Is It All in the Genes… ?

Nitric oxide (NO), the molecule of the year in 1995 and theme of the Nobel Prize in 1998, started its career as endothelium-derived relaxing factor (EDRF) almost 20 years ago.1 An unusual observation in the rabbit aorta, ie, the unexpected relaxation to acetylcholine only in preparations with endothelium, stimulated the scientific community because of its obvious physiological and clinical potential.2 The search for its identity left us with the surprising result that the answer was NO.3 This chemically unstable free radical and ancient mediator was fascinating not only because of its short half-life but also because it was the active component of all nitrovasodilators. Shortly thereafter, the enzyme nitric oxide synthase (NOS) was cloned and its substrate l-arginine identified.4 5 Thus, almost 100 years after the introduction of nitroglycerin in the treatment of angina pectoris, the endogenous nitrate was discovered, which, like its pharmacological counterpart, stimulated cGMP in vascular smooth muscle to cause vasodilatation.6 Nitroglycerin is a very effective vasodilator of epicardial coronary arteries. Vasoconstriction of these vessels contributes importantly to ischemia and angina pectoris occurring during mental stress7 but also after cold exposure or exercise.8 9 True vasospasm can even cause angina at rest or trigger myocardial infarction.10 The effectiveness of nitroglycerin in many of these patients suggested that the vascular wall, and in particular the endothelium, might have a reduced capacity to release the endogenous nitrate NO.2 Indeed, many investigators showed that in patients with cardiovascular risk factors, such as hypertension, hypercholesteremia, smoking, or diabetes, endothelium-dependent relaxation is impaired (in fact, converted into a paradoxical vasoconstriction in response to many endothelium-dependent agonists11 12 ) and the effects of NO inhibitors are reduced.13 Direct measurement of NO in human atherosclerotic plaques confirmed a markedly reduced expression of …