Mechanisms of action of nitrates.
Glyceryl trinitrate, isosorbide dinitrate, and isosorbide-5-mononitrate are organic nitrate esters commonly used in the treatment of angina pectoris, myocardial infarction, and congestive heart failure. Organic nitrate esters have a direct relaxant effect on vascular smooth muscles, and the dilation of coronary vessels improves oxygen supply to the myocardium. The dilation of peripheral veins, and in higher doses peripheral arteries, reduces preload and afterload, and thereby lowers myocardial oxygen consumption. Inhibition of platelet aggregation is another effect that is probably of therapeutic value. Effects on the central nervous system and the myocardium have been shown but not scrutinized for therapeutic importance. Both the relaxing effect on vascular smooth muscle and the effect on platelets are considered to be due to a stimulation of soluble guanylate cyclase by nitric oxide derived from the organic nitrate ester molecule through metabolization catalyzed by enzymes such as glutathione S-transferase, cytochrome P-450, and possibly esterases. The cyclic GMP produced by the guanylate cyclase acts via cGMP-dependent protein kinase. Ultimately, through various processes, the protein kinase lowers intracellular calcium; an increased uptake to and a decreased release from intracellular stores seem to be particularly important.
Torfgård
K E
KE
Department of Clinical Pharmacology, Faculty of Health Sciences, Linköping University Hospital, Sweden.
Ahlner
J
J
D000787:Angina Pectoris / Q000188:drug therapy; D001792:Blood Platelets / Q000187:drug effects; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004950:Esterases / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy; D006801:Humans; D007548:Isosorbide Dinitrate / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009203:Myocardial Infarction / Q000188:drug therapy; D009566:Nitrates / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D005996:Nitroglycerin / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D010101:Oxygen Consumption / Q000187:drug effects; D013329:Structure-Activity Relationship; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
D009566:Nitrates; D014665:Vasodilator Agents; D003577:Cytochrome P-450 Enzyme System; D005982:Glutathione Transferase; D017869:Cyclic GMP-Dependent Protein Kinases; D004950:Esterases; D005996:Nitroglycerin; D007548:Isosorbide Dinitrate; C030397:isosorbide-5-mononitrate