Endothelial alterations during inhaled NO in lambs with pulmonary hypertension: implications for rebound hypertension

Ross, Gregory A.; Oishi, Peter; Azakie, Anthony; Fratz, Sohrab; Fitzgerald, Robert D.; Johengen, Michael J.; Harmon, Cynthia; Hendricks‐Muñoz, Karen D.; Xu, Jie; Black, Stephen M.; Fineman, Jeffrey R.

doi:10.1152/ajplung.00144.2004

Cited by 20 publications

(29 citation statements)

References 45 publications

(68 reference statements)

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“…In addition, these lambs with pulmonary hypertension demonstrated attenuated responses to inhaled NO compared with age-matched controls. Furthermore, decreased sGC during inhaled NO therapy has been implicated in the pathogenesis of rebound pulmonary hypertension in a lamb model (44). Thus it appears that pulmonary expression of sGC is developmentally regulated and may contribute to changes seen in vasoreactivity to NO in the neonate.…”

Section: Discussionmentioning

confidence: 96%

Maturational changes in the regulation of pulmonary vascular tone by nitric oxide in neonatal rats

Chicoine¹,

Paffett²,

Girton³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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September 7, 2007; doi:10.1152/ajplung.00235.2006 is an important regulator of vasomotor tone in the pulmonary circulation. We tested the hypothesis that the role NO plays in regulating vascular tone changes during early postnatal development. Isolated, perfused lungs from 7-and 14-day-old Sprague-Dawley rats were studied. Baseline total pulmonary vascular resistance (PVR) was not different between age groups. The addition of KCl to the perfusate caused a concentration-dependent increase in PVR that did not differ between age groups. However, the nitric oxide synthase (NOS) inhibitor N -nitro-L-arginine augmented the K ϩ -induced increase in PVR in both groups, and the effect was greater in lungs from 14-day-old rats vs. 7-day-old rats. Lung levels of total endothelial, inducible, and neuronal NOS proteins were not different between groups; however, the production rate of exhaled NO was greater in lungs from 14-day-old rats compared with those of 7-dayold rats. Vasodilation to 0.1 M of the NO donor spermine NONOate was greater in 14-day lungs than in 7-day lungs, and lung levels of both soluble guanylyl cyclase and cGMP were greater at 14 days than at 7 days. Vasodilation to 100 M of the cGMP analog 8-(4-chlorophenylthio)guanosine-3Ј,5Ј-cyclic monophosphate was greater in 7-day lungs than in 14-day lungs. Our results demonstrate that the pulmonary vascular bed depends more on NO production to modulate vascular tone at 14 days than at 7 days of age. The observed differences in NO sensitivity may be due to maturational increases in soluble guanylyl cyclase protein levels. nitric oxide synthase; pulmonary vascular resistance; isolated perfused lungs; soluble guanylyl cyclase; guanosine-3Ј,5Ј-cyclic monophosphate NITRIC OXIDE (NO) facilitates the transition from the highresistance low-flow fetal pulmonary circulation to the lowresistance high-flow pulmonary circulation found shortly after birth (1,15,35). Studies examining the ontogeny of endothelial nitric oxide synthase (eNOS) in the developing rat lung found that eNOS protein levels and mRNA levels are low in early gestation, increase severalfold in late gestation, and are greatest at the time of birth (29,38,49). Following birth, there is a decrease of eNOS protein and mRNA to the low levels found in the adult rat. A similar pattern of eNOS expression has also been described in the developing porcine lung by Hislop et al. (25) and in the developing ovine lung by Halbower et al. (23).Thus it is likely that elevated neonatal eNOS facilitates the transition from the high-resistance fetal pulmonary circulation to the low-resistance postnatal pulmonary circulation. Both, in vivo and in vitro studies have shown that eNOS expression is upregulated by several factors, including shear stress (39) and oxygen exposure (19,31,34). Furthermore, we have found that the effect of chronic hypoxia on eNOS expression is different in the neonatal vs. the adult rat lung (13,40). In the neonatal rat lung, eNOS protein levels decreased with chronic hypoxic exposure, whereas in the...

