Capsaicin pretreatment attenuates chronic hypoxic pulmonary hypertension

Lai, Yijie; Chen, C. F.; Chien, Chiang‐Ting; Shiao, Hao-Tse; Thacker, Arthur A.; Zhang, H. Q.

doi:10.1016/0034-5687(94)00098-k

Cited by 12 publications

(4 citation statements)

References 23 publications

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“…The finding that brief exposures to moderate degrees of hypoxia can affect lung neprilysin expression is novel. We found that with exposure to hypoxia, lung NEP activity and mRNA content begin to decrease as early as 12 h into the hypoxic exposure and that enzyme activity remains significantly reduced for up to 72 h. Previous work examining the effect of hypoxia on lung neprilysin expression is limited to one preliminary report (2) noting a decrease in NEP activity after 24 h of hypoxia, and one prior study (12) showing that chronic intermittent hypoxia can decrease lung NEP activity. The present study is consistent with those earlier findings.…”

Section: Discussionmentioning

confidence: 68%

Hypoxia decreases lung neprilysin expression and increases pulmonary vascular leak

Carpenter

Stenmark

2001

American Journal of Physiology-Lung Cellular and Molecular Phys

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Although prior studies suggest that hypoxia may increase pulmonary vascular permeability, the mechanisms responsible for that effect remain uncertain. Neprilysin (neutral endopeptidase) is a cell surface metallopeptidase that degrades several vasoactive peptides including substance P and bradykinin. We hypothesized that hypoxia could reduce lung neprilysin expression, leading to increased vascular leak. Weanling rats were exposed to normobaric hypoxia (inspired O(2) fraction = 0.1). Lung neprilysin activity was significantly decreased after 24 and 48 h of hypoxia (P < 0.006). The decrease in enzyme activity was associated with decreased lung neprilysin protein content and decreased lung neprilysin mRNA expression. Immunohistochemistry showed a predominantly perivascular distribution of neprilysin, with clear reductions in neprilysin immunoreactivity after exposure to hypoxia. Exposure to hypoxia for 24 h also caused marked increases in vascular leak (P = 0.008), which were reversed by the administration of recombinant neprilysin. The hypoxia-induced increase in leak was also reversed by substance P and bradykinin receptor antagonists. We conclude that in young rats hypoxia decreases lung neprilysin expression, which contributes to increased pulmonary vascular leak via substance P and bradykinin receptors.

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Section: Discussionmentioning

confidence: 68%

Hypoxia decreases lung neprilysin expression and increases pulmonary vascular leak

Carpenter

Stenmark

2001

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…In 1995, using capsaicin to deplete tachykinins, we found that tachykinins play an important role in chronic hypoxic pulmonary hypertension (14). However, capsaicin depletes several neuropeptides in afferent C-fibers, including bombesin, calcitonin gene-related peptide, somatostatin, and tachykinins (9).…”

Section: Perspectivesmentioning

confidence: 99%

Temporal increase in the reactivity of pulmonary vasculature to substance P in chronically hypoxic rats

Lai

Chu

et al. 2002

American Journal of Physiology-Regulatory, Integrative and Comp

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Temporal increase in the reactivity of pulmonary vasculature to substance P in chronically hypoxic rats. Am J Physiol Regulatory Integrative Comp Physiol 282: R858-R864, 2002; 10.1152 10. /ajpregu.00429.2001ously demonstrated that the pulmonary vascular response to substance P (SP) increased in chronically hypoxic rats. This study explored the temporal increase in reactivity of the pulmonary vascular response to SP and its underlying mechanisms. First, young female Wistar rats were exposed to sea level (SL) or simulated high altitude (HA) for 15 h/day for 3 days, 1 wk, 2 wk, and 4 wk. Lungs were isolated and perfused with 4% bovine serum albumin in Krebs-Henseleit buffer solution. SP (1.5 ϫ 10 Ϫ4 M) induced significant increases in pulmonary arterial pressure (P pa), venous pressure (Pv), capillary pressure (P c), arterial resistance (Ra), and filtration coefficient (K fc) in SL lungs. Increases in Ppa and Ra were significantly augmented in HA lungs, with a temporal increase trend peaking at 2 wk of HA exposure. The selective neurokinin (NK) type 1 (NK 1) receptor antagonist SR-14033 significantly attenuated SP-induced increases in P pa, Pv, Pc, R a, and Kfc in SL lungs. In lungs exposed to HA for 2 wk, SR-14033 suppressed the effect of SP on P pa. Also, chronic hypoxia induced significant increases in NK 1 receptors and NK 1 receptor mRNA, with a temporal trend. We conclude that chronic hypoxia temporally augments SP-induced vascular responses, which are closely associated with increases in NK 1 receptors and gene expression. pulmonary hypertension; tachykinins; gene expression WE PREVIOUSLY DEMONSTRATED in vivo that pulmonary hypertension in chronic hypoxia was closely associated with activation of neurokinin (NK) type 1 (NK 1 ) receptors and that the pulmonary vascular response to substance P (SP) markedly increased in chronically hypoxic rats (2). SP is a member of the tachykinin family, and its action is mediated mainly via the NK 1 receptor and much less via the NK type 2 (NK 2 ) receptor (15). The time course and mechanism(s) of the enhanced pulmonary vascular reactivity to SP during chronic hypoxia are not clear.Therefore, this study was carried out, first, to investigate, using isolated perfused lungs, the temporal trend of this increased pulmonary vascular reactivity to SP in chronically hypoxic rats. In addition, we tested whether the NK 1 receptor antagonist SR-14033 (7) and the NK 2 receptor antagonist SR-48968 (6) prevent the increased vascular reactivity. Finally, we explored whether the NK 1 receptor and its gene expression are altered during the course of hypoxic exposure. MATERIALS AND METHODSThis study was performed in three parts. Part 1 was carried out to explore temporal changes in pulmonary vascular reactivity to SP in chronically hypoxic rats. Part 2 was performed using the antagonist of SP. In part 3, we analyzed the NK 1 receptor and NK1 receptor gene expression.Animal preparation. In part 1, 29 young female Wistar rats weighing 219 Ϯ 3 g were divided into five groups: sea level (SL; n...

