neuropeptide-y and Hypertension--Pulmonary

This study aims to explore the changes in endothelin-1 (ET-1), plasma neuropeptide Y, and calcitonin gene-related peptide (CGRP) in child patients before and after operation. A total of 80 child patients with congenital heart disease (CHD) complicated with pulmonary hypertension (PH) were enrolled and divided into control group (n = 40, conservative treatment for various reasons) and observation group (n = 40, active preoperative preparation and timely operative intervention) according to different treatments. There were positive correlations between systolic pulmonary arterial pressure (sPAP) and ET-1, plasma neuropeptide Y, while negative correlation between sPAP and CGRP. In conclusion, our data demonstrate that the levels of ET-1, plasma neuropeptide Y, and CGRP in PH-CHD were significantly changed after interventions, which provides new leads as alternative biomarkers to assess the efficacy of treatments against PH-CHD.

Topics: Calcitonin Gene-Related Peptide; Child; Child, Preschool; Endothelin-1; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Male; Neuropeptide Y; Postoperative Period; Preoperative Period

Pulmonary arteries (PAs) are innervated, but little is known about the role of neuronal axis in pulmonary hypertension (PH). Here, we have examined the role of the neuropeptide Y (NPY) and its Y₁ receptor in PH pathogenesis.. NPY was localized by immunofluorescence. Expression of NPY and Y₁ receptor were determined by quantitative PCR. Cellular response to NPY stimulation was assessed by Western blotting, thymidine incorporation and calcium imaging. Wire myography and isolated perfused mouse lung were applied to study pulmonary vasoactive effects of NPY. Selective receptor antagonists were used to assess the contribution of receptor subtypes in mediating NPY effects.. Samples from PH patients showed increased NPYergic innervation within the PA wall and higher Y₁ receptor expression, compared with donors. However, NPY levels were unchanged in both PA and serum. In the chronic hypoxic mouse model, Y₁ receptor were up-regulated, while expression of both NPY and Y₁ receptor was increased in the lungs of monocrotaline and SU5416-hypoxia rats. On a functional level, NPY acutely increased intracellular calcium levels and enhanced vasoconstriction of lung vessels preconstricted with adrenaline. Furthermore, NPY stimulated proliferation of human pulmonary arterial smooth muscle cells and activated p38 and PKD pathways. Correspondingly, higher phosphorylation of PKD was observed in remodelled vessels from PH patients. The selective Y₁ receptor antagonist, BIBO 3304, concentration-dependently inhibited vasoconstrictive and proliferative effects of NPY.. NPY and Y₁ receptor are possible mediators of both vasoconstriction and pulmonary vascular remodelling in PH.

Topics: Adult; Animals; Arginine; Cell Proliferation; Epinephrine; Female; Humans; Hypertension, Pulmonary; Hypoxia; In Vitro Techniques; Indoles; Lung; Male; Mice, Inbred C57BL; Monocrotaline; Myocytes, Smooth Muscle; Neuropeptide Y; Pulmonary Artery; Pyrroles; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Vasoconstriction; Vasoconstrictor Agents; Young Adult

In attempt to characterize tetrandrine on pulmonary hypertension, biological activities induced by a range of mediators implicated in the pathogenesis of pulmonary hypertension were investigated.. Pulmonary artery rings and tracheal segments were contracted with couples of bioactive substances in which a series experiments including effects of tetrandrine on calcium agonist, endothelin, thromboxane A2, angiotensin II, neuropeptide Y, histamine, 5-methyl furmethide were performed, the influences of tetrandrine in the concentration of 1 to 30 micromol/L were investigated.. Tetrandrine inhibited calcium agonist BayK8644, endothelin-1 and thromboxane A2 mimetic U46619, angiotensin II- and neuropeptide Y-induced contractile responses with depression of the maximal contraction of pulmonary artery rings in a varying extent. Tetrandrine inhibited leukotriene E4-induced concentration-response curve in a competitive antagonist manner with a pKB of (5.29+/-0.11) without any influence leukotriene C4, leukotriene D4, histamine, and 5-methyl furmethide induced contractile responses of guinea pig trachea.. Tetrandrine may produce multiple pharmacological effects against calcium channel antagonist, U46619, endothelin-1,angiotension II, and neuropeptide Y induced vasoconstriction in rat pulmonary arteries in varying extent and inhibition of leukotriene E4 rather than C4, D4, histamine, and 5-methyl furmethide induced contractile responses on rat tracheal segments. These pharmacological characteristics are considered to contribute to its antihypertensive action during pulmonary hypertension.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Alkaloids; Angiotensin II; Animals; Antihypertensive Agents; Benzylisoquinolines; Endothelin-1; Guinea Pigs; Hypertension, Pulmonary; Male; Muscle Contraction; Muscle, Smooth, Vascular; Neuropeptide Y; Pulmonary Artery; Rats; Rats, Sprague-Dawley; SRS-A

