Time-Phasic Development of Nitrate Tolerance According to the Hemodynamic Responses and the Expression of Phosphodiesterase 1A1

Abstract

Background and Objectives：Time-phasic development of nitrate tolerance in cardiovascular diseases is very important because it can contribute to the advent of blunted vasodilation or rebound ischemia even during continuous NTG treatment. In such a condition, we should change the therapeutic regimen of nitrate treatment to prevent the worsening of symptoms. Materials and Methods：We created a nitrate-tolerant rat model using an osmotic minipump, and we examined the hemodynamic response to bolus NTG infusion in vivo. We checked the phosphodiesterase (PDE)1A1 mRNA and protein level by relative quantitative RT-PCR and western blot analysis. We used 8-cpt-cGMP for investigating the development of a time-phasic nitrate tolerance mechanism after nitrate infusion. Results：NTG-treated rats revealed a significant decrease in NTG-induced MAP drop (nitrate tolerance) from 1-day and this continued to the third day. The mRNA and protein levels of PDE1A1 similarly increased during these periods. Conclusion：This study revealed the development of time-phasic nitrate tolerance from the the aspects of in vivo hemodynamic responses and PDE 1A1 gene expression, and our work supports the need for further investigation to come up with a different therapeutic strategy and new drugs.