Autonomic nervous system dysfunction alters drug effects: implications for testing drugs for the treatment of heart failure.
Blunted cardiac responses to sympathetic and vagal activation are key features of heart failure. Since the modulation of drug effects by a selective autonomic dysfunction is little known, we developed an acute rabbit model imitating these defects. Anesthetized rabbits were subject to cervical vagotomy and propranolol (1 mg/kg i.v.) pretreatment, thus eliminating vagally and sympathetically mediated cardiac responses, while maintaining the responsiveness of the peripheral circulation to these reflexes ("V-B" animals). Responses to drugs were altered in V-B compared with normal animals: Ouabain (5-50 micrograms/kg) increased myocardial contractile force more and milrinone (30-300 micrograms/kg) less, yet it increased the heart rate more; the reflex tachycardia to nitroprusside (1-10 micrograms/kg/min) was blunted and spirapril (0.1 and 1 mg/kg, all i.v.) decreased the central venous pressure only in V-B animals. Several drug effects were thus strongly modulated by autonomic dysfunction and responses of V-B animals were closer to those of heart failure patients than the responses of the normal animals, especially for milrinone.
Hof
R P
RP
Preclinical Research, Sandoz Pharma Ltd., Basel, Switzerland.
Novosel
D
D
Evenou
J P
JP
Hof
A
A
D000818:Animals; D001341:Autonomic Nervous System / Q000503:physiopathology*; D002317:Cardiovascular Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004656:Enalapril / Q000031:analogs & derivatives / Q000494:pharmacology; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects*; D020105:Milrinone; D009200:Myocardial Contraction / Q000187:drug effects*; D009599:Nitroprusside / Q000494:pharmacology; D010042:Ouabain / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology; D011817:Rabbits; D014628:Vagotomy; D014665:Vasodilator Agents / Q000494:pharmacology
D002317:Cardiovascular Agents; D011728:Pyridones; D014665:Vasodilator Agents; D009599:Nitroprusside; D010042:Ouabain; D004656:Enalapril; C052555:spirapril; D011433:Propranolol; D020105:Milrinone