Improvement of the toxic to inotropic dose ratio of digoxin by excluding central nervous system influences on the heart.
The effect of progressive digoxin administration (20 micrograms/kg/15 min, i.v.) on cardiac contractile force, cardiac output, heart rate, arterial blood pressure and total peripheral resistance was examined in chloralose anesthetized cats with and without central nervous system control of the heart. In neurally intact animals, the inotropic response (i.e., a sustained increase of 0.5 g-tension in contractile force) occurred with 83 +/- 22.1 micrograms/kg digoxin. The peak change in force occurred immediately prior to the development of ventricular arrhythmias and attained a value of + 1.88 +/- 0.84 g-tension above the control level. Toxicity (i.e., ventricular arrhythmias) occurred with 158 +/- 8.0 micrograms/kg and death occurred with 188 +/- 8.4 micrograms/kg digoxin. The toxic to inotropic, and lethal to inotropic dose ratios were 3.62 +/- 1.28 and 4.28 +/- 1.50, respectively. Elimination of central nervous system control to the heart by bilateral cervical vagotomy and spinal section at the atlanto-occipital junction significantly (p less than 0.05) improved the toxic to inotropic and lethal to inotropic dose ratios to 6.66 +/- 1.00 and 8.72 +/- 1.29, respectively. In addition, the inotropic response attained in these animals (+ 5.30 +/- 0.70 g-tension above control level) was significantly higher than the inotropic response attained in the neurally intact animals. These results suggest that when the central nervous system actions of digoxin are prevented from influencing the heart, greater increases in cardiac contractility are obtained with less likelihood of digoxin-induced toxicity.
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D002415:Cats; D002490:Central Nervous System / Q000187:drug effects*; D004077:Digoxin / Q000494:pharmacology* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005260:Female; D006321:Heart / Q000294:innervation*; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D013116:Spinal Cord / Q000502:physiology; D014655:Vascular Resistance / Q000187:drug effects
D004077:Digoxin