Nh I


This NO-induced relaxation of cardiac muscle is the same response brought about by nitroglyc-erin tablets and other nitrovasodilators taken to relieve angina, the pain caused by contraction of a heart deprived of O2 because of blocked coronary arteries. Nitric oxide is unstable and its action is brief; within seconds of its formation, it undergoes oxidation to nitrite or nitrate. Nitrovasodilators produce long-lasting relaxation of cardiac muscle because they break down over several hours, yielding a steady stream of NO. The value of nitroglycerin as a treatment for angina was discovered serendipitously in factories producing nitroglycerin as an explosive in the 1860s. Workers with angina reported that their condition was much improved during the work week but returned on weekends. The physicians treating these workers heard this story so often that they made the connection, and a drug was born.

The effects of increased cGMP synthesis diminish after the stimulus ceases, because a specific phospho-diesterase (cGMP PDE) converts cGMP to the inactive 5'-GMP. Humans have several isoforms of cGMP PDE, with different tissue distributions. The isoform in the blood vessels of the penis is inhibited by the drug sildenafil (Viagra), which therefore causes cGMP levels to remain elevated once raised by an appropriate stimulus, accounting for the usefulness of this drug in the treatment of erectile dysfunction. ■

Most of the actions of cGMP in animals are believed to be mediated by cGMP-dependent protein kinase, also called protein kinase G or PKG, which, when ac-

tivated by cGMP, phosphorylates Ser and Thr residues in target proteins. The catalytic and regulatory domains of this enzyme are in a single polypeptide (Mr ~80,000). Part of the regulatory domain fits snugly in the substrate-binding site. Binding of cGMP forces this part of the regulatory domain out of the binding site, activating the catalytic domain.

Cyclic GMP has a second mode of action in the vertebrate eye: it causes ion-specific channels to open in the retinal rod and cone cells. We return to this role of cGMP in the discussion of vision in Section 12.7.

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