Thrombosis and endothelial injury.

Our ignorance about the clinical actions of nitrates includes a lack of knowledge about individual variability of response. Dr. Cohn as well as other clinical observers" have suggested that sublingual isosorbide dinitrate may be particularly long lasting in certain subgroups of patients. While this remains an intriguing possibility, studies have not been undertaken to determine whether some patients repeatedly respond in a more prolonged fashion. Such studies are necessary to discriminate between mere statistical fluctuation and true difference in biologic response. Moreover, it is unclear that differences in response, if real, are very important, since no patient in our study was improved two hours after sublingual isosorbide dinitrate. To circumvent the myriad of unknowns mentioned above, we turned to an entirely different mode of nitrate therapy, nitroglycerin ointment, and found it highly effective in improving exercise capacity for at least three hours after treatment.10 As Dr. Cohn points out, these results must be regarded as preliminary. We explored responses to doses yielding a narrow range of physiologic change one hour after application. Furthermore, we did not attempt comparative studies in these patients receiving nitroglycerin ointment. It is possible that the observed actions might be duplicated or exceeded by appropriately chosen doses of sublingual or oral nitrates. Nevertheless, documentation of clinical benefit with other nitrates equaling or exceeding that seen after nitroglycerin ointment has not been published. Dr. Cohn indicates that even the most ardent advocates of sublingual nitrates do not claim to have achieved significant benefit for more than 21/2 hours. It remains possible that oral agents may match the prolonged and consistent efficacy of nitroglycerin ointment, but such evidence is, at present, not available. In this age of "miracle drugs' it is perhaps somewhat embarrassing that a homely remedy such as nitroglycerin ointment seems more longlasting than nitrates with more impressive structural formulas. The tortoise appears to have beaten the hare! Nitroglycerin ointment, however, may not be the "'ultimate"' long-acting nitrate. It seems logical that current technology can improve substantially on the transcutaneous route of administering nitrates perhaps physical or chemical alterations can make this approach easier to use and even more beneficial than it currently is. Although our own limited experience with nitroglycerin ointment10 and other studies of nitrate therapy3 have not revealed evidence of significant adverse effects due to prolonged use, we urge that lack of nitrate tolerance or dependence in clinical medicine should not be taken for granted. The high doses and prolonged exposure available with cutaneous nitrate administration may cause angina patients to share the ill effects that apparently appear in industrial workers with cutaneous exposure to nitroglycerin. 1 In the past, angina patients-may have been protected from possible ill effects of prolonged nitrate exposure only by the inability of standard treatment modes to produce sustained nitrate action.