Prevention of complement-induced pulmonary hypertension and improvement of right ventricular function by selective thromboxane receptor antagonism

W. J. Smith, Michael Murphy, R. F. Appleyard, R. J. Rizzo, L. Aklog, R. G. Laurence, L. H. Cohn, E. Mendeloff, L. H. Edmunds

Research output: Contribution to journalArticle

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Abstract

The effect of complement activation on the pulmonary vascular system and on right ventricular function was studied in sheep (n = 12) by injection of cobra venom factor. Animals were instrumented for measurement of pulmonary flow, mean pulmonary artery pressure, right ventricular stroke work, arterial blood gases, and systemic vascular resistance. Blood was sampled from the left atrium and pulmonary artery to measure thromboxane B2, the metabolite of thromboxane A2, by radioimmunoassay. After baseline measurements, animals were randomly assigned to receive a selective thromboxane receptor antagonist SQ30741 as a 10 mg/kg bolus with an infusion of 10 mg/kg per hour or else to receive vehicle. Cobra venom factor was then injected (30 U/kg) in all animals, and data were recorded at 15, 30, 60, 90, and 120 minutes. In control animals there was a 2.4-fold increase in mean pulmonary artery pressure and a 76% increase in right ventricular stroke work at 15 minutes from baseline (p <0.05); these values remained elevated for 30 minutes and returned to baseline by 1 hour with no change in systemic vascular resistance. Arterial oxygenation decreased by 124% at 15 minutes and remained depressed through the experiment, but in treated animals oxygen tension remained unchanged from baseline. Thromboxane B2 increased 95% from baseline in the control group and 1.5 fold in treated animals and followed a similar time course as the functional measurements (p <0.05). A pulmonary vascular thromboxane B2 gradient of approximately 1000 pg/ml was measured at 15 and 30 minutes in both control and treated groups (p <0.05). We conclude that after complement activation in this model pulmonary hypertension and decreased oxygen tension are mediated by thromboxane release from the pulmonary vascular bed. This increased afterload causes a stress on the right ventricle as demonstrated by the increased right ventricular stroke work. Selective thromboxane receptor antagonism may be a beneficial therapy for pulmonary hypertension in patients after cardiopulmonary bypass.

Original languageEnglish (US)
Pages (from-to)800-806
Number of pages7
JournalJournal of Thoracic and Cardiovascular Surgery
Volume107
Issue number3
StatePublished - 1994
Externally publishedYes

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Thromboxane Receptors
Right Ventricular Function
Pulmonary Hypertension
Thromboxane B2
Pulmonary Artery
Blood Vessels
Lung
Complement Activation
Stroke
Vascular Resistance
Oxygen
Control Groups
Thromboxane A2
Thromboxanes
Ventricular Pressure
Heart Atria
Cardiopulmonary Bypass
Heart Ventricles
Radioimmunoassay
Sheep

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery

Cite this

Prevention of complement-induced pulmonary hypertension and improvement of right ventricular function by selective thromboxane receptor antagonism. / Smith, W. J.; Murphy, Michael; Appleyard, R. F.; Rizzo, R. J.; Aklog, L.; Laurence, R. G.; Cohn, L. H.; Mendeloff, E.; Edmunds, L. H.

In: Journal of Thoracic and Cardiovascular Surgery, Vol. 107, No. 3, 1994, p. 800-806.

Research output: Contribution to journalArticle

Smith, WJ, Murphy, M, Appleyard, RF, Rizzo, RJ, Aklog, L, Laurence, RG, Cohn, LH, Mendeloff, E & Edmunds, LH 1994, 'Prevention of complement-induced pulmonary hypertension and improvement of right ventricular function by selective thromboxane receptor antagonism', Journal of Thoracic and Cardiovascular Surgery, vol. 107, no. 3, pp. 800-806.
Smith, W. J. ; Murphy, Michael ; Appleyard, R. F. ; Rizzo, R. J. ; Aklog, L. ; Laurence, R. G. ; Cohn, L. H. ; Mendeloff, E. ; Edmunds, L. H. / Prevention of complement-induced pulmonary hypertension and improvement of right ventricular function by selective thromboxane receptor antagonism. In: Journal of Thoracic and Cardiovascular Surgery. 1994 ; Vol. 107, No. 3. pp. 800-806.
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abstract = "The effect of complement activation on the pulmonary vascular system and on right ventricular function was studied in sheep (n = 12) by injection of cobra venom factor. Animals were instrumented for measurement of pulmonary flow, mean pulmonary artery pressure, right ventricular stroke work, arterial blood gases, and systemic vascular resistance. Blood was sampled from the left atrium and pulmonary artery to measure thromboxane B2, the metabolite of thromboxane A2, by radioimmunoassay. After baseline measurements, animals were randomly assigned to receive a selective thromboxane receptor antagonist SQ30741 as a 10 mg/kg bolus with an infusion of 10 mg/kg per hour or else to receive vehicle. Cobra venom factor was then injected (30 U/kg) in all animals, and data were recorded at 15, 30, 60, 90, and 120 minutes. In control animals there was a 2.4-fold increase in mean pulmonary artery pressure and a 76{\%} increase in right ventricular stroke work at 15 minutes from baseline (p <0.05); these values remained elevated for 30 minutes and returned to baseline by 1 hour with no change in systemic vascular resistance. Arterial oxygenation decreased by 124{\%} at 15 minutes and remained depressed through the experiment, but in treated animals oxygen tension remained unchanged from baseline. Thromboxane B2 increased 95{\%} from baseline in the control group and 1.5 fold in treated animals and followed a similar time course as the functional measurements (p <0.05). A pulmonary vascular thromboxane B2 gradient of approximately 1000 pg/ml was measured at 15 and 30 minutes in both control and treated groups (p <0.05). We conclude that after complement activation in this model pulmonary hypertension and decreased oxygen tension are mediated by thromboxane release from the pulmonary vascular bed. This increased afterload causes a stress on the right ventricle as demonstrated by the increased right ventricular stroke work. Selective thromboxane receptor antagonism may be a beneficial therapy for pulmonary hypertension in patients after cardiopulmonary bypass.",
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