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

Explaining the effect of rapid internationalization on horizontal foreign divestment in the retail sector. An extended penrosean perspective

Building on and extending Penrosean logic we argue that rapid international expansion by firms might lead to a breach of Penrosean constraints on efficient expansion and to subsequent divestment of international operations to bring firm scope back into Penrosean constraints. We further predict that intra-regional concentration and international experience moderate the above effect because they influence firms ability to avoid a breach of Penrosean constraints and/or weaken the consequences of such a breach. Using data on the international expansion and divestment of large retail MNEs over the period 2003-2012 we find empirical support for the proposed extended Penrose effect in explaining international divestment as well as for the moderating effects of intra-regional concentration and international experience. Our study contributes to the development of Penrosean logic and to our understanding of the factors that drive firms to divest overseas operations

Agonist-Specific Compartmentation of cGMP Action in Myometrium

Nitric oxide relaxes myometrium in a cGMP-independent manner. Although cGMP activates its cognate kinase, this is not required for the inhibitory effect of nitric oxide. Thus, nitric oxide-mediated cGMP elevation does not enjoy the same set of substrates as it does in other smooth muscles. To further understand the regulation of relaxation of uterine muscle by cGMP, we have studied the actions of peptide-mediated cGMP action in guinea pig myometrium. We used both functional and biochemical studies of the action of the particulate guanylyl cyclase activator uroguanylin and its receptor, particulate guanylyl cyclase type C, to address the relationship between cGMP elevation acting in the membrane signaling domain to that of the nonmembrane region of the cell. Uroguanylin relaxed oxytocin-induced contractions in a dose-dependent fashion only in pregnant myometrium. Both relaxation and cGMP accumulation after uroguanylin stimulation were blocked by the putative particulate guanylyl cyclase type C inhibitors 2-chloro-ATP and isatin (1H-indole-2,3-dione), but not by the soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-A]quinoxalin-1-one (ODQ). Uroguanylin stimulated cGMP accumulation only in the pregnant myometrium. Caveolin-1 expression increased in pregnancy toward term. In the caveolin-1-containing membrane domain, uroguanylin, but not the nitric-oxide donor, led to the elevation of cGMP that was insensitive to ODQ. Particulate guanylyl cyclase C was expressed and prouroguanylin was detected in pregnant myometrium. We conclude that a uroguanylin–particulate cyclase-cGMP relaxation pathway is present and cGMP is compartmented in myometrium. The agonist-mediated selectivity of relaxation to cGMP is of fundamental pharmacological interest in understanding signal transduction in smooth muscle