GMP-PDE

Cyclic nucleotide phosphodiesterases (PDEs) are a class of enzymes that catalyze the hydrolysis of 3, 5 -cyclic guanosine monophosphate (cGMP) or 3, 5 -cyclic adenosine monophosphate (cAMP) to 5 -guanosine monophosphate (GMP) or 5 -adenosine monophosphate (AMP), respectively. 

Fig. 9.1 Nitric oxide mediated inhibition of platelet activation. Abbreviations used NO, nitric oxide EDRF, endothelium-derived relaxing factor GC, guanylyl cyclase PDE, phosphodiesterase cGMP-PK, GMP-dependent protein kinase Raplb, small GTPase Raplb ...

The enzyme phosphodiesterase (PDE) converts cyclic GMP to GMP. The Pfizer scientists wanted to develop a drug to inhibit PDE so that the level of cyclic GMP remains high, so that the last mechanism step can proceed. 

The moderately selective PDE type V-inhibitor sildenafil (Viagra ) has been introduced in the treatment of erectile dysfunction. On the basis of cyclic GMP accumulation sildenafil is claimed to be a selective vasodilator in erectile tissues in the penis because of the high concentration of PDE type V in this region. Several of its adverse reactions (headache, flush, hypotension) reflect its vasodilator actions in other vascular beds than that of the penis. The drug will not be further discussed here. 

It is a relatively selective inhibitor of cyclic GMP, cyclic AMP-PDE (phosphodiesterase) type 111 family. It causes vasodilatation with a consequent decrease in systemic vascular resistance. It increases both the force of contraction and velocity of relaxation of cardiac muscles. It is administered IV 0.75 mg/kg/min as a bolus dose followed by 5-10 pg/kg/min IV infusion and total dose not to exceed 10 mg/kg. 

Activation of G-proteins by occupied receptors results usually in the dissociation of the G-protein complex, releasing an activated a subunit. In the case of Gs, the activated a subunit interacts with andfactivates the catalytic unit of adenylate cyclase by increasing the affinity of the enzyme for Mg2+, whereas the activated a subunit of transducin stimulates cyclic GMP phosphodiesterase (PDE) activity by causing the dissociation of a y subunit from the PDE, hence relieving an inhibitory effect. G appears to exert its inhibitory effect on adenylate cyclase in two distinct... 

CDK2, cell division kinase 2 cDNA, complementary DNA CDP, cytidine 5 -diphosphate CDPK, Ca2+-dependent protein kinase, calmodulin domain protein kinase CFTR, cystic fibrosis transmembrane conductance regulator cGMP, 3, 5 -c.yclic guanosine monophosphate cGMP PDE, cyclic GMP phosphodiesterase... 

Figure 15. Dose dependently c-GMP inhibits PDE or activates PKG, thereby mediating its effects on the vasculature, platelets and myocytes. The cardiac interstitial NO concentration during early ischemia and early reperfusion is increased. The increase in NO concentration is derived from activated NO synthase (NOS) isoforms (species specific) and from NOS independent pathways. Cardiac c-GMP concentration during ischemia is somewhat increased while upon reperfusion is decreased. NO seems to mediate protective as well as deleterious effects which are critically dependent on the specific experimental conditions. NO at lower concentrations preserves blood flow and attenuates platelet aggregation and neutrophil-endothelium interaction following ischemia and reperfusion. In small amounts might also be beneficial by nitration of the cardioprotective PKCe. Furthermore, NO increases cardiomyocyte function. Figure 16. At higher concentrations, NO depresses cardiomyocyte function, mediates inflammatory processes following ischemia and reperfusion, impairs mitochondrial respiration...

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