title: Thromboxane A2 mediates pulmonary hypertension after cardiopulmonary bypass in the rabbit.
abstract: Clinically, it is well established that cardiopulmonary bypass results in pulmonary dysfunction. Using a recently developed preparation for cardiopulmonary bypass in the rabbit, we have been able to mimic a similar, but more severe, condition. We found that, despite normal histologic structure of the myocardium, hearts could not be weaned from bypass because of a serious increase in pulmonary vascular resistance. Histologic studies of the lungs showed severe intravascular neutrophil aggregation and marked vasoconstriction. To identify the nature and origin of the mediator responsible for the changes in the pulmonary vasculature, we subjected groups of rabbits (n = 4 per group) to bypass with cooling to 18 degrees C, circulatory arrest for 1 hour, and rewarming on bypass to 33 degrees C. Pulmonary vascular resistance was measured at the same temperature before and after bypass. Four groups were studied: group I were untreated controls; group II received the cyclooxygenase inhibitor, indomethacin (0.2 mg/kg intravenously), before operation; group III received the thromboxane A2 synthetase inhibitor, Dazmegral (5 mg/kg intravenously), before operation together with the thromboxane A2 receptor blocker GR 32191B (2 mg/kg per 30 minutes intravenously); and group IV were treated with mustine hydrochloride (1.75 mg/kg intravenously) 3 days before the experiment to deplete the neutrophils by 90%. During circulatory arrest, the heart was protected with an initial infusion (10 ml at 4 degrees C over 1 minute) of St. Thomas' Hospital cardioplegic solution. At the end of the experiment, the heart and lungs were histologically examined. In the control group, a significant increase (+395% when compared with the value recorded before bypass) in pulmonary vascular resistance was observed after bypass. However, in none of the treated groups did pulmonary vascular resistance increase significantly (percentage changes in groups II, III, and IV were -24%, 0%, and +33%, respectively). Pulmonary histologic characteristics were normal in all treated groups, and all animals were successfully weaned from bypass. These results indicate that the increase in pulmonary vascular resistance that arises as a consequence of bypass in rabbits is primarily a result of the production of thromboxane A2, a process in which the neutrophil plays a pivotal role.
authors.affiliation: Department of Cardiovascular Research, Rayne Institute, St. Thomas' Hospital, London, England.
authors.forename: A C
authors.initials: AC
authors.lastname: Cave
authors.forename: A
authors.initials: A
authors.lastname: Manché
authors.forename: N W
authors.initials: NW
authors.lastname: Derias
authors.forename: D J
authors.initials: DJ
authors.lastname: Hearse
mesh_terms: D000818:Animals; D001772:Blood Cell Count; D001784:Blood Gas Analysis; D002315:Cardiopulmonary Bypass; D006976:Hypertension, Pulmonary / Q000473:pathology / Q000503:physiopathology*; D008168:Lung / Q000473:pathology; D009504:Neutrophils / Q000502:physiology*; D011651:Pulmonary Artery / Q000473:pathology; D011817:Rabbits; D013928:Thromboxane A2 / Q000502:physiology*; D014655:Vascular Resistance / Q000502:physiology*
chemical_list: D013928:Thromboxane A2