Plasma profile and haemodynamic tolerance to isosorbide-5-mononitrate in controlled-release form

1. Plasma concentrations and some haemodynamic parameters known to be affected by nitrates, were monitored in healthy volunteers who received three different dose regimens of isosorbide-5-mononitrate (5-ISMN) over 5 day study periods. 2. No haemodynamic tolerance was found in the 60 mg once-daily dose schedule which produced high plasma concentrations during the daytime but concentrations no greater than 100 ng ml-1 at night. In contrast, a dose regimen of 60 mg followed by 30 mg 12 h later and thereafter every 8 h until the fifth day induced complete haemodynamic tolerance. With this dose regimen the minimum plasma concentrations were never below 300 ng ml-1. A significant attenuation of haemodynamic effects was also found with the third dose regimen, 60 mg followed by 30 mg 6 h later for 5 days, which produced minimum plasma concentrations of between 100 ng ml-1 to 300 ng ml-1; the degree of attenuation rose as trough plasma concentrations increased. 3. In conclusion, 60 mg 5-ISMN in a controlled-release (Durules) preparation given once daily was the only dose regimen not inducing nitrate tolerance.