Chronic pulmonary hypertension increases fetal lung cGMP phosphodiesterase activity

Hanson, Kimberly A.; Ziegler, James W.; Rybalkin, Sergei D.; Miller, Jim; Abman, Steven H.; Clarke, William R.

doi:10.1152/ajplung.1998.275.5.l931

Cited by 83 publications

(79 citation statements)

References 27 publications

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“…The greater vasodilatation with sildenafil observed in the myographic studies in the HLNB suggests that chronic hypoxia induces a higher function of PDE5, a phenomenon supported by previous reports (15)(16)(17). Although there was a tendency to increase PDE5 mRNA in HLNB, we did not find significant differences between the HLNB and LLNB.…”

Section: Discussionsupporting

confidence: 87%

“…Although there was a tendency to increase PDE5 mRNA in HLNB, we did not find significant differences between the HLNB and LLNB. Therefore, the different myographic responses to sildenafil may be explained by a higher PDE5 protein expression and/or activity in our pulmonary hypertensive lambs (15,16). However, we did not determine the protein expression or activity of the enzyme to ascertain this mechanism.…”

Section: Discussionmentioning

confidence: 92%

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Sildenafil Reverses Hypoxic Pulmonary Hypertension in Highland and Lowland Newborn Sheep

et al. 2008

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Perinatal exposure to chronic hypoxia induces sustained hypertension and structural and functional changes in the pulmonary vascular bed. We hypothesized that highland newborn lambs (HLNB, 3600 m) have a higher pulmonary arterial pressure (PAP) due in part to a higher activity/expression of phosphodiesterase 5 (PDE5). We administered sildenafil, a PDE5 inhibitor, during basal and hypoxic conditions in the pulmonary hypertensive HLNB and compared them to lowland newborn lambs (LLNB, 580 m). Additionally, we compared the vasodilator responses to sildenafil in isolated small pulmonary arteries and the PDE5 mRNA expression and evaluated the vascular remodeling by histomorphometric analysis in these newborn lambs. Under basal conditions, HLNB had a higher PAP and cardiac output compared with LLNB. Sildenafil decreased the PAP during basal conditions and completely prevented the PAP increase during hypoxia in both groups. HLNB showed a greater contractile capacity and a higher maximal dilation to sildenafil. PDE5 mRNA expression did not show significant differences between HLNB and LLNB. The distal pulmonary arteries showed an increased wall thickness in HLNB. Our results showed that HLNB are more sensitive to sildenafil and therefore could be useful for treatment of pulmonary hypertension in high-altitude neonates. E xposure of lowland species to high altitude produces pulmonary vasoconstriction and remodeling resulting in pulmonary hypertension. Previously, we have shown that newborn lambs gestated and born at high altitude have an increased pulmonary arterial pressure (PAP) and vascular reactivity compared with those born at sea level (1). Appropriate increases in pulmonary vascular resistance (PVR) are adaptive, matching pulmonary perfusion to the reduced oxygenation. However, excessive increases in PVR, if maintained over time, lead to structural changes of the pulmonary vasculature, such as an increase in vascular muscle cells and fibrosis in the adventitia of the vessel (2-4). In newborns, either at altitude or sea level, this pulmonary arterial hypertension is ultimately due to a failure in the regulation of the PVR at birth by mechanisms not fully understood, which implies an imbalance in vasoconstrictors and vasodilators, leading to hypoxemia and sustained pulmonary hypertension. Indeed, one of the major causes of persistent pulmonary hypertension in the newborn is chronic hypoxia in utero (5) and is characterized by hypoxemia that is frequently refractory to conventional management, with a mortality rate near 10% (6). The incidence of this syndrome may be higher at high altitudes (7), an important issue considering that more than 140 million people worldwide live at more than 2500 m (8). Moreover, it has been suggested that during chronic hypoxia, production of vasoconstrictors is enhanced, while synthesis of vasodilators is reduced in the lung (9,10). A mechanism that favors this high vascular tone is the hydrolysis of cyclic guanosine monophosphate (cGMP) by phosphodiesterases (PDEs). The major ...

