Potentiation of cyclic AMP‐mediated vasorelaxation by phenylephrine in pulmonary arteries of the rat

Priest, Rachel M.; Hucks, D.; Ward, Jeremy P. T.

doi:10.1038/sj.bjp.0702525

Cited by 19 publications

(13 citation statements)

References 27 publications

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“…As it relates to vascular tone, cAMP is an intracellular second messenger that usually causes pulmonary vasodilation (12,28); therefore, cAMP downregulation can lead to increased vasoconstriction. However, ET-1-induced pulmonary vasoconstriction was significantly enhanced in PA rings from p75 Ϫ/Ϫ mice; that is, p75 NTR exerts an inhibitory effect on ET-1-mediated PA contraction.…”

Section: P75mentioning

confidence: 99%

p75 neurotrophin receptor regulates agonist-induced pulmonary vasoconstriction

Xu¹,

Remillard²,

Sachs³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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JXJ. p75 neurotrophin receptor regulates agonist-induced pulmonary vasoconstriction. Am J Physiol Heart Circ Physiol 295: H1529-H1538, 2008. First published August 8, 2008 doi:10.1152/ajpheart.00115.2008.-A member of the TNF receptor family, the p75 neurotrophin receptor (p75 NTR ) has been previously shown to play a role in the regulation of fibrin deposition in the lung. However, the role of p75 NTR in the regulation of pulmonary vascular tone in the lung is unknown. In the present study, we evaluated the expression of p75 NTR in mouse pulmonary arteries and the putative role of p75 NTR in modulating pulmonary vascular tone and agonist responsiveness using wild-type (WT) and p75 NTR knockout (p75 Ϫ/Ϫ ) mice. Our data indicated that p75 NTR is expressed in both smooth muscle and endothelial cells within the pulmonary vascular wall in WT mice. Pulmonary artery rings from p75 Ϫ/Ϫ mice exhibited significantly elevated active tension due to endothelin-1-mediated Ca 2ϩ influx. Furthermore, the contraction due to capacitative Ca 2ϩ entry (CCE) in response to phenylephrine-mediated active depletion of intracellular Ca 2ϩ stores was significantly enhanced compared with WT rings. The contraction due to CCE induced by passive store depletion, however, was comparable between WT and p75 Ϫ/Ϫ rings. Active tension induced by serotonin, U-46619 (a thromboxane A 2 analog), thrombin, 4-aminopyridine (a K ϩ channel blocker), and high extracellular K ϩ in p75 Ϫ/Ϫ rings was similar to that in WT rings. Deletion of p75 NTR did not alter pulmonary vasodilation to sodium nitroprusside (a nitric oxide donor). These data suggest that intact p75 NTR signaling may play a role in modulating pulmonary vasoconstriction induced by endothelin-1 and by active store depletion. mouse; pulmonary artery; pharmacology; vasoconstriction; store depletion NEUROTROPHINS are unique growth factors that interact with two separate types of transmembrane receptors: tropomyosin receptor kinases (Trk) and the p75 neurotrophin receptor (p75 NTR ), with the latter being a member of the TNF superfamily of membrane receptors (38). A wealth of in vitro experiments has shown that neurotrophins and pro-neurotrophins can induce apoptosis via p75 NTR (15). In vivo, p75 NTR expression and induction are associated with increased apoptosis in vascular smooth muscle cells (SMCs) from atherosclerotic lesions (15, 41) as well as in promoting apoptosis in oligodendrocytes and neurons in injury models in the nervous system (1, 2, 26). Conversely, Chu et al. (9)

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Section: P75mentioning

confidence: 99%

p75 neurotrophin receptor regulates agonist-induced pulmonary vasoconstriction

Xu¹,

Remillard²,

Sachs³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…The presence of a functioning endothelium was determined by application of acetylcholine (ACh; 10 mM) following agonist induced contraction. After 60 min equilibration the arteries were subjected to a standard run up procedure of three 4 min exposures to PSS containing high K + (KPSS, 80 mM [K + ], equimolar substitution for NaCl) (Leach et al, 1992;Priest et al, 1999). Arteries producing less than 1 mN mm 71 were discarded.…”

Section: Tissue Preparationsmentioning

confidence: 99%

Critical dependence of the NO‐mediated component of cyclic AMP‐induced vasorelaxation on extracellular L‐arginine in pulmonary arteries of the rat

Hucks

Ward

2000

British J Pharmacology

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1 A component of isoprenaline-mediated vasorelaxation in pulmonary arteries is mediated by nitric oxide (NO). We examined the eects of physiological concentrations (4400 mM) of L-arginine on isoprenaline-induced relaxation in rat pulmonary arteries, and following inhibition of L-arginine uptake with L-lysine. In addition, we examined the role of the endothelium, and whether L-arginine aected acetylcholine (ACh)-induced relaxation. 2 Isoprenaline-induced relaxation was potentiated by 400 mM L-arginine in pulmonary arteries; maximum relaxation was increased from 83+4% of initial tone to 94+4% (P50.05). L-lysine (10 mM) not only abolished the potentiation by L-arginine, but suppressed relaxation compared to control (70+4%, P50.05), even in the absence of L-arginine added to the bath. Blockade of NO synthase with 100 mM L-NMMA or removal of the endothelium inhibited isoprenaline-induced relaxation to the same extent as L-lysine, and under these conditions the presence or absence of 400 mM L-arginine made no dierence. L-lysine had no additional eect when applied in combination with L-NMMA. 3 The eect of extracellular L-arginine was concentration dependent, with an apparent EC 50 of *1±7 mM. 4 Relaxation to the membrane permeant cyclic AMP analogue CPT cyclic AMP was also potentiated by L-arginine and inhibited by L-lysine. There was however no dierence in relaxation induced by acetylcholine (ACh) in the presence of L-arginine or L-lysine, and isoprenaline-induced relaxation of mesenteric arteries was unaected by L-arginine or L-lysine. 5 These results strongly suggest that extracellular L-arginine is critically important for development of the NO-and endothelium-dependent component of cyclic AMP-induced vasorelaxation in rat pulmonary arteries, but is not required for ACh-induced relaxation. As the apparent EC 50 for this eect is in the low micromolar range it is likely to be fully activated in vivo, as plasma L-arginine is 4150 mM.

