Nucleotides and Relaxation

Cyclic nucleotide activity is regulated by the actions of three different enzymes. These are the cyclases, which catalyze the formation of cyclic nucleotides from triphosphate precursors, the low cyclic nucle- 

There are no well-characterized activators of the cyclic nucleotide protein kinases, except for several series of cAMP or cGMP mimetics. These agents often are poorly permeable in intact cell systems, and thus are of limited usefulness. 

In the past ten years, efforts have been directed at characterizing and designing inhibitors of the cyclic nucleotide PDEs. The remainder of this section will focus on three families of isozymes that play important roles in modulating smooth muscle tone. 

There are now as many as seven distinct families of PDE isozymes (Beavo, 1988 Beavo and Reifsnyder, 1990 Michaeli etal., 1993). These isozymes are distinct based on protein sequences and catalytic activity for the different cyclic nucleotides. In smooth muscle, cAMP hydrolysis is regulated by either PDE III, PDE IV, or both enzymes. Cyclic GMP hydrolysis is primarily regulated by PDE V, although PDE I (which is calmodulin regulated) may also play a role in relaxation. 

PDE IV is another family of isozymes present in most smooth muscles. This PDE also hydrolyzes cAMP, but there is no regulation by cGMP. Selective inhibitors of this isozyme include rolipram and RO 20-1724. 

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