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“…Capsaicin is a TRPV1 agonist which over the longer term, produces very substantial downregulation of the TRPV1 and several other TRP receptors. It is interesting, therefore that several studies showed that capsaicin pretreatment over a period of days produces greatly decreased PAH induction [275][276][277].…”

Section: Trp Receptors and Also Intracellularmentioning

confidence: 99%

“…ere are a variety of additional studies showing that elevated intracellular calcium levels have causal roles in PAH [273][274][275][276][277][278][279][280][281][282], including studies using calcium channel blockers [279][280][281][282] to obtain clinical improvement. It follows that agents lowering intracellular calcium may also be useful in therapy.…”

Section: Trp Receptors and Also Intracellularmentioning

confidence: 99%

Pulmonary Hypertension Is a Probable NO/ONOO⁻Cycle Disease: A Review

Pall

2013

ISRN Hypertension

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e NO/ONOO − cycle is a primarily local biochemical/physiological vicious cycle that appears to cause a series of chronic in�ammatory diseases. is paper focuses on whether the cycle causes pulmonary arterial hypertension (PAH) when located in the pulmonary arteries. e cycle involves 12 elements, including superoxide, peroxynitrite (ONOO − ), nitric oxide (NO), oxidative stress, NF-B, in�ammatory cytokines, iNOS, mitochondrial dysfunction, intracellular calcium, tetrahydrobiopterin depletion, NMDA activity, and TRP receptor activity. 10 of the 12 are elevated in PAH (NMDA?, NO?) and 11 have documented causal roles in PAH. Each stressor that initiates cases of PAH acts to raise cycle elements, and may, therefore, initiate the cycle in this way. PAH involves a primarily local mechanism as required by the cycle and the symptoms and signs of PAH are generated by elements of the cycle. Endothelin-1, which acts as a causal factor in PAH, acts as part of the cycle; its synthesis is stimulated by cycle elements, and it, in turn, increases each element of the cycle. is extraordinary �t to the principles of the NO/ONOO − cycle allows one to conclude that PAH is a NO/ONOO − cycle disease, and this �t supports the cycle as a ma�or paradigm of chronic in�ammatory disease.

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Capsaicin pretreatment attenuates chronic hypoxic pulmonary hypertension

Cited by 12 publications

References 23 publications

Hypoxia decreases lung neprilysin expression and increases pulmonary vascular leak

Hypoxia decreases lung neprilysin expression and increases pulmonary vascular leak

Temporal increase in the reactivity of pulmonary vasculature to substance P in chronically hypoxic rats

Pulmonary Hypertension Is a Probable NO/ONOO⁻Cycle Disease: A Review

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Capsaicin pretreatment attenuates chronic hypoxic pulmonary hypertension

Cited by 12 publications

References 23 publications

Hypoxia decreases lung neprilysin expression and increases pulmonary vascular leak

Hypoxia decreases lung neprilysin expression and increases pulmonary vascular leak

Temporal increase in the reactivity of pulmonary vasculature to substance P in chronically hypoxic rats

Pulmonary Hypertension Is a Probable NO/ONOO−Cycle Disease: A Review

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Pulmonary Hypertension Is a Probable NO/ONOO⁻Cycle Disease: A Review