Soluble guanylate cyclase activation production

Dimethyl-l,2,5-oxadiazolo[3,4-d]pyridazine 1,5,6-trioxide (41) is also an old product [7,11, 31] that has recently been found to react with GSH to give S-nitrosogluta-thione, NO and HNO [32]. It stimulates partially purified rat lung soluble guanylate cyclase, but not the heme-deficient enzyme. The activation is inhibited by ODQ. The product also displays significant vasodilator activity on rat thoracic aorta rings at nanomolar concentrations. Finally, [l,2,5]oxadiazolo[3,4-d]pyrimidine-5,7-dione 1-oxide derivatives (42, R,Ri=CH3,H) release NO, detected as nitrite, in the presence of thiols. A mechanism for this release has been proposed [33]. 

In general, the NOS isoforms can be grouped into two classes as determined by their expression in cells. Certain NOS isoforms, termed constitutive, appear to be expressed at a fairly constant level in their host cells. However, these isoforms are inactive in their native state and require that the Ca -binding protein calmodulin associate with them in order to generate NO (Schmidt et al., 1991 Busse and Mulsch, 1990 Bredt and Snyder, 1994). Thus NO production by constitutive NOS isoforms is often linked to Ca +-mediated signal transduction cascades that involve soluble guanylate cyclase, which is a hemeprotein that is activated by NO (Arnold et al., 1977). 

Neuronal production of NO is triggered when an activated neuron releases a chemical messenger (glutamate) from the presynaptic neuron to bind to receptor sites (A-methyl-D-aspartate) on the postsynaptic neuron. The transmission of this nerve impulse opens a channel in the receptor allowing the influx of calcium ions. These ions can then bind to calmodulin already present in the cell, forming a Ca / CaM complex that binds to and activates nNOS [90]. The NO radical that is produced in turn activates soluble guanylate cyclase in the postsynaptic neuron and potentially in the presynaptic neuron. 

---