Effects of glyceryl trinitrate tolerance on vascular responsiveness to constrictor agents in bovine isolated coronary artery

1. Recent clinical studies have raised the possibility that intermittent nitrate dose regimens, while limiting the extent of nitrate tolerance development, may trigger rebound aggravation of ischaemia after abrupt withdrawal of nitrate. To date, only limited studies have been performed to examine the mechanism of this phenomenon. 2. In a bovine isolated coronary artery model, we tested the hypothesis that induction of glyceryl trinitrate (GTN) tolerance might affect large coronary artery responsiveness to a variety of non-catecholamine constrictor agents. Glyceryl trinitrate tolerance was induced by pre-exposure to GTN (10 mumol/L) for 60 min followed by 15 min washout. In some experiments, the effect of prior endothelial removal on putative interactions was also examined. 3. Our results showed that GTN tolerance did not affect responses to KCl, the thromboxane A2 mimetic U46619, endothelin-1 and 5-HT, irrespective of presence or absence of endothelium. None of the constrictor agents tested induced endothelium-dependent constriction. 4. We conclude that in this model of GTN tolerance induction, there is no evidence of 'rebound' vasoconstriction to this group of non-catecholamine vasoconstrictors with GTN withdrawal