Abstract 308: Papaverine Inhibits Force of Human Saphenous Vein Through Actin Depolymerization and Myosin Light Chain Dephosphorylation
Background Papaverine has been used to combat vasospasm in human saphenous veins (HSV) as an alternative to high pressure distension techniques. Papaverine acts as a nonspecific inhibitor of phosphodiesterases, increasing both cGMP and cAMP. We hypothesized that the mechanism by which papaverine reduces force through regulation of actin depolymerization and myosin light chain dephosphorylation.
Methods HSV was pretreated with 1 mM papaverine followed by 5 μM norepinephrine. Force and intracellular [Ca2+]i levels were concurrently measured using a Fluoroplex. Tissue was snap frozen for biochemical analyses.
Results Papaverine completely inhibited norepinephrine-induced force development and intracellular [Ca2+]i. Papaverine pretreatment led to increases in the phosphorylation of heat shock-related protein 20 (HSPB6), dephosphorylation of myosin light chain, and depolymerization of actin. Pretreament of papaverine led to an association of HSPB6 with 14-3-3 eta as determined by immunoprecipitation and mass spectrometry analysis. The interaction of HSPB6 with 14-3-3 leads to dissociation and activation of cofilin, an actin depolymerizing protein.
Conclusions These results suggest that papaverine-induced force inhibition of HSV involves decreases in intracellular [Ca2+]i by inhibiting the calcium regulatory pathways, leading to the dephosphorylation of myosin light chain. Additionally papaverine induces the phosphorylation of HSPB6, which leads to depolymerization of actin. Papaverine inhibits HSV spasm via multiple molecular mechanisms.
- © 2013 by American Heart Association, Inc.