[Mechanism of cellular action of nitrate derivatives]

Nitrate derivatives have to undergo metabolic activation in the smooth muscle cell or in the plasma with a sulflydryl radical. This transformation results in the formation of nitric oxide and/or S-nitrosothiols. These products stimulate an enzyme, the soluble guanylate cyclase in the sarcoplasm of the smooth muscle cell; giving rise to the formation of intracellular cyclic GMP from GTP. The cyclic GMP activates a kinase protein which in turn activates a number of other protein enzymes involved in the recaptation of calcium by the sarcoplasmic reticulum and in the extrusion of calcium from the cell. In addition, cyclic GMP reduces the level of phosphorylation of the myosin light chain, thereby reducing the sensitivity of the contractile proteins to intracellular calcium. All these phenomena cause smooth muscle relaxation so explaining most of the vasodilator effect of nitrate derivatives.