title: Dose response of intravenous sildenafil on systemic and regional hemodynamics in hypoxic neonatal piglets.
abstract: In neonates with acute pulmonary hypertension (PHT), the dose-response effect of sildenafil citrate, a selective phosphodiesterase-5 inhibitor that can alleviate PHT, has not been detailedly examined. We tested the hypothesis that the treatment of hypoxia-induced acute PHT with sildenafil would dose-dependently reduce the elevated pulmonary and systemic arterial pressures (PAP and SAP, respectively) with no effect on the oxygenation in newborn animals. We also examined the regional hemodynamic responses. Using a randomized controlled design, piglets (age range, 1-3 days; weight range, 1.5-2.1 kg) were anesthetized and acutely instrumented to measure cardiac index, left common carotid, superior mesenteric and left renal arterial flow indexes, SAP, and PAP. After stabilization, hypoxia was induced with fractional inspired oxygen concentration at 0.15 and, subsequently, piglets were randomized to receive i.v. sildenafil at 0.06, 0.2, or 2.0 mg/kg per hour or normal saline (controls) for 90 min (n = 6 each). Within 30 min of hypoxia (PaO2, 31 +/- 5 mmHg), the piglets developed PHT (PAP, 33 +/- 5 vs. 26 +/- 4 mmHg at baseline; P < 0.05. Sildenafil dose-dependently reduced the hypoxia-induced PHT (PAP at 90 min: 33 +/- 6, 29 +/- 6, and 26 +/- 6 mmHg of 0.06, 0.2, and 2.0 mg/kg per hour, respectively, vs. 44 +/- 8 mmHg of controls; P < 0.05. Sildenafil at 2.0 mg/kg per hour had the greatest decrease in SAP (P < 0.05) with no significant change at 0.06 and 0.2 mg/kg per hour. Pulmonary selectivity (PAP:SAP ratio) was best in the group treated with 0.2 mg/kg per hour dosage of sildenafil (P < 0.05). There were no differences in cardiac index and regional flow indexes between groups. Although hypoxia decreased oxygen delivery and increased oxygen extraction with no significant effect on oxygen consumption, the administration of sildenafil did not affect the oxygen metabolism (vs. controls). In neonatal piglets, i.v. sildenafil dose-dependently alleviates the hypoxia-induced acute PHT, with the best pulmonary selectivity at 0.2 mg/kg per hour, and shows no significant effect on regional circulation and oxygen metabolism.
authors.affiliation: Department of Surgery, University of Alberta, Edmonton, Alberta, Canada, T6G 2S2.
authors.forename: Erika
authors.initials: E
authors.lastname: Haase
authors.forename: David L
authors.initials: DL
authors.lastname: Bigam
authors.forename: Olga
authors.initials: O
authors.lastname: Cravetchi
authors.forename: Po-Yin
authors.initials: PY
authors.lastname: Cheung
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects*; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D000860:Hypoxia / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D007668:Kidney / Q000098:blood supply*; D010101:Oxygen Consumption / Q000187:drug effects; D010879:Piperazines / Q000008:administration & dosage*; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones; D013552:Swine; D014665:Vasodilator Agents / Q000008:administration & dosage*
chemical_list: D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate