Pharmacodynamics of in Vivo Nitroglycerin Tolerance in Normal Conscious Rats: Effects of Dose and Dosing Protocol

Purpose. We examined the effects of dose and dosing protocol on the pharmacodynamics of in vivo nitroglycerin (NTG) tolerance in conscious rats. Mechanism-based pharmcokinetic/pharmacodynamic (PK/PD) models were tested for their ability to describe the observed data. Methods. Rats were infused with 1,3, or 10 μg/min of NTG or vehicle for 10 h. Peak mean arterial pressure (MAP) response to an hourly 30 μg i.v. NTG challenge dose (CD) was measured before, during, and at 12 and 24 h after infusion. In separate experiments, the MAP effects of repeated bolus doses of NTG were compared to those after a continuous infusion, both at a total dose of 510 μg NTG. Results. NTG tolerance was indicated by a decrease in peak MAP response to the CD, relative to the preinfusion peak MAP response. Tolerance toward the MAP effects of bolus CD was observed within 1 h of 10 μg/min of NTG infusion (26.8 ± 2.8% vs. 10.6 ± 0.4% for 0 and 1 h, respectively, p < 0.001), and the rate and extent of tolerance development increased with the infusion dose. No apparent MAP tolerance was observed when NTG was given as multiple bolus doses whereas significant MAP tolerance was observed when this dose was infused continuously. PK/PD modeling indicated that a cofactor/ enzyme depletion mechanism could adequately describe the composite data. Conclusions. Our data showed that in vivo nitrate tolerance was dose- and dosing protocol-dependent. The pharmacodynamics of tolerance development are consistent with depletion of either critical enzymes or cofactors that are necessary to induce vasodilation.