Effects of chronic glyceryl trinitrate on left ventricular haemodynamics in a rat model of congestive heart failure: demonstration of a simple animal model for the study of in vivo nitrate tolerance

Abstract

The aim of the study was to investigate the problem of pharmacological tolerance to nitrate therapy in congestive heart failure, using an animal model. The effects of chronic glyceryl trinitrate infusions were studied in a rat model of congestive heart failure, induced by myocardial infarction, wherein surgical procedures have been developed to permit continuous monitoring of ventricular pressures in conscious animals for up to 4-5 d. male Sprague-Dawley rats were used, weight 300-325 g, n = 3-7 per experiment. Glyceryl trinitrate infusion (18 micrograms.kg-1.min-1) in rats with congestive heart failure caused by a 28.5(SEM 3.5)% infarction induced a rapid fall in left ventricular end diastolic pressure from 12.0(0.8) mm Hg to a peak effect of 5.5(0.6) mm Hg within 30 min (n = 7), but rapid attenuation developed beginning about 4 h after the start of the infusion. Complete abolition of the haemodynamic effects of glyceryl trinitrate was observed after 8 h of infusion. After a 12 h wash out period, responsiveness to a new infusion of glyceryl trinitrate (same dose) was restored. Withdrawal of nitrovasodilator dose led to rapid return to baseline left ventricular end diastolic pressure values. Infusion of vehicle to control animals (infarct size not different from treatment group) caused no haemodynamic effects. The haemodynamic changes caused by glyceryl trinitrate resemble those seen in man and suggest a possible use for this animal model in examining the mechanisms of nitrate action and tolerance.