Effect of inhibition of extracellular signal-regulated kinase on relaxations to β-adrenoceptor agonists in porcine isolated blood vessels

Background and purpose: Stimulation of vascular beta-adrenoceptors causes vasodilatation through activation of adenylyl cyclase (AC) and plasma membrane potassium channels, and beta-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 beta-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% O-2/5% CO2 and maintained at 37 degrees C. Tissues were pre-contracted with the thromboxane mimetic U46619, endothelin-1 or KCl. Cumulative concentration-response curves to beta-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 mu M) or U0126 (10 mu M). Key results: PD98059 caused a concentration-dependent leftward shift in response to isoprenaline (pEC(50) control, 7.5 +/- 0.1; 50 mu M PD98059, 8.1 +/- 0.1: P < 0.05). Inhibition of MEK also enhanced the maximum relaxation seen with salbutamol, but not the responses to the beta(1)-adrenoceptor selective agonist xamoterol or the AC activator forskolin. There was no enhancement of the relaxations to beta-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 beta(2)-adrenoceptor-mediated vasodilatation through a mechanism which may involve inactivation of plasma membrane potassium channels.