Parathyroid hormone-related protein-mediated responses in pulmonary arteries and veins of newborn lambs.
PTHrP has important roles in lung development and function. Here we determined the vasomotor responses of isolated pulmonary arteries and veins of newborn and adult sheep to PTHrP. In vessels constricted with endothelin-1, PTHrP (PTHrP 1-34) caused greater relaxation of veins than of arteries. In both vessel types, relaxation to the peptide was less in adult than in newborn vessels. In newborn lambs, PTHrP-induced relaxation was not affected by endothelium removal, inhibition of eNOS, or inhibition of adenylyl cyclases by SQ-22536. However, relaxation was attenuated by 4-aminopyridine, inhibitor of voltage-dependent potassium channels, in both arteries and veins, and by charybdotoxin, inhibitor of calcium-activated potassium channels, in veins. When vessels were saturated with 8-BrcAMP (3 x 10(-4) M), to eliminate relaxation mediated by endogenous cAMP, PTHrP-induced relaxation was partially attenuated. In vessels treated with 8-BrcAMP (3 x 10(-4) M), 4-aminopyridine but not charybdotoxin inhibited relaxation induced by PTHrP 1-34 in both arteries and veins. Radioimmunoassay showed that, in the presence of a general phosphodiesterase inhibitor, PTHrP caused a concentration-dependent increase in intracellular cAMP content in arteries and veins, which was largely abolished by SQ-22536. Our results demonstrate that PTHrP is a potent vasodilator of pulmonary vessels, with a greater effect in veins than in arteries. Relaxation induced by the peptide contains both cAMP-dependent and -independent components. In both arteries and veins, voltage-dependent potassium channels mediate the response to PTHrP, at least in part, in a cAMP-independent fashion; and in veins, calcium-activated potassium channels may be stimulated by elevated cAMP levels.
Gao
Yuansheng
Y
Division of Neonatology, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA 90502, USA. ysgao@labiomed.org
Raj
J Usha
JU
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D018999:Charybdotoxin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D019332:Endothelin-1 / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008168:Lung / Q000098:blood supply; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D009924:Organ Culture Techniques; D044162:Parathyroid Hormone-Related Protein / Q000494:pharmacology*; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors / Q000378:metabolism; D011651:Pulmonary Artery / Q000502:physiology*; D011667:Pulmonary Veins / Q000502:physiology*; D034561:Sheep, Domestic; D014664:Vasodilation / Q000187:drug effects*
D000067956:Adenylyl Cyclase Inhibitors; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D044162:Parathyroid Hormone-Related Protein; D024681:Potassium Channels, Calcium-Activated; D024642:Potassium Channels, Voltage-Gated; D018999:Charybdotoxin; C017759:9-(tetrahydro-2-furyl)-adenine; D000242:Cyclic AMP; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D000262:Adenylyl Cyclases; D000225:Adenine