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“…pulmonary hypertension; vascular smooth muscle; phosphodiesterase 5; pulmonary vasodilator INTRACELLULAR CYCLIC NUCLEOTIDE [cAMP and guanosine 3Ј,5Ј-cyclic monophosphate (cGMP)] concentration is implicated in the control of the vascular smooth muscle tone including in the pulmonary artery (PA) (3, 9). Agents elevating cAMP or cGMP concentration relax precontracted PA (35,36,38). For instance, the endothelium-derived factor nitric oxide (NO) induces a dose-dependent increase in cGMP concentration and a step-wise relaxation of PA (30,45).…”

mentioning

confidence: 99%

“…Agents elevating cAMP or cGMP concentration relax precontracted PA (35,36,38). For instance, the endothelium-derived factor nitric oxide (NO) induces a dose-dependent increase in cGMP concentration and a step-wise relaxation of PA (30,45).…”

mentioning

confidence: 99%

Sildenafil alters calcium signaling and vascular tone in pulmonary arteries from chronically hypoxic rats

Pauvert

Bonnet²,

Rousseau³

et al. 2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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Pauvert, Olivier, Sébastien Bonnet, Eric Rousseau, Roger Marthan, and Jean-Pierre Savineau. Sildenafil alters calcium signaling and vascular tone in pulmonary arteries from chronically hypoxic rats. Am J Physiol Lung Cell Mol Physiol 287: L577-L583, 2004. First published May 21, 2004 10.1152/ajplung.00449.2003.-Sildenafil, a potent type 5 nucleotide-dependent phosphodiesterase (PDE) inhibitor, has been recently proposed as a therapeutic tool to treat or prevent pulmonary artery hypertension (PAHT). We thus studied the effect of sildenafil on both the calcium signaling of isolated pulmonary artery smooth muscle cells (PASMCs) and the reactivity of pulmonary artery (PA) obtained from chronic hypoxia (CH)-induced pulmonary hypertensive rats compared with control (normoxic) rats. CH rats were maintained in an hypobaric chamber (50.5 kPa) for 3 wk leading to full development of PAHT. Intracellular calcium concentration ([Ca 2ϩ ]i) was measured in PASMCs loaded with the calcium fluorophore indo 1. Unlike in control rats, sildenafil (10 -100 nM) decreased the resting [Ca 2ϩ ]i value in PASMCs obtained from CH rats. In PASMCs from both control and CH rats, sildenafil concentration dependently inhibited the [Ca 2ϩ ]i response induced by G-coupled membrane receptor agonists such as angiotensin II and phenylephrine but had no effect on the amplitude of the [Ca 2ϩ ]i response induced by caffeine. Sildenafil (0.1 nM-1 M) concentration dependently reduced basal PA tone that is present in CH rats and relaxed PA rings precontracted with phenylephrine in both control and CH rats. These data show that sildenafil is a potent pulmonary artery relaxant in CH rats and that it normalizes CH-induced increases in resting [Ca 2ϩ ]i and basal tone. Consequently, pharmacological inhibition of sildenafil-sensitive PDE5 downregulates the Ca 2ϩ signaling pathway involved in this model of pulmonary hypertension. pulmonary hypertension; vascular smooth muscle; phosphodiesterase 5; pulmonary vasodilator INTRACELLULAR CYCLIC NUCLEOTIDE [cAMP and guanosine 3Ј,5Ј-cyclic monophosphate (cGMP)] concentration is implicated in the control of the vascular smooth muscle tone including in the pulmonary artery (PA) (3, 9). Agents elevating cAMP or cGMP concentration relax precontracted PA (35,36,38). For instance, the endothelium-derived factor nitric oxide (NO) induces a dose-dependent increase in cGMP concentration and a step-wise relaxation of PA (30,45). In smooth muscle cells, concentration of cGMP is mainly dependent on the balance between the production by guanylate cyclase and the degradation by phosphodiesterases (PDEs), which represent the unique degradation pathway for these intracellular compounds (34, 44). As a consequence, PDE activity is also implicated in the control of smooth muscle tone, and PDE inhibition relaxes smooth muscle (21,41,46). In PA from rats and humans, four types of PDE (PDE1, 3, 4, and 5) have been identified (23,31,34,36). Hence, the pharmacological modulation of PDE activity (e.g., using selective PDE inhibitor...

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Potentiation of cyclic AMP‐mediated vasorelaxation by phenylephrine in pulmonary arteries of the rat

Cited by 19 publications

References 27 publications

p75 neurotrophin receptor regulates agonist-induced pulmonary vasoconstriction

p75 neurotrophin receptor regulates agonist-induced pulmonary vasoconstriction

Critical dependence of the NO‐mediated component of cyclic AMP‐induced vasorelaxation on extracellular L‐arginine in pulmonary arteries of the rat

Sildenafil alters calcium signaling and vascular tone in pulmonary arteries from chronically hypoxic rats

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