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 92%

Sildenafil Reverses Hypoxic Pulmonary Hypertension in Highland and Lowland Newborn Sheep

et al. 2008

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“…[55][56][57][58][59][60][61] Phosphodiesterase type 5 is strongly expressed in the lung, and phosphodiesterase type 5 gene expression and activity are increased in chronic PH. 62,63 Several phosphodiesterase type 5 inhibitors, including dipyridamole, E4021, zaprinast, DMPPO, and others, cause potent pulmonary vasodilation in animal models [55][56][57][58][59]61 of acute and chronic PH.…”

Section: Rationalementioning

confidence: 99%

Medical Therapy For Pulmonary Arterial Hypertension

Badesch

Abman

Ahearn

et al. 2004

Chest

546

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“…PDE5 is a cGMP-specific PDE isoform whereas PDE1 can hydrolyze both cAMP and cGMP, and both isoforms are abundant in the lung (11)(12)(13)(14). PDE5 activity is increased in pulmonary arteries from rats with chronic hypoxia-induced pulmonary hypertension (14) and in lambs with pulmonary hypertension after in utero aortopulmonary vascular graft placement (15) or with PPHN induced by compression of the ductus arteriosus in utero (16). Moreover, the specific PDE5 inhibitor sildenafil has been recently reported to be a selective pulmonary vasodilator useful for the treatment of adult pulmonary hypertension (17)(18)(19).…”

mentioning

confidence: 99%

Postnatal Maturation of Phosphodiesterase 5 (PDE5) in Piglet Pulmonary Arteries: Activity, Expression, Effects of PDE5 Inhibitors, and Role of the Nitric Oxide/Cyclic GMP Pathway

et al. 2004

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After birth and during the first days of extrauterine life, pulmonary arterial pressure is progressively reduced to reach the adult values. We hypothesized that changes in PDE5 activity might be involved in the pulmonary postnatal maturation of the nitric oxide (NO)/cGMP pathway. The PDE5 inhibitor sildenafil produced vasorelaxant responses in isolated pulmonary arteries. These effects were similar in newborn (3-18 h) and 2-wk-old piglets, unchanged by endothelium removal, and markedly inhibited by the soluble guanylyl cyclase inhibitor ODQ. The peak of the transient vasorelaxant response to NO gas increased with postnatal age but was unaffected by PDE inhibition. However, the duration of the response to NO was significantly increased. The vasorelaxant response to sodium nitroprusside was potentiated by sildenafil in both age groups. The PDE5 inhibitors dipyridamole and zaprinast, produced qualitatively similar effects but with lower potency. Both total and PDE5-dependent cGMP hydrolytic activity and PDE5 protein expression increased with postnatal age. All these results suggest that PDE5 is a key regulator of NO-induced vasodilation in the postnatal pulmonary arteries. PDE5 inhibition is able to produce pulmonary vasodilation even in the absence of a functional endothelium and potentiates the vasorelaxant response to exogenous NO and nitroprusside. However, PDE5 is not responsible for the maturational increase of NO bioactivity during the first days of extrauterine life. Successful adaptation of the newborn to postnatal conditions requires a dramatic transition of the pulmonary circulation. During the first minutes of extrauterine life, as the lung becomes responsible for blood oxygenation and there is a marked reduction in pulmonary vascular resistance (1,2). A second phase of pulmonary vascular resistance reduction takes place over the first 2 wk of extrauterine life in pigs and humans to reach the pulmonary pressure values characteristic of the adult (1,3). Several groups have consistently reported a low activity of the NO/cGMP pathway for smooth muscle vasodilation during the first hours of extrauterine life in rabbit, lamb, and piglet pulmonary arteries (4 -8). This NO activity increases during the first 2 wk in parallel with the postnatal reduction in pulmonary arterial pressure. Some infants fail to achieve or sustain the normal decrease in pulmonary vascular resistance at birth, which leads to severe respiratory distress and hypoxemia, referred to as PPHN (1,9).cGMP is a key second messenger in the regulation of vascular smooth muscle tone (10) whose intracellular concentrations are tightly controlled by the balance between its synthesis and hydrolysis. cGMP is synthesized by a family of guanylyl cyclases (10)

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Chronic pulmonary hypertension increases fetal lung cGMP phosphodiesterase activity

Cited by 83 publications

References 27 publications

Sildenafil Reverses Hypoxic Pulmonary Hypertension in Highland and Lowland Newborn Sheep

Sildenafil Reverses Hypoxic Pulmonary Hypertension in Highland and Lowland Newborn Sheep

Medical Therapy For Pulmonary Arterial Hypertension

Postnatal Maturation of Phosphodiesterase 5 (PDE5) in Piglet Pulmonary Arteries: Activity, Expression, Effects of PDE5 Inhibitors, and Role of the Nitric Oxide/Cyclic GMP Pathway

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