Mechanisms underlying lysophosphatidylcholine‐induced potentiation of vascular contractions in the Otsuka Long‐Evans Tokushima Fatty (OLETF) rat aorta

Background and purpose: The effect of lysophosphatidylcholine (LPC) on aortic contractions in Otsuka Long‐Evans Tokushima Fatty (OLETF) rats, a type 2 diabetic model, was studied. Experimental approach: Using OLETF rats and control (Long Evans Tokushima Otsuka (LETO)) rats, the effects of LPC on the contractions induced by high‐K + (10‐40 mM), UK14,304 (10∼100 nM; a selective α 2 ‐adrenoceptor agonist) and sodium orthovanadate (SOV; 10 μM∼3 mM) in endothelium‐denuded aortae were compared. Aortic ERK activity and the mRNA expression for GPR4 (a putative LPC receptor) were also measured. Key results: OLETF rats exhibited (vs. age‐matched LETO rats): (1) greater potentiation of high‐K + ‐induced contraction by 10 μM LPC – a potentiation attenuated by 10 μM genistein, protein tyrosine kinase (PTK) inhibitor, (2) greater potentiation of UK14,304 (10∼100 nM)‐induced contractions by LPC (1 μM∼10 μM) – a potentiation attenuated by 10 μM genistein, 50 μM tyrphostin A23 (PTK inhibitor) or 10 μM PD98059 (MEK 1/2 inhibitor), (3) greater basal and LPC (1 μM)‐induced ERK activities, (4) greater basal and 100 nM UK14,304‐stimulated ERK2 activities in both the absence and presence of 10 μM LPC, (5) greater SOV (10 μM∼3 mM)‐induced contractions, (6) greater potentiation of SOV‐induced contractions by 10 μM LPC – a potentiation suppressed by 10 μM PD98059 or 10 μM genistein, (7) upregulation of GPR4 mRNA. Conclusions and implications: These results suggest that the LPC‐induced potentiation of contractions in the OLETF rat aorta may be attributable to increased PTKs or ERK activity and/or to receptor upregulation. British Journal of Pharmacology (2006) 149 , 931–941. doi: 10.1038/sj.bjp.0706937