During sepsis vasoactive arachidonic acid metabolites of the cyclo-oxygenase pathway and the endothelium-derived vasoconstrictor endothelin-1 (ET-1) are released. The effects of cyclo-oxygenase pathway inhibition by diclofenac on the endotoxin shock response and ET-1 turnover, were investigated in five groups of pigs. In the first group (n = 7; controls) endotoxin (15 micrograms.kg-1.h-1 i.v.) was infused for two hours. In a second endotoxin group (n = 7), the animals were pretreated with diclofenac (3 mg.kg-1 i.v.). In a third group (n = 7), high-dose ET-1 was infused (20 pmol.kg-1.min-1 i.v.) and in a fourth group (n = 7), the ET-1 infusion was preceded by diclofenac. In a fifth group (n = 4), a low and intermediate dose of ET-1 (0.2 and 4 pmol.kg-1.min-1) was infused. A significant increase in ET-1-like immunoreactivity (LI) plasma levels was observed in both endotoxin groups, but in the diclofenac group the increase was comparatively delayed. Furthermore, this group showed a more stable haemodynamic course and in the biphasic increase of pulmonary vascular resistance seen in endotoxin controls, the initial peak was abolished by diclofenac. Exogenous ET-1 infusion indicated that not only locally released but possibly also circulating ET-1 could be a mediator of vascular responses to endotoxin. Indications of release from the lungs were seen during endotoxin infusion. Diclofenac had no effect on basal ET-1-LI plasma levels or on the disappearance rate from plasma of ET-1-LI and the haemodynamic changes seen on ET-1 infusion. The inhibition of cyclo-oxygenase pathway by diclofenac resulted in prevention of the initial pulmonary hypertension and a delayed increase in plasma ET-1-LI levels in porcine endotoxin shock and this latter effect is not due to an increased rate of disappearance from plasma but rather to a decreased release of ET-1.

Topics: Animals; Arachidonic Acids; Blood Pressure; Cardiac Output; Cyclooxygenase Inhibitors; Diclofenac; Endothelins; Endotoxins; Escherichia coli; Heart Rate; Hypertension, Pulmonary; Lipopolysaccharides; Lung; Neuropeptide Y; Norepinephrine; Shock, Septic; Swine; Vascular Resistance

Nitric oxide (10 ppm) inhaled by pigs before or during endotoxin shock induced by an infusion of E. coli lipopolysaccharide. Nitric oxide inhalation selectively attenuated pulmonary hypertension during endotoxin infusion without influencing mean arterial blood pressure and cardiac output. Upon cessation of nitric oxide inhalation, pulmonary artery pressure rapidly increased to levels seen in endotoxin-treated controls. The oxygenation and pH of arterial blood were significantly higher in the animals receiving nitric oxide. A marked increase in arterial plasma noradrenaline and neuropeptide Y was seen in endotoxin-treated control pigs while in the nitric oxide-treated pigs this increase was markedly reduced. The increase in arterial plasma endothelin-1 was not influenced by nitric oxide inhalation. Infusion of L-arginine (substrate for nitric oxide synthesis) also attenuated the pulmonary hypertension but was not selective for the pulmonary vasculature. L-Nitro-arginine (a nitric oxide synthesis inhibitor) initiated a rapid but brief elevation of arterial blood pressure and of pulmonary artery pressure as well as a reduction in cardiac output. Nitric oxide inhalation selectively reduces pulmonary hypertension in porcine endotoxin shock and improves arterial oxygenation and pH with a marked attenuation of sympathetic activation.

