HMG-CoA reductase inhibitors, or statins, are widely used as cholesterol-lowering agents in the treatment of dyslipidemias. Statins have also been reported to have pleiotropic effects, independent of their effects on cholesterol synthesis, possibly through inhibition of the monomeric G proteins Ras and Rho, which are able to signal through ERK and Rho kinase activities, respectively. We have previously demonstrated that inhibition of ERK activation enhances β-adrenoceptor-mediated vasodilatation in the porcine isolated coronary artery. As statins can also inhibit ERK activation, the initial aim of this study was to determine whether statins have a similar influence on β-adrenoceptor-evoked vasodilatation. Segments of porcine distal coronary artery were mounted in a Mulvany wire myograph and bathed in Krebs-Henseleit buffer gassed with 95% O(2)/5% CO(2) and maintained at 37 °C. Tissues were pre-contracted with the thromboxane mimetic U46619 prior to cumulative concentration-response curves to the β-adrenoceptor agonist salbutamol in the absence or presence of simvastatin (1, 5 or 10 μM), pravastatin (10 μM), or lovastatin (10 μM). Simvastatin inhibited the salbutamol-induced relaxation of the coronary artery. Similar effects were seen with lovastatin, but not pravastatin or the sodium salt of simvastatin. Simvastatin, but not pravastatin also inhibited the relaxations to the Ca(2+)-activated K(+) channel opener NS1619 and the K(ATP) channel opener pinacidil. Unexpectedly, these data indicate that, rather than enhancing β-adrenoceptor-mediated vasodilatation, lipophilic statins impair these responses. This is likely to be due to effects on K(+) channels.

Background and purpose: Stimulation of vascular b-adrenoceptors causes vasodilatation through activation of adenylyl cyclase (AC) and plasma membrane potassium channels, and b-adrenoceptors have been linked to activation of extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase in various cell lines. However, how these findings relate to functional responses in intact tissues is largely unknown. The aim of this study, therefore, was to investigate the role of ERK in b-adrenoceptor-induced vasodilatation. Experimental approach: Segments of porcine coronary artery were mounted in a Mulvany wire myograph and bathed in Krebs-Henseleit buffer gassed with 95% O2/5% CO2 and maintained at 37°C. Tissues were pre-contracted with the thromboxane mimetic U46619, endothelin-1 or KCl. Cumulative concentration-response curves to b-adrenoceptor agonists or forskolin were then carried out in the absence or presence of the mitogen-activated protein kinase kinase (MEK) inhibitors PD98059 (10 or 50 mM) or U0126 (10 mM). Key results: PD98059 caused a concentration-dependent leftward shift in response to isoprenaline (pEC50 control, 7.5 Ϯ 0.1; 50 mM PD98059, 8.1 Ϯ 0.1: P < 0.05). Inhibition of MEK also enhanced the maximum relaxation seen with salbutamol, but not the responses to the b1-adrenoceptor selective agonist xamoterol or the AC activator forskolin. There was no enhancement of the relaxations to b-adrenoceptor agonists after inhibition of ERK activation in tissues pre-contracted with KCl or treated with the K + channel blocker tetraethylammonium. Conclusions and implications:These data indicate that ERK inhibits b2-adrenoceptor-mediated vasodilatation through a mechanism which may involve inactivation of plasma membrane potassium channels.