Development and Disappearance of Tolerance to Organic Nitrates in Conscious Dogs

Abstract

Although there is a considerable number of well-conducted clinical investigations that clearly document the antianginal efficacy of long-acting nitrates for preventing anginal attacks or for the treatment of myocardial ischemia (for review see Abrams, 1980), the long-term effectiveness of nitrates has been questioned on the grounds of a possible development of tolerance toward these drugs. Whereas clinical studies of this topic are controversial in their conclusions (Blasini et al., 1980; Lee, 1978; Winsor and Berger, 1975; Thadani et al., 1982), most experimental investigations performed on in vitro or in vivo models indicate the development of tolerance to nitrates (Bogaert, 1968; Bogaert and de Schaepdryver, 1968; Needleman, 1970; Parker et al., 1975). However, the experimental conditions, such as doses and dose intervals of most of these studies have been quite artifical. Thus, the results of such experiments demonstrate the pharmacologic phenomenon, tolerance, but do not show its relevance to the clinical use of these drugs.