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Section: Discussionmentioning

confidence: 96%

Maturational changes in the regulation of pulmonary vascular tone by nitric oxide in neonatal rats

Chicoine¹,

Paffett²,

Girton³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Inhaled NO is normally administered in the setting of increased pulmonary vascular tone. The signaling described in the intact lamb may differ in lambs with preexisting pulmonary hypertension, for example (25). In fact, H 2 O 2 may be a pulmonary vasoconstrictor in certain disease states (18,38); under these conditions PEG-SOD administration may increase H 2 O 2 production and thereby worsen rebound pulmonary hypertension.…”

Section: Discussionmentioning

confidence: 99%

Inhaled nitric oxide induced NOS inhibition and rebound pulmonary hypertension: a role for superoxide and peroxynitrite in the intact lamb

Oishi¹,

Grobe²,

Benavidez³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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Previous in vivo studies indicate that inhaled nitric oxide (NO) decreases nitric oxide synthase (NOS) activity and that this decrease is associated with significant increases in pulmonary vascular resistance (PVR) upon the acute withdrawal of inhaled NO (rebound pulmonary hypertension). In vitro studies suggest that superoxide and peroxynitrite production during inhaled NO therapy may mediate these effects, but in vivo data are lacking. The objective of this study was to determine the role of superoxide in the decrease in NOS activity and rebound pulmonary hypertension associated with inhaled NO therapy in vivo. In control lambs, 24 h of inhaled NO (40 ppm) decreased NOS activity by 40% (P<0.05) and increased endothelin-1 levels by 64% (P<0.05). Withdrawal of NO resulted in an acute increase in PVR (60.7%, P<0.05). Associated with these changes, superoxide and peroxynitrite levels increased more than twofold (P<0.05) following 24 h of inhaled NO therapy. However, in lambs treated with polyethylene glycol-conjugated superoxide dismutase (PEG-SOD) during inhaled NO therapy, there was no change in NOS activity, no increase in superoxide or peroxynitrite levels, and no increase in PVR upon the withdrawal of inhaled NO. In addition, endothelial NOS nitration was 18-fold higher (P<0.05) in control lambs than in PEG-SOD-treated lambs following 24 h of inhaled NO. These data suggest that superoxide and peroxynitrite participate in the decrease in NOS activity and rebound pulmonary hypertension associated with inhaled NO therapy. Reactive oxygen species scavenging may be a useful therapeutic strategy to ameliorate alterations in endogenous NO signaling during inhaled NO therapy.

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“…The inhaled NO lamb model has been reported previously (41,46). In this lamb model, inhaled NO [40 parts per million (ppm)] was delivered in nitrogen in the inspiratory limb of the ventilator (Inovent; Ohmeda, Liberty, NJ) and continued for 24 h. The inspired concentrations of NO and nitrogen dioxide were continuously quantified by electrochemical methodology (Inovent).…”

Section: Lamb Model Of Inhaled No Deliverymentioning

confidence: 99%

GTP cyclohydrolase I expression is regulated by nitric oxide: role of cyclic AMP

Kumar¹,

Sun²,

Sharma³

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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Our previous studies have demonstrated that nitric oxide (NO) leads to nitric oxide synthase (NOS) uncoupling and an increase in NOS-derived superoxide. However, the cause of this uncoupling has not been adequately resolved. The pteridine cofactor tetrahydrobiopterin (BH(4)) is a critical determinant of endothelial NOS (eNOS) activity and coupling, and GTP cyclohydrolase I (GCH1) is the rate-limiting enzyme in its generation. Thus the initial purpose of this study was to determine whether decreases in BH(4) could underlie, at least in part, the NO-mediated uncoupling of eNOS we have observed both in vitro and in vivo. Initially we evaluated the effect of inhaled NO levels on GCH1 expression and BH(4) levels in the intact lamb. Contrary to our hypothesis, we found that there was a significant increase in both plasma BH4 levels and peripheral lung GCH1 protein levels. Furthermore, in vitro, we found that exposure to the NO donor spermine NONOate (SPNONO) led to an increase in GCH1 protein and BH(4) levels in both COS-7 and pulmonary arterial endothelial cells. However, SPNONO treatment also caused a significant increase in phospho-cAMP response element binding protein (CREB) levels, as detected by Western blot analysis, and significantly increased cAMP levels, as detected by enzyme immunoassay. Furthermore, utilizing GCH1 promoter fragments fused to a luciferase reporter gene, we found that GCH1 promoter activity was enhanced by SPNONO in a CREB-dependent manner, and electromobility shift assays revealed an NO-dependent increase in the nuclear binding of CREB. These data suggest that NO increases BH(4) levels through a cAMP/CREB-mediated increase in GCH1 transcription and that the eNOS uncoupling associated with exogenous NO does not involved reduced BH(4) levels.

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Endothelial alterations during inhaled NO in lambs with pulmonary hypertension: implications for rebound hypertension

Cited by 20 publications

References 45 publications

Maturational changes in the regulation of pulmonary vascular tone by nitric oxide in neonatal rats

Maturational changes in the regulation of pulmonary vascular tone by nitric oxide in neonatal rats

Inhaled nitric oxide induced NOS inhibition and rebound pulmonary hypertension: a role for superoxide and peroxynitrite in the intact lamb

GTP cyclohydrolase I expression is regulated by nitric oxide: role of cyclic AMP

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