The cardiac pharmacology of tolbutamide.
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.
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002415:Cats; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004558:Electric Stimulation; D005260:Female; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007269:Injections, Intra-Arterial; D007545:Isoproterenol / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009638:Norepinephrine / Q000008:administration & dosage / Q000494:pharmacology; D010210:Papillary Muscles / Q000187:drug effects; D011690:Purkinje Fibers / Q000187:drug effects; D011817:Rabbits; D013045:Species Specificity; D013268:Stimulation, Chemical; D013806:Theophylline / Q000494:pharmacology; D014044:Tolbutamide / Q000008:administration & dosage / Q000494:pharmacology*
D014044:Tolbutamide; D013806:Theophylline; D007545:Isoproterenol; D009638:Norepinephrine