[Pharmacology of nitrates and other NO donors]

The identification of nitric oxide (NO) as an endothelium derived relaxing factor (EDRF) has allowed a thorough investigation of the effects of organic nitrate esters as well as other nitrogen containing vasodilators such as nitrites, nitrosothioles, sydnonimines and nitroprusside. These substances can release NO or mediators derived from it, and have thus received annotation as NO donors. The pharmacokinetic characteristics of NO donors as well as the reactions which might mediate their bioactivation shall be reviewed. For organic nitrates this is of particular interest, since clinical tolerance arises because mechanisms involved in their bioactivation become exhausted. In contrast however, both the molsidomine metabolite SIN-1 as well as nitroprusside are considered to act as direct NO donors since their biological activity is not limited by the mode of their bioactivation. The principles of NO¿s actions as well as the related biological activities of NO donors will be covered in this article. The vascular selectivity and dose dependency of the haemodynamic nitrate effects shall also be described as well as the potential interactions of nitrates with endothelium, thrombocytes and leukocytes. The significance of specific tolerance to nitrates and the loss of responsiveness due to neurohormonal counter-regulation, which has also been observed with molsidomine, shall be discussed. Newly acquired knowledge therefore justifies consideration of NO donors as therapeutic substitutes for the protective autacoid NO, which is the basis for further pharmacological and clinical development of NO donors.