Vascular Activity Models

Denileukin diftitox is a combination of the active sections of interleukin 2 and diphtheria toxin. It binds to high-affinity interleukin 2 receptors on the cancer cell (and other cells), and the toxin portion of the molecule inhibits protein synthesis to result in cell death. The pharmacokinetics of denileukin diftitox are best described by a two-compartment model, with an a half-life of 2 to 5 minutes and a terminal half-life of 70 to 80 minutes. Denileukin diftitox is used for the treatment of persistent or recurrent cutaneous T-cell lymphoma whose cells express the CD25 receptor. Side effects include vascular leak syndrome, fevers/chills, hypersensitivity reactions, hypotension, anorexia, diarrhea, and nausea and vomiting. 

Fig. 4.1. Cellular model illustrating cell types in vascular wall involved in vasorelaxation induced by SERMs. Putative targets of SERMs are indicated within cyan tags. SERMs directly affect L-type VDCC, BK fil subunit in smooth muscle cells, and ER in endothelial cells. L-type VDCC L-type voltage-dependent calcium channel BK calcium-activated large conductance K+ channel PKG protein kinase G eNOS endothelial nitric oxide synthase GC soluble guanylate cyclase cGMP cyclic GM P V electrochemical membrane potential ER estrogen receptor. See text for further details...

Another important point to keep in mind when reviewing the cardiovascular effects of SERMs is that, in the absence of clinical studies of consistency comparable to estrogens, most of the available evidence has been obtained in experimental models. The work has concentrated on the selective areas of vascular physiology that have shown susceptibility to ER activation and, therefore, has followed steps that often overlap with those taken in research with estrogens. 

Most work on the SR and diseased smooth muscle has concerned vascular smooth muscle in hypertensive animals, and bladders from animal models of outflow obstruction. The tools used to study SR function are mainly indirect, and include recording tension or intracellular [Ca2+] with fluorescent probes, measuring Ca2+ fluxes with 45Ca, and investigating the effects of drugs known to block SERCA or activate store release. More directly, some measurement of the activity of SERCA in microsomal preparations has been undertaken (e.g. Zderic et al 1996). 

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