Central effects of endothelin on respiratory output during development

Both endothelin-1 protein and endothelin-1 specific binding sites have been identified in areas of the medulla oblongata involved in respiratory control. We examined whether endothelin acting centrally affects respiratory output during early postnatal life. We initially examined the effect of intracisternally administrated endothelin on respiratory output in 10 2- to 18-day-old piglets. Endothelin-1 administration at 50 nmol to 1 mumol caused respiratory inhibition. We subsequently examined whether this response is mediated through chemosensitive areas of the ventral medulla. Endothelin-1 was microinjected into specific ventral or dorsal medullary regions in 31 14- to 22-day-old piglets. Microinjection of endothelin-1 (10 fmol to 0.1 pmol) just above the hypoglossal roots, lateral to the pyramids, and within 1 mm from the surface (n = 24) attenuated respiratory output, and complete apnea occurred with 1 pmol in all animals. However, microinjection of endothelin-1 3 mm below the ventral surface (n = 5) and into the dorsal medulla (n = 3) had no inhibitory effect. Comparable doses of angiotensin II (n = 5) and norepinephrine (n = 5) microinjected into the endothelin-1 sensitive area also did not influence respiratory output. These effects of endothelin-1 were not altered by prior endothelin-B receptor blockade (IRL-1038) but could be reversed by endothelin-A receptor blockade (BQ-610). These results suggest that endothelin-1 release may cause ventilatory depression mediated through endothelin-A receptors located in the chemosensitive areas of the ventrolateral medulla.

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Pirenzepine prevents diethyl pyrocarbonate inhibition of central CO2 sensitivity

Journal of Applied Physiology ◽

10.1152/jappl.1988.65.5.1962 ◽

1988 ◽

Vol 65 (5) ◽

pp. 1962-1966 ◽

Cited By ~ 1

Author(s):

E. E. Nattie ◽

J. W. Mills ◽

L. C. Ou

Keyword(s):

Ventral Surface ◽

Blocking Agent ◽

Inhibitory Effect ◽

Ventrolateral Medulla ◽

Inhibitory Effects ◽

Co2 Sensitivity ◽

Diethyl Pyrocarbonate ◽

Maximum Value ◽

Chemosensitive Areas ◽

Co2 Chemosensitivity

Application by pledget of the M1-antimuscarinic receptor agent pirenzepine (40 mM) to the rostral chemosensitive areas of the ventrolateral medulla in anesthetized, paralyzed, vagotomized, glomectomized, and servoventilated cats inhibited the slope of the integrated phrenic response to CO2 by 32.5% (P less than 0.03) and the maximum value by 21.1% (P less than 0.01). Similar application of the imidazole-histidine blocking agent diethyl pyrocarbonate (DEPC) decreased the slope by 40.3% (P less than 0.01) and the maximum value by 29.3% (P less than 0.05). Both responses confirm previous results. DEPC treatment decreased the effectiveness of subsequent pirenzepine application such that although slope and maximum were further decreased, the values were not significantly different from those after DEPC. Pirenzepine treatment prevented any subsequent DEPC inhibitory effect. The results raise the possibility that the inhibitory effects of DEPC on CO2 chemosensitivity are via muscarinic receptors and that muscarinic receptor involvement in CO2 chemosensitivity requires the presence of imidazole-histidine. Analysis by scintillation counting of successive 100-micron sections of medulla after rostral area application of [3H]pirenzepine indicated that the pirenzepine and DEPC effects are most probably within 2.0 mm of the ventral surface as measured from the midline, well away from the dorsal and ventral respiratory group neurons.

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Inhibitory effect of endothelin A receptor blockade on tumor growth and liver metastasis of a human gastric cancer cell line

Gastric Cancer ◽

10.1007/s10120-007-0421-z ◽

2007 ◽

Vol 10 (2) ◽

pp. 123-128 ◽

Cited By ~ 8

Author(s):

Rika Fukui ◽

Hidefumi Nishimori ◽

Fumitake Hata ◽

Takahiro Yasoshima ◽

Keisuke Ohno ◽

...

Keyword(s):

Gastric Cancer ◽

Liver Metastasis ◽

Gastric Cancer Cell ◽

Gastric Cancer Cell Line ◽

Cancer Cell Line ◽

Inhibitory Effect ◽

Human Gastric Cancer ◽

Receptor Blockade ◽

Endothelin A Receptor ◽

Endothelin A

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New bone formation in an osteoblastic tumor model is increased by endothelin-1 overexpression and decreased by endothelin A receptor blockade

Urology ◽

10.1016/s0090-4295(98)00658-x ◽

1999 ◽

Vol 53 (5) ◽

pp. 1063-1069 ◽

Cited By ~ 131

Author(s):

Joel B Nelson ◽

Son H Nguyen ◽

Jinshyun R Wu-Wong ◽

Terry J Opgenorth ◽

Douglas B Dixon ◽

...

