Circulatory effects of PAF-acether in newborn piglets

Abstract

Platelet-activating factor (PAF-acether) is a lipid mediator that can exhibit potent vasoconstrictor influence in the pulmonary vessels. Therefore, the release of PAF-acether during inflammatory conditions in newborns might cause deleterious increases in pulmonary vascular tone. Thirty-four anesthetized open-chest newborn piglets were given 0.01-1 nmol PAF-acether iv. In separate experiments, animals were untreated or treated with either indomethacin (a cyclooxygenase inhibitor), SQ 29548 (a thromboxane receptor blocker), or LY 171883 (a leukotriene receptor blocker). The primary hemodynamic change was a 67 to 1,537% increase in the pulmonary vascular resistance index (PVRI) (P less than 0.01): mean pulmonary artery pressure (PAP) rose significantly at all doses tested, whereas only the largest dose consistently decreased cardiac index. Treatment with indomethacin or SQ 29548 prevented the decrease in cardiac index and attenuated the PAF-acether-induced rises in PAP and PVRI. Vehicle and LY 171883 had no effect. The inhibitory influence of indomethacin and SQ 29548 suggests that an important component of PAF-acether's pulmonary vasoconstrictor action is mediated (at least in the newborn piglet) by cyclooxygenase products, most likely thromboxane.

Influence of Thromboxane A2 Receptor Antagonism on Pulmonary Vasoconstrictor Responses

“…Polyethylene cannulae were inserted into the right ventricle and main pulmonary artery. Since the ductus arteriosus is not patent in this preparation (20), a calibrated electromagnetic flow transducer (North Carolina Instruments, King, NC) was placed around the main pulmonary artery to measure cardiac output. Two pairs of 1-mm ultrasonic crystals (Dimension 3, Cardiff-bySea, CA) were positioned 10 mm apart and embedded 1-2 mm beneath the anterior epicardial surface of the right and left ventricles.…”

“…Two pairs of 1-mm ultrasonic crystals (Dimension 3, Cardiff-bySea, CA) were positioned 10 mm apart and embedded 1-2 mm beneath the anterior epicardial surface of the right and left ventricles. Myocardial segment length was recorded continuously from each region using appropriate signal processing instrumentation (Sonomicrometer 120, Triton Technology, San Diego, CA) and previously described techniques (20 Baseline hemodynamic measurements were taken and determined to be stable for at least 1 h after the surgery in all animals. During the stabilization period, all animals received 0.9% NaCl 10 mL/kg.…”

“…Animals then received PAFacether 0.1 nmol/kg intravenous bolus using a standardized 2-s injection technique. This dose of PAF-acether was chosen to produce reversible, near-maximal hemodynamic changes based on previous experiences in our laboratory (20). All parameters were recorded continuously.…”

“…Elevated TxA2 levels are also present in human infants with persistent pulmonary hypertension (24). Cyclooxygenase and thromboxane synthesis blockade have been shown to attenuate, but not abolish, the pulmonary vasoconstrictor response to group Bp-hemolytic Streptococcus (14,16), PAF-acether (20), and LT (19). Neither cyclooxygenase nor thromboxane synthetase blockade has been demonstrated to affect U-466 19 induced PV.…”

“…TxA2 is necessary for pulmonary venous constriction during hypoxia in isolated lamb lungs, but appears not to mediate hypoxic PV alone (19). TxA2 release accompanies septic (14-1 7) and PAF-acether-induced (20) PV in newborn experimental animals and mediates LT response in sheep but not in cats or pigs (8, 2 1-23). Elevated TxA2 levels are also present in human infants with persistent pulmonary hypertension (24).…”