EVect of isosorbide mononitrate on the human optic nerve and choroidal circulations

Aims—To assess the eVects of the nitric oxide donor 5-isosorbide mononitrate (ISMO) on blood flow in the optic nerve head (ON flow) and choroid (Ch flow). Methods—Laser Doppler flowmetry was used to measure ON flow and Ch flow in 12 normal subjects by aiming the laser beam at the fovea and at the temporal rim, respectively. In a double masked, randomised, crossover design, each subject received orally on separate days either 20 mg of 5-isosorbide mononitrate (ISMO) or placebo. Ch flow and ON flow were determined monocularly at baseline and 1 hour after dosing. In the last six subjects, additional measurements were obtained at 3 hours. Mean arterial blood pressure (BPm), heart rate, and intraocular pressure (IOP) were monitored, and ocular perfusion pressure (PP) was estimated. Results—No significant changes in ON flow, PP, IOP, or BPm were observed following placebo. Following ISMO, ON flow increased from baseline by 19.8% (SEM 9.3%) at 1 hour (paired t test, p= 0.058) and by 33.1% (7.5%) at 3 hours (p= 0.007). Compared with the changes following placebo, statistically significant increases in ON flow were observed both at 1 (p=0.050) and 3 hours (p=0.041) after ISMO treatment. Compared with placebo, PP decreased significantly 1 hour after ISMO dosing (p=0.039), mainly as a function of reduced BPm. A significant inverse correlation (R=−0.618; p=0.032) was observed between the percentage changes in PP and ON flow 1 hour following ISMO administration, but not after placebo. No significant change in foveal Ch flow was documented. Conclusions—These results suggest that, in normal subjects, ISMO increases significantly ON flow but not Ch flow. The inverse correlation observed between PP and ON flow suggests that the same mechanism(s) responsible for systemic vasodilatation and blood pressure decrease may also cause the ON flow increase. (Br J Ophthalmol 1999;83:162–167) Recent reports by Zurakowski et al 1 and Afshari et al 2 have suggested that glaucoma patients who receive nitrate therapy for systemic conditions unrelated to glaucoma have less progression of glaucomatous optic neuropathy and visual field function loss than patients that do not receive these compounds. In an attempt to elucidate the possible mechanism(s) by which nitrates may protect from glaucomatous damage, Grunwald et al 3 investigated whether chronic nitrate treatment was associated with retinal vasodilatation. Their study has shown that glaucoma patients receiving chronic nitrate therapy for cardiac conditions have significantly larger retinal vein diameters than glaucoma patients who were not receiving nitrate therapy. Possibly, vasodilatation could be associated with improved perfusion of the retina and perhaps the optic nerve, in a similar fashion to what has been observed in the circulation of the heart, providing a potential rationale for the observations reported by Zurakowski et al 1 and Afshari et al. Nitrates are well known vasodilating agents eVective in a dose dependent manner on both veins and, to a lesser extent, arteries. Nitrates produce vasodilatation by acting as nitric oxide donors. The prototype of nitrates, nitroglycerin, has a rapid onset of action, but is rapidly cleared from the blood stream. Long acting nitrates such as isosorbide dinitrate (ISDN) are more suitable for chronic therapies, but first pass hepatic metabolism can limit bioavailability, requiring multiple dose administrations that stimulate tolerance. In the past few years, the long acting compound 5-isosorbide mononitrate (ISMO, Wyeth-Ayerst Laboratories, Philadelphia, PA, USA) has become available for use in clinical practice. ISMO is the active metabolite of ISDN, requiring no first pass hepatic metabolism, which guarantees nearly 100% bioavailability. 7 Maximum serum concentrations are achieved in 45–60 minutes, peak eVect is maintained between 1 and 4 hours, and half life is 4–5 hours. The recommended regimen to attain therapeutic levels is 20 mg twice daily. The high bioavailability limits the number of dose administrations required to attain therapeutic levels, and circumvents the risk for tolerance during long term nitrate treatment protocols. 8 The eVects of ISMO on the ocular microcirculation are unknown. We investigated the eVects of a single dose of ISMO on the circulation of the choroid and optic disc vessels, in an attempt to assess the eVect of nitrates on the human ocular circulation and their potential role in the management of ocular vascular diseases. Materials and methods Twelve healthy volunteers aged 19–37 years (mean 29 (SEM 1.7) years) were included in this study. All subjects had no history of Br J Ophthalmol 1999;83:162–167 162 Department of Ophthalmology, Scheie Eye Institute, School of Medicine, University of Pennsylvania, Philadelphia, USA J E Grunwald A Iannaccone* J DuPont *Currently aYliated with the