Lysophosphatidylcholine potentiates phenylephrine responses in rat mesenteric arterial bed through modulation of thromboxane A2

R. Zhang, B. Rodrigues, K. M. MacLeod. Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.

Elevated levels of lysophosphatidylcholine (LPC) have been found to be associated with diabetes and its cardiovascular complications. Previously, LPC was shown to produce altered vasoreactivity in conduit arteries, and to modulate intracellular signaling pathways in a variety of cells (Prokazova et al., 1998). The present study was designed to investigate the effects of LPC on vasoconstrictor and vasodilator responsiveness in the rat mesenteric resistance arterial bed (MAB).

MABs were isolated from male Wistar rats (300-400g) and perfused with Krebs-bicarbonate solution at a constant flow rate. Responses to bolus injections of phenylephrine (PE, 0.9-300nmol, n=12), or KCl (50-800µmol, n=5) were obtained before, following 40 min perfusion with 10µM LPC, and after washout of LPC for 60 minutes. Effects of LPC on the maximum relaxation to acetylcholine (Ach, n=5) in PE-precontracted MAB were also studied. The ability of 20 µM indomethacin (a cyclooxygenase inhibitor) or 0.3µM SQ-29548 (a thromboxane A2 receptor antagonist) to inhibit the modulatory effects of LPC on the PE response was determined. In addition, the effect of PE in the absence and presence of LPC on levels of thromboxane B2 (TxB2) in the perfusate were also determined by enzyme immunoassay (EIA).

Basal perfusion pressure and KCl-contractions were not significantly altered by LPC perfusion or washout. Perfusion with LPC reduced the maximum relaxation to Ach from 93±5% to 7±4% (p<0.001), without affecting the PE response. Following LPC washout, the maximum relaxation to Ach improved (55±9%, p<0.05), while PE responses were significantly potentiated, the maximum response increasing from 105±5% to 199±24% (p<0.001) and the pD2 value increasing from 7.50±0.04 to 8.13±0.15 (p<0.001). This potentiation could be reversed by pre-treatment with either indomethacin or SQ-29548. Based on the TxB2 EIA, LPC itself did not appear to change TxA2 release. However, PE produced a dose-dependent increase in TxA2 production, which was suppressed by LPC perfusion, but was significantly enhanced after washout of LPC.

These results suggest that LPC causes endothelial dysfunction in the rat MAB, but only potentiates PE responses following its removal. Moreover, this potentiation is related to increased production of TxA2. Further studies are required to investigate the link between LPC and TxA2 signaling.

Prokazova, N., et al. (1998) Biochemistry (Mosc). 63(1): 31-7.

Supported by a program grant from the Heart and Stroke Foundation of BC & Yukon.