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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
Author(s) -
Kavanagh Mélanie,
Battistini Bruno,
Jean Sonia,
Crochetière Josiane,
Fournier Louis,
Wessale Jerry,
Opgenorth Terry J,
Cloutier Raymond,
Major Diane
Publication year - 2001
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0704424
Subject(s) - congenital diaphragmatic hernia , medicine , pulmonary hypertension , pulsatile flow , hypoxemia , anesthesia , endothelins , endocrinology , endothelin receptor , receptor , fetus , biology , pregnancy , genetics
Postnatal mortality in isolated congenital diaphragmatic hernia (CDH) is mainly related to the associated pulmonary hypertension (PH) and to right‐to‐left shunting. 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). 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. 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. 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). 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. 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.British Journal of Pharmacology (2001) 134 , 1679–1688; doi: 10.1038/sj.bjp.0704424