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The cardiac pharmacology of tolbutamide
Abstract:
Recent clinical studies have suggested an association of tolbutamide therapy with an increased incidence of cardiovascular deaths. Due to the paucity of information concerning the acute cardiac actions of tolbutamide, the effects of this agent upon cardiac contractility and automaticity were examined under in vivo and in vitro conditions in rabbit, cat and dog heart muscle preparations. Tolbutamide (10(-6) to 3 x 10(-3) M) produced a biphasic inotropic response with a peak positive inotropic response at 3 X 10(-3) M which was 13.7 +/- 5.1% of the maximal obtainable increase in tension. Similar studies in cat papillary muscle resulted in a response that averaged 19% of the maximal increase in contractile force. In contrast, canine papillary muscles as well as the intact canine heart failed to develop a positive inotropic response to tolbutamide. Responses of rabbit atrial strips to isoproterenol were not potentiated by previous exposure to tolbutamide. Exposure of rabbit atria to theophylline, 2.5 X 10(-4) M, did not potentiate the inotropic effects of tolbutamide. Stidies in spontaneously beating rabbit right atria and cat papillary muscle-Purkinje fiber preparations demonstrated that tolbutamide does not have the potential to augment automaticity in these tissues. In intact dog heart, the intracoronary administration of tolbutamide did not lead to disturbances in cardiac rhythm, providing additional evidence that tolbutamide does not increase ventricular automaticity. It is concluded that tolbutamide possess a species-specific positive inotropic effect in rabbit and cat but not in the dog. The inotropic effect is small when compared to the maximum inotropic response and is observed only in vitro. Tolbutamide lacks the ability to enhance cardiac pacemaker activity. These data do not support the conclusions of previous investigatirs concerning the possible deleterious cardiac effects of tolbutamide.
Insights
Tolbutamide shows a small, species-specific positive inotropic effect in rabbit and cat hearts but not in dogs. This study found no evidence that tolbutamide increases cardiac automaticity or poses a risk for cardiovascular events.
Area of Science:
- Pharmacology
- Cardiovascular Physiology
Background:
- Clinical studies suggest tolbutamide therapy may increase cardiovascular deaths.
- Limited information exists on tolbutamide's acute cardiac effects.
Purpose of the Study:
- To investigate the acute cardiac effects of tolbutamide on contractility and automaticity.
- To determine if tolbutamide influences cardiac function in different species.
Main Methods:
- In vivo and in vitro studies using rabbit, cat, and dog heart muscle preparations.
- Assessment of cardiac contractility and automaticity in response to tolbutamide.
- Examination of tolbutamide's interaction with other cardiac stimulants.
Main Results:
- Tolbutamide induced a small, biphasic positive inotropic response in rabbit and cat heart muscle (in vitro).
- No positive inotropic effect was observed in canine papillary muscles or the intact canine heart.
- Tolbutamide did not augment automaticity in spontaneously beating atria or Purkinje fiber preparations.
- Intracoronary administration in dogs did not cause cardiac rhythm disturbances.
Conclusions:
- Tolbutamide exhibits a species-specific, minor positive inotropic effect in rabbits and cats, primarily in vitro.
- Tolbutamide does not enhance cardiac pacemaker activity or ventricular automaticity.
- These findings do not support previous concerns about deleterious cardiac effects of tolbutamide.