Correlation between positive chronotropic effect and norepinephrine release induced by acetone in the rat right atrium

Abstract

The effects of acetone on contraction rate and norepinephrine (NE) release of rat right atrium were investigated. Acetone, in the concentration range 10–210 mM increased the atrial contraction rate (ACR) in a dose-dependent manner, but in concentrations exceeding 210 mM, caused a gradual reduction in the ACR from the peak. The positive chronotropic effect of acetone on ACR can be reduced by adding 0.002 mM of propranolol (a non-selective β 1- and β 2-adrenergic receptor blocker), or by pretreating the rat with reserpine (an NE depleter) (5 mg/kg body weight, i.p., 24 h prior to experiment). These findings lead to the hypothesis that the increase in ACR induced by acetone may be partly due to an increase in NE release from sympathetic nerve endings in the atrium by acetone. To test this speculative hypothesis, the effect of acetone on [ 14C]NE + cold NE release from the right atrium, preinoculated with 0.25 μM of [ 14C]NE + cold NE for 20 min at 35°C, was carried out using a simple technique developed in our laboratory. The acetone (10–1000 mM)-stimulated peak of NE release (pmol/g atrium/min) and summed NE release (pmol/g atrium/5 min) in excess of the basal spontaneous NE release were analyzed. The dose-response curves of the effect of 10–210 mM of acetone on the ACR and the peak of NE release were parallel. However, acetone concentrations above 210 mM caused a gradual drop of the curve of the ACR from its maximum while still enhancing the curve of the NE release. This continued gradually up to an acetone concentration of 500 mM. The atrial NE release reached a maximum at acetone concentrations between 500 and 1000 mM. This indicates that the increase in ACR caused by acetone in the range 10–210 mM may be partly due to an increase in NE release from the sympathetic nerve terminals in the atrium. However, an acetone concentration above 210 mM may be too toxic to the muscle fibers and/or the pacemaker and/or the conducting system, and so even though the NE release is still increasing, it can not enhance the ACR any further. It is generally speculated that the release of NE from the sympathetic nerve endings in the heart induced by the great number of organic solvents and general anesthetics contributes to the cause of tachycardia, arrhythmia and fibrillation of the heart. Direct evidence from in vitro experiments such as the one used here may help to elucidate these speculations in the future.