hypertrophy, and hence, may be a link between stress and potential chronic changes in blood vessels.
Asunto(s)
Neuropéptido Y/fisiología , Estrés Fisiológico/fisiopatología , Animales , Presión Sanguínea , División Celular , Frío , Estrógenos/fisiología , Femenino , Humanos , Masculino , Músculo Liso Vascular/citología , Ratas , Ratas Wistar , Factores Sexuales , Testosterona/fisiologíaRESUMEN
Studies of cardiovascular physiology are frequently performed under barbiturate anesthesia even though the effect of barbiturates on the pressor response to catecholamines is controversial, and their effect on the response to other agonists is unknown. The effect of pentobarbital (PB) anesthesia on the pressor and heart rate (HR) dose responses to norepinephrine (NE), angiotensin II (AII), vasopressin (VP) and neuropeptide Y (NPY) was studied in vivo in normal and endotoxemic rats. Four groups of rats (5-6 rats/group) were studied for each agonist: 1) anesthetized/endotoxemic, 2) anesthetized/control, 3) conscious/endotoxemic, and 4) conscious/control. Anesthesia was maintained with 10 mg/kg of PB i.v. q 45 minutes. Endotoxemia was established by infusion of a non-hypotensive dose of E. coli lipopolysaccharide 0127:B8, (LPS, 10 micrograms/10 microliters/min) throughout the experiment. One hour after the LPS (or saline control) infusion was started, dose response curves of the pressor and HR responses to agonists were established. LPS infusion resulted in marked suppression of the pressor response to NE, AII, and VP in both conscious and anesthetized rats. LPS infusion suppressed the response to NPY in conscious, but not in anesthetized rats. LPS did not affect the baroreceptor reflex. In both normal and endotoxemic rats, PB anesthesia suppressed the pressor response and attenuated the baroreceptor reflex to AII and NPY, enhanced the pressor response without affecting the heart rate response to NE, and attenuated the baroreceptor reflex to VP. The pressor response to VP was suppressed by anesthesia in normal, but not in endotoxemic rats. PB anesthesia interferes with the cardiovascular effects of different agonists in a variable manner, depending on the agonist tested and the presence or absence of endotoxemia, indicating their different modes of action. These effects should be considered when planning in vivo experiments with these and other agonists.
Asunto(s)
Pentobarbital/farmacología , Presorreceptores/efectos de los fármacos , Toxemia/fisiopatología , Anestesia , Angiotensina II/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Interacciones Farmacológicas , Escherichia coli/metabolismo , Frecuencia Cardíaca/efectos de los fármacos , Lipopolisacáridos/farmacología , Masculino , Neuropéptido Y/farmacología , Norepinefrina/farmacología , Presorreceptores/fisiología , Ratas , Ratas Wistar , Vasoconstrictores/farmacología , Vasopresinas/farmacologíaRESUMEN
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.
Asunto(s)
Epinefrina/sangre , Hipertensión/sangre , Neuropéptido Y/sangre , Norepinefrina/sangre , Adulto , Factores de Edad , Presión Sanguínea/fisiología , Estudios de Evaluación como Asunto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores Sexuales , Estadística como AsuntoRESUMEN
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.
