Altered endothelium-dependent responses in lambs with pulmonary hypertension and increased pulmonary blood flow.
To investigate early endothelial function associated with increased pulmonary blood flow, vascular shunts were placed between the ascending aorta and main pulmonary artery in 18 late-gestation fetal sheep. Four weeks after delivery, the lambs were instrumented to measure vascular pressures and blood flows, and blood was collected to measure plasma concentrations of guanosine 3',5'-cyclic monophosphate [cGMP, the second messenger to nitric oxide (NO)-mediated vasodilation] and L-arginine (the precursor for NO synthesis). The responses to the endothelium-dependent vasodilators acetylcholine (ACh, 1.0 microgram/kg) and ATP (0.1 mg.kg-1.min-1), the endothelium-independent vasodilators M & B-22948 (a cGMP-specific phosphodiesterase inhibitor, 2.5 mg/kg) and inhaled NO (40 ppm), and N omega-nitro-L-arginine (an inhibitor of NO synthase, 5 mg/kg) were then compared with responses in 12 age-matched controls. Vasodilator responses in control lambs were determined during pulmonary hypertension induced by U-46619 (a thromboxane A2 mimic). Shunted lambs displayed a selective impairment of endothelium-dependent pulmonary vasodilation, an augmented pulmonary vasoconstricting response to NO synthase inhibition, increased plasma cGMP concentrations, and decreased L-arginine concentrations. Taken together, these data suggest that lambs with pulmonary hypertension and increased pulmonary blood flow have early aberrations in endothelial function, as manifested by increased basal NO activity, that cannot be further increased by agonist-induced endothelium-dependent vasodilators.
Reddy
V M
VM
Department of Cardiothoracic Surgery, University of California, San Francisco 94143-0106, USA.
Wong
J
J
Liddicoat
J R
JR
Johengen
M
M
Chang
R
R
Fineman
J R
JR
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000109:Acetylcholine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001120:Arginine / Q000097:blood; D006152:Cyclic GMP / Q000097:blood; D004730:Endothelium, Vascular / Q000378:metabolism*; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000503:physiopathology*; D009569:Nitric Oxide / Q000819:agonists / Q000378:metabolism / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011450:Prostaglandin Endoperoxides, Synthetic; D011652:Pulmonary Circulation; D011688:Purinones / Q000494:pharmacology; D012756:Sheep; D013928:Thromboxane A2 / Q000031:analogs & derivatives; D014662:Vasoconstrictor Agents
D010726:Phosphodiesterase Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic; D011688:Purinones; D014662:Vasoconstrictor Agents; D019335:Nitroarginine; D009569:Nitric Oxide; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000255:Adenosine Triphosphate; D001120:Arginine; D019001:Nitric Oxide Synthase; C011145:zaprinast; D006152:Cyclic GMP; D000109:Acetylcholine