title: Autonomic nervous system dysfunction alters drug effects: implications for testing drugs for the treatment of heart failure.
abstract: 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.
authors.affiliation: Preclinical Research, Sandoz Pharma Ltd., Basel, Switzerland.
authors.forename: R P
authors.initials: RP
authors.lastname: Hof
authors.forename: D
authors.initials: D
authors.lastname: Novosel
authors.forename: J P
authors.initials: JP
authors.lastname: Evenou
authors.forename: A
authors.initials: A
authors.lastname: Hof
mesh_terms: 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
chemical_list: D002317:Cardiovascular Agents; D011728:Pyridones; D014665:Vasodilator Agents; D009599:Nitroprusside; D010042:Ouabain; D004656:Enalapril; C052555:spirapril; D011433:Propranolol; D020105:Milrinone