Cardiovascular and pharmacological implications of haem-deficient NO-unresponsive soluble guanylate cyclase knock-in mice

Oxidative stress, a central mediator of cardiovascular disease, results in loss of the prosthetic haem group of soluble guanylate cyclase (sGC), preventing its activation by nitric oxide (NO). Here we introduce Apo-sGC mice expressing haem-free sGC. Apo-sGC mice are viable and develop hypertension. The haemodynamic effects of NO are abolished, but those of the sGC activator cinaciguat are enhanced in apo-sGC mice, suggesting that the effects of NO on smooth muscle relaxation, blood pressure regulation and inhibition of platelet aggregation require sGC activation by NO. Tumour necrosis factor (TNF)-induced hypotension and mortality are preserved in apo-sGC mice, indicating that pathways other than sGC signalling mediate the cardiovascular collapse in shock. Apo-sGC mice allow for differentiation between sGC-dependent and -independent NO effects and between haem-dependent and -independent sGC effects. Apo-sGC mice represent a unique experimental platform to study the in vivo consequences of sGC oxidation and the therapeutic potential of sGC activators

Managing Knowledge in Policymaking and Decision Making

The combined effect of increasing problem complexity and growing demand for participation in decisions has forced policymaking and decision making in organizations to become less an analytic endeavor and more a process of "knowledge management ' This requires an intermediarv to mediate among conflicting perspectives and integrate the different forms and levels of knowledge This article describes one such approach to knowledge management that utilizes a third party to create and facilitate a temporary task organization Following a brief case example, some research resultsfrom an evaluation of six past applications of the approach are presented These results provide insight into the effective structuring and conduct of knowledge management proceduresPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68626/2/10.1177_107554708600800106.pd