Pre-contraction with U46619 enhances the contraction to perivascular adipose tissue in porcine coronary artery: effect of statins.

T. Alsahli, R. Roberts, M. Randall. School of life sciences, University of Nottingham, Nottingham, United Kingdom.

Introduction: Perivascular adipose tissue (PVAT) is recognized as an important local regulator of vascular function and dysfunction through the release of a wide range of adipokines (1).Statins or HMG-CoA reductase inhibitors have been shown to exert significant effects beyond their impact on lowering cholesterol synthesis (2).Whether statins and cardiovascular drugs alter PVAT functional responses is unknown. The present study was carried out to determine the effects of statins on PVAT-induce contraction in PCA in the absence or presence of the thromboxane agonist U46619.

Method: Contraction in distal PCA was measured by wire myography. PCAs were cleaned of fat and incubated with simvastatin (1 and 10μM) or pravastatin (10μM) for two hours, or with indomethacin (10μM) for 30 minutes. 0.3g of PVAT was then added to 7.5ml bath either at baseline or after pre-contracting the vessel with the thromboxane mimetic U46619 (1nM to 20nM) and changes in vessel tone measured. Contractile responses were expressed as a percentage of the response to 60mM KCl. Data were analysed using two-way ANOVA, followed by Sidak test with p<0.05 indicating significance.

Results: At baseline tone PVAT caused time-dependent contractions of the PCA peaking at 60 min (12±3%,n=12). In the presence of U46619 the contraction to PVAT was more rapid and enhanced (22±2% peaking at 13 min,n=15,P<0.001). Simvastatin caused a concentration-dependent inhibition of the PVAT-induced contraction, Rmax was reduced from 10±1% to 2±0.2% (P<0.001) in the presence of 10μM simvastatin at baseline tone and reduced from 30±3% to 4±0.6% when PVAT was added in the presence of U46619 (n=6,P<0.001). Pravastatin (10μM) had no effect on PVAT-induced contraction either at baseline or with U46619 pre-contraction (n=6). The pre-treatment of PCA with 10μM indomethacin reduced the Rmax from 7±0.7% to 4±0.5% (P<0.005) at baseline but had no effect on the PVAT-induced contraction in the presence of U46619 (n=6).

Conclusion: PVAT vasoconstrictor effect in PCA is partly mediated via the cyclooxygenase products. Pre-contraction with U46619 enhances the PVAT-induced contraction in PCA, however, under these conditions, the PVAT-induced contraction is no longer dependent upon cyclooxygenase. The lipophilic simvastatin (but not hydrophilic pravastatin) has the ability to inhibit the contractile effect of PVAT in PCA indicating that the inhibition effect of statins may be dependent upon their lipophilicity and ability to cross cell membrane of PVAT and/or PCA.

References:

1. Brown Nicholas et al. (2014). Arteriosclerosis, thrombosis, and vascular biology 34.8: 1621-1630.

2. Zhou Q and Liao J (2010). Circulation Journal 74.5: 818-826.