Phosphodiesterase Activity in Intrapulmonary Arteries and Veins of Perinatal Lambs

Okogbule-Wonodi, Adora C.; Ibe, Basil O.; Yue, Brian; Hsu, Sung Po; Raj, J. Usha

doi:10.1006/mgme.1998.2756

Cited by 15 publications

(15 citation statements)

References 23 publications

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“…This augmentation of the iNO-induced pulmonary vasodilation occurred in parallel with an additional rise in transpulmonary cGMP release. Interestingly, the cGMP-specific PDE activity in isolated ovine pulmonary veins has been demonstrated to be more sensitive to inhibition by zaprinast compared with pulmonary arteries (27). In the present study, we found no significant differences in the longitudinal expression of the PDE1 isozymes in the pulmonary vasculature.…”

Section: Discussionsupporting

confidence: 40%

Inhibition of phosphodiesterase 1 augments the pulmonary vasodilator response to inhaled nitric oxide in awake lambs with acute pulmonary hypertension

Evgenov

Busch²,

Evgenov³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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Phosphodiesterase 1 (PDE1) modulates vascular tone and the development of tolerance to nitric oxide (NO)-releasing drugs in the systemic circulation. Any role of PDE1 in the pulmonary circulation remains largely uncertain. We measured the expression of genes encoding PDE1 isozymes in the pulmonary vasculature and examined whether or not selective inhibition of PDE1 by vinpocetine attenuates pulmonary hypertension and augments the pulmonary vasodilator response to inhaled NO in lambs. Using RT-PCR, we detected PDE1A, PDE1B, and PDE1C mRNAs in pulmonary arteries and veins isolated from healthy lambs. In 13 lambs, the thromboxane A(2) analog U-46619 was infused intravenously to increase mean pulmonary arterial pressure to 35 mmHg. Four animals received an intravenous infusion of vinpocetine at incremental doses of 0.3, 1, and 3 mg.kg(-1).h(-1). In nine lambs, inhaled NO was administered in a random order at 2, 5, 10, and 20 ppm before and after an intravenous infusion of 1 mg.kg(-1).h(-1) vinpocetine. Administration of vinpocetine did not alter pulmonary and systemic hemodynamics or transpulmonary cGMP or cAMP release. Inhaled NO selectively reduced mean pulmonary arterial pressure, pulmonary capillary pressure, and pulmonary vascular resistance index, while increasing transpulmonary cGMP release. The addition of vinpocetine enhanced pulmonary vasodilation and transpulmonary cGMP release induced by NO breathing without causing systemic vasodilation but did not prolong the duration of pulmonary vasodilation after NO inhalation was discontinued. Our findings demonstrate that selective inhibition of PDE1 augments the therapeutic efficacy of inhaled NO in an ovine model of acute chemically induced pulmonary hypertension.

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Section: Discussionsupporting

confidence: 40%

Inhibition of phosphodiesterase 1 augments the pulmonary vasodilator response to inhaled nitric oxide in awake lambs with acute pulmonary hypertension

Evgenov

Busch²,

Evgenov³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…In lungs of fetal lambs, immunolabeling and immunoblot analyses show that staining for eNOS and soluble guanylate cyclase is more pronounced in veins than in arteries (156). In fetal and newborn lambs as well as in adult pigs, phosphodiesterase activity is more pronounced in pulmonary arteries than in pulmonary veins (11,104). Thus the functional consequences of the differences in the activities of eNOS, soluble guanylyl cyclase, and phosphodiesterases may be the greater relaxation responses to the nitric oxide-cGMP pathway in pulmonary veins.…”

Section: Vasodilators Of Pulmonary Arteries and Veinsmentioning

confidence: 96%

“…Data are shown as means Ϯ SE; n ϭ 5-9 for each group. *Significant difference between the arteries and veins; P Ͻ 0.05. dation of the cyclic nucleotide in veins of fetal lungs makes them less responsive to EDNO than in neonatal lungs (104).…”

Section: Vasodilators Of Pulmonary Arteries and Veinsmentioning

confidence: 99%

Role of veins in regulation of pulmonary circulation

Gao¹,

Raj²

2005

American Journal of Physiology-Lung Cellular and Molecular Phys

104

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Pulmonary veins have been seen primarily as conduit vessels; however, over the past two decades, a large amount of evidence has accumulated to indicate that pulmonary veins can exhibit substantial vasoactivity. In this review, the role of veins in regulation of the pulmonary circulation, particularly during the perinatal period and under certain pathophysiological conditions, is discussed. In the fetus, pulmonary veins contribute a significant fraction to total pulmonary vascular resistance. At birth, the veins as well as the arteries relax in response to endothelium-derived nitric oxide and dilator prostaglandins, thereby assisting in the fall in pulmonary vascular resistance. These effects are oxygen dependent and modulated by cGMP-dependent protein kinase. Under chronic hypoxic conditions, pulmonary veins undergo remodeling and demonstrate substantial constriction and hypertrophy. In a number of species, including the human, pulmonary veins are also the primary sites of action of certain vasoconstrictors such as endothelin and thromboxane. In various pathological conditions, there is an increased synthesis of these vasoactive agents that may lead to pulmonary venous constriction, increased microvascular pressures for fluid filtration, and formation of pulmonary edema. In conclusion, the significant role of veins in regulation of the pulmonary circulation needs to be appreciated to better prevent, diagnose, and treat lung disease.

