Effect of ABT-627 (A-147627), a potent selective ET(A) receptor antagonist, on the cardiopulmonary profile of newborn lambs with surgically-induced diaphragmatic hernia.
1. Postnatal mortality in isolated congenital diaphragmatic hernia (CDH) is mainly related to the associated pulmonary hypertension (PH) and to right-to-left shunting. 2. Endothelins (ETs) are potent vasoconstrictors and pro-mitogenic peptides. Strong evidences support their participation in CDH and in the etiology of PH via the activation of ET(A) receptors (ET(A)-Rs). 3. Evaluation of the effect of ABT-627, a selective non-peptidic ET(A)-R antagonist, given from -15 to 210 min post-delivery (1 mg kg(-1) bolus +0.01 mg kg(-1) h(-1) infusion, i.v.), was conducted in the lamb model of CDH. 4. Severity of CDH was assessed in comparison to untreated controls (n=5). Untreated CDH lambs (n=7) had a higher mean pulmonary arterial pressure (MPAP; P<0.0001), lower mean blood pressure (MBP; P=0.0004), higher MPAP / MBP ratio (P<0.0001), lower arterial pH (P<0.0001), higher paCO(2) (P<0.0001), lower paO(2) (P<0.0001) and lower post-ductal pulsatile SaO(2) (P<0.0001) than untreated controls. 5. Treated controls (n=7) showed a higher MPAP, lower MBP, higher MPAP/MBP ratio, lower arterial pH, higher paCO(2), lower paO(2), lower post-ductal pulsatile SaO(2) and lower plasmatic ir-ET ratios compared to untreated controls (P<0.0001). 6. Treated CDH lambs (n=8) showed a higher MBP (P<0.0001), lower MPAP / MBP ratio (P<0.0001), higher arterial pH (P<0.0001), lower paCO(2) (P<0.0001), higher paO(2) (P=0.0228), higher post-ductal pulsatile SaO(2) (P=0.0016) and lower plasmatic ir-ET ratios (P=0.0247) when compared to untreated CDH lambs. 7. These observations revealed that, although acute perinatal treatment with a selective non-peptidic ET(A)-R antagonist had some adverse effects in controls, it attenuated the progressive cardiopulmonary deterioration that occurred after birth in CDH lambs.
Kavanagh
M
M
Anaesthesiology and Neonatology Investigation Laboratory, Laval University Research Centre / Pediatric Unit, CHUQ / CHUL, Sainte-Foy, Québec, G1V 4G2, Canada.
Battistini
B
B
Jean
S
S
Crochetière
J
J
Fournier
L
L
Wessale
J
J
Opgenorth
T J
TJ
Cloutier
R
R
Major
D
D
D000818:Animals; D000831:Animals, Newborn; D000077868:Atrasentan; D001794:Blood Pressure / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006548:Hernia, Diaphragmatic / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology*; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000196:embryology / Q000503:physiopathology; D007262:Infusions, Intravenous; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D016555:Matched-Pair Analysis; D010100:Oxygen / Q000378:metabolism; D011247:Pregnancy; D011659:Pulmonary Gas Exchange; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology*; D044022:Receptor, Endothelin A; D012119:Respiration / Q000187:drug effects; D012756:Sheep; D013997:Time Factors
D065128:Endothelin Receptor Antagonists; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D010100:Oxygen; D000077868:Atrasentan