[Isolated human venous segments as a model for the study of problems of nitrate tolerance]

Concentration-dependent relaxation (6-70%) of segments of human saphenous veins under isometric conditions could be demonstrated with cumulative concentrations of isosorbide dinitrate (ISDN) and Glycerol trinitrate GTN (10(-9)-10(-5) M). Vein segments were obtained during coronary by-pass surgery. Nitrate (GTN)-induced relaxation was accompanied by a 2- to 3-fold increase of cyclic GMP content in the vessel walls. However, no change of concentrations in the vessel walls could be determined for the metabolites of prostaglandines: (PG E2, PG F2 alpha, TX B2, 6-keto-PGF1 alpha). Pretreatment of patients with 40 mg ISDN (standard release formulation) 4 times daily for 1 week prior to surgery with the last dose 1 hour before harvesting the vein segments did not influence relaxation. by ISDN. Immersion of vein segments for 1 hour in buffer solution containing 10(-6) M ISDN (= therapeutic concentration) prior to relaxation with cumulative concentrations of ISDN did not influence relaxation either. Induction of in vitro tolerance required ISDN concentrations which exceeded the range achieved under therapeutic conditions: 4.4 x 10(-4) M. This in vitro tolerance could be widely reversed by 10 mM N-Acetylcysteine (NAC) suggesting involvement of sulfhydril (SH) groups. Since tolerance in this experimental model was not seen under concentrations achieved in patients it seems likely that clinical tolerance is caused by activation of counterregulatory forces.