Nitrate tolerance--can it be prevented?

Tolerance develops during therapy with all organic nitrates, particularly when dosing strategies are designed to provide therapeutic effects throughout 24 h. Such tolerance can be demonstrated by assessing haemodynamic, anti-anginal and anti-ischaemic effects during therapy. The mechanism of nitrate tolerance is not completely understood. Tolerance may be related to depletion of reduced sulfhydryl groups in vascular smooth muscle with resultant reduction in nitric oxide production, adenylate cyclase activation and cyclic guanosine monophosphate (GMP) production. Nitrate exposure also activates counter-regulating influences which lead to fluid retention and augmented vasoconstrictor effects. Intermittent nitrate therapy avoids the problem of tolerance by providing a period of washout. Controlled-release formulations of oral nitrates providing a period of low nitrate exposure should prevent tolerance. This has been documented by studies with a controlled-release formulation of isosorbide-5-mononitrate.