Pertussis toxin attenuates platelet-activating factor-induced pulmonary hemodynamic alterations in pigs.

Abstract

To determine whether platelet-activating factor (PAF)-induced release of cyclooxygenase products might be dependent on G proteins in vivo, we administered pertussis toxin (PTX) (9.7-10.0 micrograms/kg iv) to conscious pigs approximately 48 h before bolus infusions of PAF (10 ng/kg). Autoradiography of ADP-ribosylated lung cell membrane proteins from PTX-treated pigs demonstrated marked reduction in the amount of radiolabel ([32P]NAD) incorporated, indicating that PTX induced ADP-ribosylation of G proteins in vivo. PAF, infused at hourly intervals from 0-4 h, caused increases in plasma concentrations of thromboxane B2 (TxB2) concomitant with pulmonary hypertension and vasoconstriction in anesthetized pigs. These physiological changes were blocked or markedly attenuated by indomethacin, indicating they were dependent on cyclooxygenase products. In PTX-treated pigs, the PAF-induced pulmonary hypertension and vasoconstriction were modestly attenuated, whereas the increases in plasma TxB2 were markedly attenuated. PTX prevented PAF-induced aggregation of platelets in vivo as evidenced by blockade of thrombocytopenia. However, in vitro, PAF-induced aggregation of platelets was independent of PTX. Moreover, incubation of platelet-rich plasma with 50 microM PAF failed to increase TxB2 levels. These findings suggested that a PTX-sensitive cell other than the platelet was responsible for triggering release of TxA2 and thrombocytopenia in vivo. We conclude that PAF-induced release of TxA2, pulmonary vasoconstriction, and thrombocytopenia in anesthetized pigs are dependent on a PTX-sensitive G protein; however, the residual hemodynamic effects indicate involvement of a PTX-insensitive G protein, or alternatively, G protein independent pathways.

• Authors: N C Olson, K T Kruse-Elliott, A R Whorton, J R Dodam
• Journal: The American journal of physiology (Am J Physiol) Vol. 264 Issue 3 Pt 1 Pg. L213-21 (Mar 1993) ISSN: 0002-9513 [Print] United States
• PMID: 8460710 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Platelet Activating Factor
• Virulence Factors, Bordetella
• Calcimycin
• Sodium Chloride
• Thromboxane B2
• Prostaglandin-Endoperoxide Synthases
• Pertussis Toxin
• GTP-Binding Proteins
• Indomethacin

Topics

• Animals
• Blood Platelets (metabolism)
• Calcimycin (pharmacology)
• GTP-Binding Proteins (metabolism, physiology)
• Hemodynamics (drug effects, physiology)
• Indomethacin (pharmacology)
• Injections, Intravenous
• Lung (blood supply, physiology)
• Pertussis Toxin
• Phosphorylation
• Platelet Activating Factor (administration & dosage, metabolism, pharmacology)
• Prostaglandin-Endoperoxide Synthases (metabolism)
• Sodium Chloride (pharmacology)
• Swine (physiology)
• Thrombocytopenia (chemically induced)
• Thromboxane B2 (blood)
• Time Factors
• Vasoconstriction (drug effects, physiology)
• Virulence Factors, Bordetella (administration & dosage, pharmacology)