Endothelin-1 Modulation of cAMP in Rat Pulmonary Arteries: Effect of Chronic Hypoxia

The effect of hypoxic shock on the ability of endothelin (ET) receptors to interact with the cAMP second messenger system was assessed in rat pulmonary arteries. Whole pieces of tissue were dissected from the pulmonary arterial system of control and hypoxic (10% O2, 14 days) rats, incubated, where appropriate, with ET-1 (0.1 microM), and the levels of intracellular cAMP measured. Maintenance of rats under hypoxic conditions significantly reduced the basal cAMP levels in all of the arterial branches with the exception of the pulmonary resistance vessels, in which no change was observed. Incubation of the main and first branch extralobar pulmonary arteries from control rats with ET-1 resulted in a consistent decrease in the levels of intracellular cAMP. The ETA receptor antagonist FR139317 partially blocked this ET-1-mediated inhibition of cAMP accumulation in the main extralobar artery. In contrast, ET-1 caused a threefold increase in the levels of this cyclic nucleotide in the pulmonary resistance vessels from the normoxic rat. No ET-1-mediated reduction in intracellular cAMP levels was observed in any of the vessels isolated from hypoxic animals. All vessels showed ligand-activated increases in cAMP production. These results suggest differential modulation of cAMP in the different pulmonary arteries, either by direct activation through Gi and Gs or indirectly via a uncharacterized cross-talk mechanism.