Simvastatin evokes an unpredicted inhibition of β-adrenoceptor-mediated vasodilatation in porcine coronary artery

Abstract

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.

Acute Simvastatin Inhibits KATP Channels of Porcine Coronary Artery Myocytes

“…Activation of cardiac K ATP channels by statins has been reported [14], [35], [36]. However, a recent study [37] and our current study demonstrated that simvastatin inhibits pinacidil-induced relaxation in porcine isolated coronary artery. Furthermore, our result illustrate that simvastatin consistently suppressed, instead of enhanced, cromakalim- and pinacidil-induced K ATP channel openings of arterial myocytes of pig coronary artery and human left internal mammary artery.…”

Effect of simvastatin on vascular tone in porcine coronary artery: Potential role of the mitochondria

“…For example, lovastatin has been shown to inhibit calcium influx through L-type calcium channels in rat basilar artery (Bergdahl et al, 2003), although it is not clear how this inhibition occurs. Rosuvastatin has been proposed to improve Ca 2+ -activated K + channel function (Miller et al, 2004) and rosuvastatin-induced relaxation of rat aorta may be due to opening of Ca 2+ -activated K + channels (Lopez et al, 2008), which in turn could lead to reduced calcium influx However, in contrast to this, simvastatin has been shown to inhibit Ca 2+ -activated K + channels in coronary artery smooth muscle (Seto et al, 2007) which may be responsible for the inhibition of β-adrenoceptor-mediated relaxations that we have observed (Uhiara et al, 2012).…”

“…However, in this current study we have demonstrated that neither the selective K ATP potassium channel inhibitor glibenclamide, nor the non-selective inhibitor of K + channels TEA altered the simvastatin relaxation, suggesting that activation of K + channels is not involved in the relaxation response. In fact, our previous studies demonstrate that simvastatin actually inhibits K + channel-mediated relaxations in the porcine coronary artery (Uhiara et al, 2012). Other studies have suggested that simvastatin increases mitochondrial K ATP channel activity (Jones et al, 2003;Zhao et al, 2006).…”

“…The anterior proximal descending branch of the coronary artery was dissected out, cleaned of fat and connective tissues and set up for isometric tension recording, as previously described (Uhiara et al, 2012). In order to account for variability in responses between animals, internal controls using adjoining segments from each coronary artery were employed in each experiment.…”

Treatment of moyamoya disease by multipoint skull drilling for indirect revascularization combined with mobilization of autologous bone marrow stem cells

“…Statins can mobilize bone marrow endothelial stem cells and promote recovery from nerve injury. Mobilization of autologous BMSCs has improved treatment of ischemic cerebrovascular diseases to a certain extent (Almansob et al, 2012;Uhiara et al, 2012). Vasculogenesis and neurogenesis are two major pathophysiologic processes that occur in the brain after cerebral ischemia.…”