Asunto(s)
Enfermedades del Sistema Nervioso Autónomo/fisiopatología , Hipertensión/fisiopatología , Neuropéptido Y/fisiología , Receptores Adrenérgicos alfa/fisiología , Receptores Adrenérgicos beta/fisiología , Traumatismos de la Médula Espinal/fisiopatología , Vejiga Urinaria/fisiopatología , Animales , Enfermedades del Sistema Nervioso Autónomo/etiología , Presión Sanguínea/fisiología , Bloqueadores Ganglionares/farmacología , Frecuencia Cardíaca/fisiología , Hexametonio/farmacología , Hipertensión/etiología , Masculino , Prazosina/farmacología , Propranolol/farmacología , Ratas , Ratas Sprague-Dawley , Traumatismos de la Médula Espinal/complicaciones , Sistema Nervioso Simpático/fisiopatología , Vejiga Urinaria/inervación , Cateterismo UrinarioRESUMEN
Hypotension during endotoxic shock is related to reduced vascular responsiveness to vasoconstrictors. Neuropeptide Y (NPY) is known to potentiate the pressor response to some agonists, and NPY infusion has been shown to improve hemodynamics and survival in endotoxemic rats. We therefore studied the effect of NPY infusion on the suppressed pressor effect of norepinephrine (NE), angiotensin II (AII), vasopressin (VP), and endothelin (ET) in conscious endotoxemic rats. Chronically cannulated conscious rats were infused with a non-hypotensive dose of endotoxin (LPS, 10 micrograms/10 microliters/min) throughout the experiment. Infusion of NPY, 40 pmol/10 microliters/min was started 15 minutes before the LPS infusion, and continued for 65 minutes. Five minutes after the termination of NPY infusion, increasing agonist doses were administered i.v. to construct dose-response curves. Each experiment included one control group where saline replaced LPS, and one control group where saline replaced NPY. LPS infusion caused suppression of the pressor responses to all four agonists, as expressed by ED50 and by decreased pressor response to the individual agonist doses. In addition, LPS infusion altered the bradycardic response to AII and ET. NPY infusion prior to the administration of NE, AII and VP resulted in partial reversal of the LPS-induced suppressed responsiveness to these agonists. NPY infusion had no effect on the response to ET in either control or endotoxemic rats. Partial reversal of the suppressed responsiveness to the three agonists by NPY infusion may contribute to the observed NPY-induced improvement of blood pressure and survival rate during endotoxic shock.
Asunto(s)
Endotoxinas/antagonistas & inhibidores , Neuropéptido Y/farmacología , Choque Séptico/tratamiento farmacológico , Animales , Endotelinas/farmacología , Hemodinámica/efectos de los fármacos , Hipotensión/tratamiento farmacológico , Hipotensión/fisiopatología , Lipopolisacáridos , Masculino , Norepinefrina/farmacología , Presorreceptores/efectos de los fármacos , Ratas , Ratas Wistar , Choque Séptico/fisiopatología , Vasopresinas/farmacologíaRESUMEN
Neuropeptide Y (NPY) is a vasoconstrictor sympathetic cotransmitter and a modulator of adrenergic function whose role in hypertension is yet unknown. We studied the co-release of NPY and noradrenaline (NA) in patients with essential hypertension (13 females, 11 males, age 42 +/- 13 years) by measuring plasma levels of NPY-immunoreactivity (-ir, radioimmunoassay) and NA (radioenzymatic method) following administration of clonidine (CL 300 micrograms, p.o.). At rest, only NPY-ir levels significantly correlated with diastolic blood pressure (DBP, r = 0.42, p < 0.05). Three hours after CL, there were a decrease in mean arterial pressure and plasma NA (by 31 +/- 14 mmHG, p < 0.05 and 92 +/- 10 pg/ml, p < 0.01) but no change in NPY-ir levels. Patients were subsequently subdivided into groups with high (> or = 90 mmHg) or normal DBP (< or = 89 mmHg) and with or without elevated plasma NA levels (above or below 414 pg/ml, a normotensive mean +1 standard deviation). In hypertensives, but not in those with normal DBP, plasma NPY-ir correlated not only with DBP but also with systolic and mean blood pressure (r = 0.53 and r = 0.60, respectively) at rest. Hypertensives with "high" NA had significantly lower resting plasma NPY-ir levels than those with "low" NA (7.1 +/- 3.6 vs 14.7 +/- 6.0 fmol/ml, p < 0.05). In the former group, CL evoked the greatest fall in plasma NA, and also decreased NPY-ir levels by 50% (p < 0.05). Thus, patients with essential hypertension were found to display differential patterns of changes in sympathetic cotransmitters to clonidine. NPY may contribute to the increased blood pressure in hypertensives and together with NA, mediate hypotensive action of clonidine but only in the hyperadrenergic subgroup of hypertensives.