Topics: Administration, Inhalation; Animals; Arginine; Blood Gas Analysis; Blood Pressure; Endothelins; Female; Hemodynamics; Hypertension, Pulmonary; Male; Neuropeptide Y; Nitric Oxide; Nitroarginine; Norepinephrine; Pulmonary Circulation; Pulmonary Gas Exchange; Shock, Septic; Swine; Vascular Resistance

In order to investigate the general cause of beta-adrenergic receptor neuroeffector abnormalities in the failing human heart, we measured ventricular myocardial adrenergic receptors, adrenergic neurotransmitters, and beta-adrenergic receptor-effector responses in nonfailing and failing hearts taken from nonfailing organ donors, subjects with endstage biventricular failure due to idiopathic dilated cardiomyopathy (IDC), and subjects with primary pulmonary hypertension (PPH) who exhibited isolated right ventricular failure. Relative to nonfailing PPH left ventricles, failing PPH right ventricles exhibited (a) markedly decreased beta 1-adrenergic receptor density, (b) marked depletion of tissue norepinephrine and neuropeptide Y, (c) decreased adenylate cyclase stimulation in response to the beta agonists isoproterenol and zinterol, and (d) decreased adenylate cyclase stimulation in response to Gpp(NH)p and forskolin. These abnormalities were directionally similar to, but generally more pronounced than, corresponding findings in failing IDC right ventricles, whereas values for these parameters in nonfailing left ventricles of PPH subjects were similar to values in the nonfailing left ventricles of organ donors. Additionally, relative to paired nonfailing PPH left ventricles and nonfailing right ventricles from organ donors, failing right ventricles from PPH subjects exhibited decreased adenylate cyclase stimulation by MnCl2. These data indicate that: (a) Adrenergic neuroeffector abnormalities present in the failing human heart are due to local mechanisms; systemic processes do not produce beta-adrenergic neuroeffector abnormalities. (b) Pressure-overloaded failing right ventricles of PPH subjects exhibit decreased activity of the catalytic subunit of adenylate cyclase, an abnormality not previously described in the failing human heart.

Topics: Adenylyl Cyclases; Adult; Cardiomyopathy, Dilated; Catecholamines; Female; Heart; Heart Failure; Humans; Hypertension, Pulmonary; Iodocyanopindolol; Isoproterenol; Male; Myocardial Contraction; Neuropeptide Y; Pindolol; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta

We tested the possibility that neuropeptide Y (NPY) may contribute to the pulmonary hypertension that occurs after massive sympathetic activation produced by intracisternal veratrine administration in the chloralose-anesthetized dog. In six dogs, veratrine caused arterial NPY-like immunoreactivity (NPY-LI) to rise from 873 +/- 150 (SE) pg/ml to peak values of 3,780 +/- 666 pg/ml by 60-120 min. (In 3 animals, adrenalectomy significantly reduced the increases in NPY-LI.) In five additional dogs, we infused porcine NPY for 30 min in doses that increased arterial NPY-LI to 8,354 +/- 1,514 pg/ml and observed only minor changes in pulmonary hemodynamics. In three isolated perfused canine left lower lung lobe (LLL) preparations, increasing doses of NPY were administered, producing levels of plasma NPY-LI, at the highest dose, that exceeded those observed after veratrine administration by three orders of magnitude. No changes in LLL arterial or double-occlusion capillary pressures were observed at any dose. Similarly, no changes in LLL hemodynamics were observed in three additional lobes when NPY was administered while norepinephrine was being infused. We conclude that it is unlikely that NPY plays a role as a circulating vasoactive agent in producing the pulmonary hypertension and edema that occur in this model.

Topics: Adrenal Glands; Adrenalectomy; Animals; Dogs; Hypertension, Pulmonary; In Vitro Techniques; Neuropeptide Y; Norepinephrine; Pulmonary Circulation; Sympathetic Nervous System; Veratrine

Nerves containing peptides that supply the human intrapulmonary vasculature were studied in 21 controls aged one month to 24 years and in 13 patients with pulmonary hypertension aged 11 days to eight years. An indirect immunofluorescence technique was used to study the distribution and relative density of nerve fibres containing the general neuronal marker, protein gene product 9.5; tyrosine hydroxylase; synaptophysin; neuropeptide tyrosine; vasoactive intestinal polypeptide; substance P, somatostatin; and calcitonin gene related peptide. At all ages in normal and hypertensive lungs neuropeptide tyrosine was the predominant neuropeptide associated with the pulmonary vascular nerves. In normal lungs the relative density of nerve fibres increased during childhood only in the arteries of the respiratory unit. Pulmonary hypertension was associated with the premature innervation of these arteries during the first year of life. Innervation of small, abnormally thick-walled pre-capillary vessels by predominantly vasoconstrictor nerves may help to explain the susceptibility of infants to pulmonary hypertensive crises.

Topics: Age Factors; Child; Child, Preschool; Fluorescent Antibody Technique; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Lung; Nerve Fibers; Neuropeptide Y; Neuropeptides; Pulmonary Artery; Pulmonary Veins