Keyword(s):

Bone Formation ◽

Tumor Model ◽

Receptor Blockade ◽

New Bone Formation ◽

Endothelin 1 ◽

Endothelin A Receptor ◽

Endothelin A

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Kainic acid on the rostral ventrolateral medulla inhibits phrenic output and CO2 sensitivity

Journal of Applied Physiology ◽

10.1152/jappl.1988.65.4.1525 ◽

1988 ◽

Vol 65 (4) ◽

pp. 1525-1534 ◽

Cited By ~ 29

Author(s):

E. E. Nattie ◽

J. W. Mills ◽

L. C. Ou ◽

W. M. St John

Keyword(s):

Kainic Acid ◽

Neuronal Cell ◽

Ventral Surface ◽

Ventrolateral Medulla ◽

Co2 Response ◽

Specific Amino Acid ◽

Amino Acid Receptors ◽

Neuronal Cell Bodies ◽

Chemosensitive Areas ◽

End Tidal

We used the neurotoxin, kainic acid, which is known to stimulate neuronal cell bodies as opposed to axons of passage by binding to specific amino acid receptors to determine whether cells with such receptors have access to the ventrolateral medullary surface and are involved in central ventilatory chemosensitivity. Pledgets with 4.7 mM kainic acid were placed bilaterally on the rostral, intermediate, or caudal ventilatory chemosensitive areas for 1-2 min in chloralose-urethan-anesthetized, paralyzed, vagotomized, glomectomized, and servo-ventilated cats. Application of kainic acid on the caudal or intermediate areas produced no consistent significant effects on eucapnic phrenic output or on the slope or maximum value of the phrenic nerve response to increased end-tidal PCO2. Rostral area kainic acid produced immediate augmentation and then diminution of blood pressure and phrenic output. Apnea developed in six of nine cats by 40 min. In all five cats in which it could be tested, the slope of the CO2 response was clearly decreased. Of [3H]kainic acid applied to the rostral area, 88.4% was shown to be within 2 mm of the ventral surface. Comparison of surface application sites of this and other studies suggests that an area overlapping the border of the original rostral and intermediate areas allows access to neurons involved in the chemoreception process, which may also provide tonic facilitatory input to cardiorespiratory systems.

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The effect of cold blockade of the medullary chemoreceptors on the CO2 modulation of vascular tone and heart rate

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y79-070 ◽

1979 ◽

Vol 57 (5) ◽

pp. 461-468 ◽

Cited By ~ 26

Author(s):

Brian D. Hanna ◽

Franco Lioy ◽

Canio Polosa

Keyword(s):

Heart Rate ◽

Vascular Tone ◽

Perfusion Pressure ◽

Respiratory Control ◽

Ventral Surface ◽

Sodium Pentobarbital ◽

Artificial Cerebrospinal Fluid ◽

Chemosensitive Areas ◽

Ventral Medullary Surface

We have previously reported that a direct relationship exists between neurogenic vascular tone in the cat hindlimbs and arterial CO2 tension [Formula: see text]. Since this relationship is not appreciably changed by deafferentiation of peripheral chemoreceptors, we have studied the possible role of structures on the ventral surface of the medulla in mediating the CO2 sensitivity of neurogenic tone. The vagosympathetic trunks and the carotid sinus nerves were sectioned bilaterally in cats under sodium pentobarbital anesthesia. The ventral surface of the medulla was perfused with artificial cerebrospinal fluid of physiological [Formula: see text], pH, and temperature. The animals were hyperventilated with different mixtures of CO2 (0, 4, and 10% in O2), so as to change [Formula: see text] from 12.6 ± 1.2 to 57.4 ± 1.8 mmHg (mean ± SE). The perfusion pressure of the hindlimbs, vascularly isolated and perfused at constant flow, was positively correlated with [Formula: see text]. Bilateral chemosensitive areas of the ventral surface of the medulla oblongata (7 mm caudal to the foramen coecum and 3 mm lateral to the midline) were cooled to a temperature of 12 °C by means of small thermodes. This maneuver decreased the heart rate and perfusion pressure present at each level of [Formula: see text] and also the sensitivity of the perfusion pressure to changes in [Formula: see text]. Cold blockade (12 °C) of the rest of the ventral medullary surface induced a further decrease in heart rate and perfusion pressure but not in the slope of the [Formula: see text] – perfusion pressure relation. Similar results were obtained in a group of adrenalectomized animals. These experiments suggest that the medullary areas which mediate the central CO2-sensitivity of respiratory control systems also play a role in cardiovascular control.

