Tedisamil and dofetilide-induced torsades de pointes, rate and potassium dependence

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73908/1/sj.bjp.0703967.pd

Role of cyclic GMP, cyclic GMP-dependent protein kinase and protein phosphorylation in the control of smooth muscle tension

Numerous agents are capable of activating guanylyl cyclases and increasing tissue levels of guanosine 3':5'-cyclic monophosphate (cGMP). A detailed analysis of the literature concerning the role of cGMP in mediating vascular smooth muscle relaxation confirms that the criteria necessary to determine that cGMP is involved in this effect have been satisfied. However, the cGMP hypothesis may only apply in certain smooth muscles. One aim of the present study was to further investigate the role of cGMP in uterine contractility in an attempt to resolve some of the apparent inconsistencies regarding the importance of cGMP in this tissue. The results of our studies in the rat myometrium confirm the previous suggestion that the rat myometrium can be classified as a "non-responsive" smooth muscle with respect to the fact that it does not relax in response to increases in the tissue levels of cGMP. Sodium nitroprusside (SNP) was shown to significantly increase cGMP levels and to activate cyclic GMP-dependent protein kinase (PKG) in our myometrial preparations but did not cause relaxation of the tissue. Therefore, a lack of PKG activation cannot be used to explain the failure of cGMP-elevating agents such as SNP to cause relaxation of the rat myometrium. In vascular smooth muscle, it is generally well accepted that the cGMPdependent component of relaxation involves activation of a specific PKG. The protein targets of PKG and the underlying mechanisms by which this kinase leads to a relaxant response have not been completely elucidated. The final objective of our studies was to investigate the smooth muscle substrates of PKG in intact rat aorta, rat myometrium and rat vas deferens using two-dimensional gel electrophoresis. In intact rat aorta, seven PKG substrates and two calcium-dependent phosphorylation events were detected during relaxation of the tissue. None of the PKG substrates identified in the rat aorta could be identified in the myometrium or vas deferens following administration of numerous cGMP-elevating agents. In addition, we were unable to detect changes in phosphorylation of any other proteins. Thus, the failure of the rat myometrium and rat vas deferens to relax in the face of cGMP elevation and PKG activation may be due to a lack of PKG substrate phosphorylation.Medicine, Faculty ofAnesthesiology, Pharmacology and Therapeutics, Department ofGraduat