Characterization of purine receptors in fetal lamb pulmonary circulation

Abstract

Activation of P1 purinergic receptors by adenosine and P2 receptors by ATP plays an important role in pulmonary vasodilation that occurs at birth in fetal lambs. Purine receptors occur in several subtypes, and the effects of their stimulation vary with the specific type involved. We characterized the subtypes of P1 receptors in fetal lamb pulmonary circulation at 128-132 d gestation by investigating the effects of the following adenosine analogs: N6-cyclopentyl adenosine (A1 selective), 2-phenylaminoadenosine (A2 selective), 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (A(2A) selective), N6-benzyl-5'-N-ethylcarboxamidoadenosine (A3 selective), and adenosine and 5'-N-ethylcarboxamidoadenosine (nonselective). We repeated the studies after treatment of animals with A1 antagonist 1,3-dipropyl-8- cyclopentylxanthine or A2 antagonist 1,3-dipropyl-7-methylxanthine. Identification of P2 receptors was done by investigation of the effects of P(2x) agonist β,γ-methylene-L-ATP and P(2x) and P(2y) agonist ATP. The studies were repeated after the treatment of animals with P(2x) antagonist suramin and the P(2y) antagonist cibacron blue. N6-cyclopentyl adenosine caused a significant decrease in heart rate and did not change pulmonary blood flow or pulmonary vascular resistance (PVR). The effect of N6- cyclopentyl adenosine on heart rate was abolished by 1,3-dipropyl-8- cyclopentylxanthine but not by 1,3-dipropyl-7-methylxanthine. 2- Phenylaminoadenosine, 2-p-(2-carboxyethyl)phenethylamino-5'-N- ethylcarboxamidoadenosine, 5'-N-ethylcarboxamidoadenosine, and adenosine caused significant increases in pulmonary flow and decreases in PVR, and their vasodilator effects were attenuated by the A2 antagonist 1,3-dipropyl- 7-methylxanthine and not by 1,3-dipropyl-8-cyclopentylxanthine. N6-benzyl- 5'-N-ethylcarboxamidoadenosine did not alter pulmonary flow or PVR. The P(2x) agonist β,γ-methylene-LATP caused a decrease in heart rate and had no effect on pulmonary flow and PVR. ATP caused a significant increase in pulmonary flow and decrease in PVR without affecting heart rate. The vasodilator effects of ATP were attenuated by cibacron blue and not by suramin. These data demonstrate that adenosine and ATP cause pulmonary vasodilation by activation of A(2A) and P(2y) receptors, respectively, in fetal lambs.