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Phosphodiesterase activity in intrapulmonary arteries and veins of perinatal lambs
A C Okogbule-Wonodi1, B O Ibe, B W Yue
1UCLA School of Medicine, Harbor-UCLA Medical Center, Torrance, California, 90509, USA.
Insights
Pulmonary vascular tone reduction during transition to newborn life involves cyclic nucleotides. Phosphodiesterase hydrolysis rates of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) were slower in newborn lamb lung vessels compared to fetal.
Area of Science:
- Pulmonary vascular physiology
- Neonatal transition
- Intracellular signaling
Background:
- Transition from fetal to newborn life requires decreased pulmonary vascular tone.
- This transition is mediated by intracellular second messengers cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP).
- Phosphodiesterases (PDEs) regulate intracellular levels of cGMP and cAMP by catalyzing their hydrolysis.
Purpose of the Study:
- To compare the rates of PDE-catalyzed hydrolysis of cGMP and cAMP in fetal and newborn lamb intrapulmonary vessels.
- To investigate potential differences in PDE activity that may contribute to the regulation of pulmonary vascular tone during neonatal transition.
Main Methods:
- Intrapulmonary vessels (second to sixth generations) were dissected from fetal and newborn lambs.
- Cytosol was prepared, and PDE activity was measured using a radiometric assay.
- Hydrolysis rates of exogenous cGMP and cAMP were determined at 30°C.
Main Results:
- Rates of cGMP hydrolysis were significantly higher in fetal lung arteries and veins compared to newborn lambs.
- Rates of cAMP hydrolysis were also higher in fetal lung arteries and veins than in newborn lambs.
- Inhibition studies with zaprinast (cGMP-specific) and rolipram (cAMP-specific) indicated greater PDE inhibition in veins of both fetal and newborn lambs.
Conclusions:
- Hydrolysis rates of cGMP and cAMP by PDEs are faster in fetal lamb lung vessels than in newborn lambs.
- Slower hydrolysis in newborn vessels may lead to greater accumulation of cGMP and cAMP, particularly in veins.
- This accumulation could contribute to reduced pulmonary vascular tone in newborn lambs.
Abstract:
The transition from fetal to newborn life is marked by a reduction in pulmonary vascular tone mediated by the intracellular second messengers, cGMP and cAMP. We have compared the rates of phosphodiesterase (PDE)-catalyzed hydrolysis of cGMP and cAMP in intrapulmonary vessels of fetal (146 +/- 2 days gestation) and newborn (3-7-day-old) lambs, each n = 6. Lung vessels of second to sixth generations were dissected and cytosol was prepared by differential centrifugation. PDE activity in cytosol was determined by radiometric assay of the hydrolysis of exogenous nucleotides at 30 degrees C for 10 min. Rates of hydrolysis (pmol/min/mg protein) of cGMP were 225 +/- 38 in fetal arteries and different from 151 +/- 7 in veins. In newborn vessels, the rates were 155 +/- 49 and 63 +/- 13 in arteries and veins, respectively. Rates of cAMP hydrolysis by the fetus were 80 +/- 11 in arteries and 45 +/- 16 veins. In newborn lambs the rates were 69 +/- 10 in arteries and different from 18 +/- 4 in veins. Inhibition of PDE activity by zaprinast, a cGMP-specific PDE inhibitor, and rolipram, a cAMP-specific PDE inhibitor, was more in veins of fetal and newborn lambs. Our data show that rates of hydrolysis of the cyclic nucleotides were faster in fetal vessels than in the newborn. We speculate that this would result in a greater accumulation of the cyclic nucleotides in newborn vessels, particularly the veins, and therefore endow the veins with less vascular tone.