Tolerance to the organic nitrates: new ideas, new mechanisms, continued mystery.

Nitroglycerin (NTG) and other organic nitrates continue to be important drugs that are often used in cardiovascular medicine. All organic nitrates undergo denitrification, releasing nitric oxide (NO) through a biotransformation process that remains poorly understood to date. NO activates the enzyme soluble guanylyl cyclase in smooth muscle cells, causing increased levels of the second messenger cGMP. Finally, cGMP activates a cGMPdependent protein kinase. This enzyme mediates vasorelaxation through inhibitory phosphorylation of different proteins involved in the regulation of intracellular Ca levels.