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“…It has been demonstrated that basal concentrations, as well as the increase of cGMP in response to NO, were greater in pulmonary veins than in pulmonary arteries of newborn lambs (45). This could be accounted for, at least partly, by a higher activity of cGMP-specific phosphodiesterases, which produced faster hydrolysis and inactivation of cGMP in pulmonary arteries when compared with pulmonary veins (46).…”

Section: Vascular Response To Carbon Monoxidementioning

confidence: 97%

Relaxant Effects of Carbon Monoxide Compared with Nitric Oxide in Pulmonary and Systemic Vessels of Newborn Piglets

et al. 2000

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Nitric oxide (NO) has been implicated in a number of diverse physiologic processes, including regulation of vascular tone. Carbon monoxide (CO) is another endogenously generated diatomic gas that may play an important physiologic role in vascular smooth muscle homeostasis. The purpose of this study was to compare the responses to exogenous NO and CO in isolated vessels (pulmonary arteries, pulmonary veins, and mesenteric arteries) from 12-to 24-h-old and 2-wk-old piglets. Vessels precontracted with the thromboxane A 2 mimetic U46619 (10 Ϫ7 M) relaxed in response to CO (2 ϫ 10 Ϫ6 to 2 ϫ 10 Ϫ4 M) and NO (2 ϫ 10 Ϫ9 to 2 ϫ 10 Ϫ7 M); these effects were not affected by endothelium removal but were completely abolished by the soluble guanylate cyclase inhibitor ODQ (10 Ϫ5 M). In pulmonary arteries, the maximal relaxation to NO increased with postnatal age from 33 Ϯ 4% of the precontraction value to 56 Ϯ 5%, in 12-to 24-h-old and 2-week-old piglets, respectively (p Ͻ 0.01), but the response to CO decreased from 25 Ϯ 3% to 12 Ϯ 1%, respectively (p Ͻ 0.01). The maximal response to CO was greater in pulmonary veins than in pulmonary or mesenteric arteries for both age groups (p Ͻ 0.01). Vasorelaxation induced by endogenous NO (stimulated by acetylcholine) was also greater in pulmonary veins when compared with pulmonary arteries and increased with postnatal age in both vessels. In contrast, no age-related differences were observed in the vasorelaxation induced by the cGMP analog 8-bromo cGMP in pulmonary arteries. When the response to NO was analyzed under three different extracellular O 2 concentrations (PO 2 4.51 Ϯ 0.03, 19.32 Ϯ 0.17, and 86 Ϯ 0.62, kPa), no significant differences were found. However, in the presence of superoxide dismutase (100 U/mL). the response to CO remained unchanged, and the response to NO improved in pulmonary arteries from 2-week-old but not from newborn piglets. In conclusion, both NO and CO relaxed neonatal vessels through soluble guanylate cyclase activation. However, when compared with NO, CO exhibited a poor vasorelaxant activity. Pulmonary vasorelaxation induced by NO increased with postnatal age, whereas that induced by CO decreased. Changes in extracellular oxygen concentration did not alter the pulmonary vascular response to NO. However, the presence of superoxide dismutase improved the response to NO, indicating that oxidant activity limits the vasorelaxant response to NO but not to CO. (Pediatr Res 48: 546-553, 2000) Abbreviations NO, nitric oxide CO, carbon monoxide sGC, soluble guanylate cyclase HO, heme oxygenase SOD, superoxide dismutase U46619, 9,11-dideoxy-11␣,9␣-epoxymethano-prostaglandinNO is known to be involved in the regulation of multiple physiologic processes, including the regulation of pulmonary vascular tone (1). On the other hand, another diatomic gas, CO, traditionally considered as a toxic pollutant, poisons by binding to the iron-containing heme group found in Hb and other enzymes (2). Recently, evidence is accumulating that CO can be also a physiologic endogenous ...

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Phosphodiesterase Activity in Intrapulmonary Arteries and Veins of Perinatal Lambs

Cited by 15 publications

References 23 publications

Inhibition of phosphodiesterase 1 augments the pulmonary vasodilator response to inhaled nitric oxide in awake lambs with acute pulmonary hypertension

Inhibition of phosphodiesterase 1 augments the pulmonary vasodilator response to inhaled nitric oxide in awake lambs with acute pulmonary hypertension

Role of veins in regulation of pulmonary circulation

Relaxant Effects of Carbon Monoxide Compared with Nitric Oxide in Pulmonary and Systemic Vessels of Newborn Piglets

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