Mechanisms of endothelin-1-induced pulmonary vasodilatation in neonatal pigs.
1. We determined the contributions of three independent vasodilator mechanisms (cyclo-oxygenase metabolites, nitric oxide and ATP-sensitive potassium channels) in the mediation of pulmonary vasomotor effects of endothelin-1 (ET-1) in neonatal pigs. 2. Lungs of piglets (2.7 +/- 0.3 days old) were perfused at constant flow (60 ml min-1) with recirculating Ringer-albumin solution. We measured pulmonary artery pressure (Ppa) and the distribution of pulmonary vascular resistance using the double-occlusion method. 3. ET-1 (10(-12)-10(-9) M) produced concentration-dependent pulmonary vasodilatation. ET-1 (10(-9) M) decreased Ppa from 24.5 +/- 3.1 to 17.0 +/- 3.0 cmH2O with a nadir occurring at 1 min, followed by a slow return to baseline over 60 min (time for half-recovery (t1/2R) of 17.2 min). The decrease in Ppa was the result of pulmonary precapillary vasodilatation. Endothelin-3 (ET-3) (10(-12) and 10(-11) M) also induced vasodilatation comparable to equimolar concentrations of ET-1, whereas the selective ETB receptor agonist IRL 1620 at equimolar concentrations caused a more protracted vasodilatation response. 4. Neither the cyclo-oxygenase inhibitor indomethacin (10(-5) M) nor the KATP+ (ATP-sensitive) potassium channel blocker glibenclamide (10(-5) M) significantly altered the baseline Ppa; moreover, neither inhibitor affected the ET-1-induced vasodilatation, indicating the lack of involvement of cyclo-oxygenase metabolites and KATP+ channel activity in the mediation of the pulmonary vasodilator response to ET-1. 5. Addition of 10(-5) M reduced haemoglobin, which antagonizes the action of nitric oxide (NO), increased Ppa over prehaemoglobin levels. Haemoglobin significantly decreased the duration (t1/2R, 3.8 +/- 0.7 min) of pulmonary vasodilatation to ET-1, but did not abolish the initial phase of the response. L-N-Monomethylarginine, an inhibitor of NO synthesis, either alone or in combination with haemoglobin, similarly reduced the duration of ET-1-induced pulmonary vasodilatation. 6. The ETA receptor antagonist [Dpr1-Asp15]-ET-1 (Dpr, diaminoproprionic acid) had no effect on pulmonary vasodilatation induced by ET-1, ET-3 or IRL 1620 (suc-(Glu9,Ala11,15)-ET-1(8-21)). This finding combined with the observed relative potencies of the peptides (IRL 1620 > ET-1 = ET-3) suggests that pulmonary vasodilatation was mediated by activation of the non-selective ETB receptor. 7. The results indicate that the sustained ET-1-induced pulmonary vasodilatation in neonates is probably mediated via ETB receptor activation and that it is critically dependent on NO.
Pinheiro
J M
JM
Department of Pediatrics, Albany Medical College of Union University, NY 12208.
Malik
A B
AB
D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D016232:Endothelins / Q000494:pharmacology*; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D006454:Hemoglobins / Q000494:pharmacology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010477:Perfusion; D015221:Potassium Channels / Q000187:drug effects; D011652:Pulmonary Circulation / Q000187:drug effects*; D017466:Receptors, Endothelin / Q000187:drug effects; D013552:Swine; D014664:Vasodilation / Q000187:drug effects*; D019323:omega-N-Methylarginine
D016232:Endothelins; D006454:Hemoglobins; D010446:Peptide Fragments; D015221:Potassium Channels; D017466:Receptors, Endothelin; C074308:sovateltide; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D005905:Glyburide; D007213:Indomethacin