Purine nucleotides contribute to pulmonary vasodilation caused by birth-related stimuli in the ovine fetus.
We investigated the hypothesis that the purine nucleotides ATP and adenosine mediate the pulmonary vasodilation that occurs at birth in fetal lambs. We instrumented 44 fetal lambs to measure left pulmonary arterial pressure and flow. In control studies, we investigated the effects of sequential ventilation with 10, 50, and 100% O2 on fetal pulmonary arterial pressure and flow and pulmonary vascular resistance (PVR). We also measured the blood and plasma ATP levels in the pulmonary artery and left atrium in the control studies. In three separate groups of studies, we investigated the effects of 8-phenyltheophylline, an adenosine-receptor antagonist, and cibacron blue, an inhibitor of ATP-sensitive P2y receptors, given alone or in combination, on the response of PVR to sequential ventilation. Fetal arterial PO2 increased during ventilation with 50 and 100% O2 but not with 10% O2. Ventilation with 10% O2 caused a 4-fold increase in pulmonary blood flow and a 10-fold decrease in PVR. Ventilation with 50 and 100% O2 caused a 7-fold increase in pulmonary blood flow and a 20-fold decrease in PVR. Blood and plasma ATP levels in the pulmonary artery and blood ATP levels in the left atrium increased significantly during ventilation with 50 and 100% O2 but not with 10% O2. Pretreatment of animals with 8-phenyltheophylline attenuated the increase in pulmonary flow and decrease in PVR caused by ventilation at all fractions of inspired O2 (FIO2 levels). Pretreatment of animals with cibacron blue attenuated pulmonary vasodilation at 50 and 100% FIO2. Combined treatment with 8-phenyltheophylline and cibacron blue caused complete inhibition of the decrease in PVR in response to ventilation at the three FIO2 levels. Incubation of fetal red blood cells in vitro with 100% O2 caused an increase in ATP production. An increase in arterial PO2 in the fetus causes an increase in blood ATP levels, and an inhibition of ATP receptors attenuates the O2-induced decrease in PVR. Adenosine-receptor inhibition attenuates both ventilation- and O2-induced changes in PVR. Increased synthesis and release of ATP plays a major role in causing pulmonary vasodilation in response to birth-related stimuli in the ovine fetus.
Konduri
G G
GG
Department of Pediatrics, Children's Hospital of Michigan, Hutzel Hospital, Detroit, USA.
Mital
S
S
Gervasio
C T
CT
Rotta
A T
AT
Forman
K
K
D000241:Adenosine / Q000097:blood; D000255:Adenosine Triphosphate / Q000097:blood; D000818:Animals; D001784:Blood Gas Analysis; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D006863:Hydrogen-Ion Concentration; D007743:Labor, Obstetric; D010100:Oxygen / Q000378:metabolism; D011247:Pregnancy; D011652:Pulmonary Circulation; D011685:Purine Nucleotides / Q000378:metabolism*; D058915:Purinergic P1 Receptor Antagonists; D058919:Purinergic P2 Receptor Antagonists; D012119:Respiration; D012756:Sheep; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D014227:Triazines / Q000494:pharmacology; D014664:Vasodilation
D011685:Purine Nucleotides; D058915:Purinergic P1 Receptor Antagonists; D058919:Purinergic P2 Receptor Antagonists; D014227:Triazines; C012842:Cibacron Blue F 3GA; D000255:Adenosine Triphosphate; D013806:Theophylline; C028322:8-phenyltheophylline; D000241:Adenosine; D010100:Oxygen