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Chronic endothelin A receptor blockade in lambs with increased pulmonary blood flow and pressure

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00093.2004 ◽

2004 ◽

Vol 287 (3) ◽

pp. L592-L597 ◽

Cited By ~ 10

Author(s):

Sohrab Fratz ◽

Barbara Meyrick ◽

Boaz Ovadia ◽

Michael J. Johengen ◽

Olaf Reinhartz ◽

...

Keyword(s):

Blood Flow ◽

Pulmonary Hypertension ◽

Pulmonary Blood Flow ◽

Unit Area ◽

Right Atrial ◽

Receptor Blockade ◽

Structural Effects ◽

Endothelin 1 ◽

Endothelin A Receptor ◽

Endothelin A

Endothelin receptor blockade is an emerging therapy for pulmonary hypertension. However, hemodynamic and structural effects and potential changes in endogenous nitric oxide (NO)-cGMP and endothelin-1 signaling of chronic endothelin A receptor blockade in pulmonary hypertension secondary to congenital heart disease are unknown. Therefore, the objectives of this study were to determine hemodynamic and structural effects and potential changes in endogenous NO-cGMP and endothelin-1 signaling of chronic endothelin A receptor blockade in a lamb model of increased pulmonary blood flow following in utero placement of an aortopulmonary shunt. Immediately after spontaneous birth, shunt lambs were treated lifelong with either an endothelin A receptor antagonist (PD-156707) or placebo. At 4 wk of age, PD-156707-treated shunt lambs ( n = 6) had lower pulmonary vascular resistance and right atrial pressure than placebo-treated shunt lambs ( n = 8, P < 0.05). Smooth muscle thickness or arterial number per unit area was not different between the two groups. However, the number of alveolar profiles per unit area was increased in the PD-156707-treated shunt lambs (190.7 ± 5.6 vs. 132.9 ± 10.0, P < 0.05). Plasma endothelin-1 and cGMP levels and lung NOS activity, cGMP, eNOS, preproendothelin-1, endothelin-converting enzyme-1, endothelin A, and endothelin B receptor protein levels were similar in both groups. We conclude that chronic endothelin A receptor blockade attenuates the progression of pulmonary hypertension and augments alveolar growth in lambs with increased pulmonary blood flow.

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The Inhibitory Effect of Heparin and Related Glycosaminoglycans on Neutrophil Chemotaxis

Thrombosis and Haemostasis ◽

10.1055/s-0038-1661157 ◽

1984 ◽

Vol 52 (02) ◽

pp. 134-137 ◽

Cited By ~ 69

Author(s):

Yaacov Matzner ◽

Gerard Marx ◽

Ruth Drexler ◽

Amiram Eldor

Keyword(s):

Specific Binding ◽

Anticoagulant Activity ◽

Neutrophil Migration ◽

Inhibitory Effect ◽

Chemotactic Factor ◽

Human Neutrophils ◽

Boyden Chamber ◽

Neutrophil Chemotaxis ◽

Inhibitory Effects ◽

Chemotactic Factors

SummaryClinical observations have shown that heparin has antiinflammatory activities. The effect of heparin on neutrophil chemotaxis was evaluated in vitro in the Boyden Chamber. This method enabled differentiation between the direct effects of heparin on neutrophil migration and locomotion, and its effects on chemotactic factors. Heparin inhibited both the random migration and directed locomotion of human neutrophils toward zymosan-activated serum (ZAS) and F-met-leu-phe (FMLP). Inhibition was found to be dependent on the concentrations of the heparin and of the chemotactic factors. No specific binding of heparin to the neutrophils could be demonstrated, and heparin’s inhibitory effects were eliminated by simple washing of the cells. When added directly to the chamber containing chemotactic factor, heparin inhibited the chemotactic activity of ZAS but not that of FMLP, suggesting a direct inhibitory effect against C5a, the principal chemotactic factor in ZAS.Experiments performed with low-molecular-weight heparin, N-desulfated heparin, dextran sulfate, chondroitin sulfate and dextran indicated that the inhibitory effects of heparin on neutrophil chemotaxis are not related to its anticoagulant activity, but probably depend on the degree of sulfation of the heparin molecule.

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