Asunto(s)
Clonidina/farmacología , Hipertensión/metabolismo , Neuropéptido Y/metabolismo , Receptores Adrenérgicos alfa/metabolismo , Adulto , Presión Sanguínea/efectos de los fármacos , Femenino , Humanos , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Norepinefrina/metabolismo , Receptores Adrenérgicos alfa/efectos de los fármacosRESUMEN
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)
Asunto(s)
Hipertensión/metabolismo , Neuropéptido Y/fisiología , Médula Suprarrenal/metabolismo , Agonistas alfa-Adrenérgicos/farmacología , Animales , Plaquetas/metabolismo , Catecolaminas/sangre , Hipertensión/fisiopatología , Masculino , Neuropéptido Y/sangre , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Sistema Nervioso Simpático/metabolismoRESUMEN
Neuropeptide Y (NPY), a sympathetic and platelet-derived vasoconstrictor, acts both directly and by potentiating adrenergic responsiveness and therefore may be beneficial in endotoxic shock, where suppressed vascular responsiveness to adrenergic agents is a key factor. This was studied in anesthetized rats. First, infusion of a nonhypotensive dose of endotoxin (lipopolysaccharide, LPS) markedly suppressed the pressor response to increasing doses of norepinephrine (NE), angiotensin II, and vasopressin but did not suppress the response to NPY. Second, in rats rendered hypotensive by intravenous LPS, continuous NE infusion (0.1-1.0 microgram.kg-1 x min-1 started 5 min after LPS for 1 h) did not alter hemodynamics. In contrast, 5 nmol.kg-1 x min-1 of NPY (equipotent to 0.1 microgram.kg-1 x min-1 of NE in normal rats) increased mean arterial pressure (MAP, from 64 to 114% of baseline), total peripheral resistance index (TPRI, from 64 to 154% of baseline), and left ventricular stroke work index (from 36 to 73% of baseline), without changing cardiac index (CI). Third, in a similar experimental protocol, pretreatment of the hypotensive rats with phentolamine blocked the pressor effect of NE infusion, but only partially attenuated the response to NPY. Finally, addition of low-dose NPY to NE infusion improved survival following a lethal dose of LPS compared with treatment with NE alone (P < 0.01). Thus, unlike other vasoconstrictors tested, NPY-mediated vasoconstriction is preserved during endotoxemia. The beneficial effect of NPY is mediated by increased TPRI without reduction in CI; both NPY receptor-mediated vasoconstriction and potentiation of adrenergic responsiveness may be involved.
Asunto(s)
Neuropéptido Y/farmacología , Choque Séptico/mortalidad , Choque Séptico/fisiopatología , Antagonistas Adrenérgicos alfa/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Endotoxinas/sangre , Hemodinámica/efectos de los fármacos , Infusiones Intravenosas , Masculino , Norepinefrina/farmacología , Fentolamina/farmacología , Ratas , Ratas Wistar , Análisis de SupervivenciaRESUMEN
Immunoreactive-neuropeptide Y (i-NPY) is present in platelets of rats, and has recently been demonstrated to be authentic rat NPY based on its amino acid sequence. This potent vasoconstrictor and putative smooth muscle mitogen is released during platelet activation, suggesting a role in platelet-vascular interactions. We have now extended this work to several strains of rats and mice, and humans of both sexes. Among mice, strains in which NPY mRNA has been demonstrated in megakaryocytes have markedly higher levels of i-NPY (0.63-1.11 pmol/ml in NZB/B1NJ, NZBWF1/J, BXSB/MpJYaa, BALB/cJ) in platelet rich plasma (PRP) than other strains (DBA/2J, CBA/J, C3H/HeJ, MRL/MpJ-lpr, C57BL/6J; each < 0.02 pmol/ml). In rats, high content of i-NPY was observed in PRP and platelets of all strains examined (Sprague-Dawley, Wistar, Wistar Kyoto). i-NPY level was 30.6, 3.7 and 10.1 pmol/ml in PRP of the three strains, respectively. In humans, low levels of i-NPY occur in plasma and platelet fractions compared to rodents (0.069 and 0.048 pmol/ml in male and female PRP, respectively), but they, too, have greater i-NPY in platelet rich plasma and platelets than in platelet poor plasma. Assuming this is authentic NPY, platelet-derived NPY might have a role in pathophysiological states involving activation of platelets in humans.