title: Antagonism of the cardiodepressant effects of adenosine during acute hypoxia.
abstract: OBJECTIVE
  To determine whether pharmacologic antagonism of adenosine A1-receptor-mediated cardiovascular changes can improve cardiac function and prolong survival during systemic hypoxia.
  
  
  METHODS
  Rats were anesthetized with ketamine, instrumented [including left ventricular (LV) pressure transducing catheters], paralyzed with vecuronium, then ventilated to pCO2 = 35-40 torr. After 10 minutes of equilibration (baseline), treatment commenced with saline (n = 7), NPC-205, an adenosine A1 receptor selective antagonist, at doses of 1 mg/kg (n = 10) or 10 mg/kg (n = 10), or drug vehicle (n = 9). Ten minutes later, inspired oxygen was reduced to 5%.
  
  
  RESULTS
  Survival duration (min) post-hypoxia increased in a dose-dependent fashion from 10.4 +/- 1.4 (mean +/- SEM) with vehicle control to 23.0 +/- 4.7 and 41.1 +/- 5.7 with 1 and 10 mg/kg NPC-205, respectively (p < 0.000). Five minutes post-hypoxia, dose-dependent increases were also seen in the percentage of pre-hypoxic values of LV contractility [25.9 +/- 8.1 (vehicle), 39.5 +/- 9.6 (1 mg/kg NPC-205), and 56.5 +/- 8.7 (10 mg/kg NPC-205), p = 0.01], heart rate [60.6 +/- 8.3 (vehicle), 74.7 +/- 8.2 (1 mg/kg NPC-205), and 90.4 +/- 24.1 (10 mg/kg NPC-205), p = 0.02], and blood pressure [16.1 +/- 4.8 (vehicle), 28.8 +/- 8.6 (1 mg/kg NPC-205), and 51.7 +/- 8.2 (10 mg/kg NPC-205), p = 0.004].
  
  
  CONCLUSIONS
  The adenosine A1 selective antagonist prolonged survival in this model. This prolongation was attributed to inhibition of adenosine A1 receptor-mediated decline in cardiac inotropy and chronotropy. Adenosine A1 receptor-selective antagonists show promise as adjunctive therapy for hypoxia-induced cardiac insufficiency by prolonging the treatment window until more definitive resuscitation measures are taken.
authors.affiliation: Department of Emergency Medicine, Albert Einstein Medical Center, Philadelphia, PA 19141, USA.
authors.forename: J
authors.initials: J
authors.lastname: Cummings
authors.forename: J L
authors.initials: JL
authors.lastname: Kaplan
authors.forename: E
authors.initials: E
authors.lastname: Gao
authors.forename: D
authors.initials: D
authors.lastname: Clas
authors.forename: W C
authors.initials: WC
authors.lastname: Dalsey
authors.forename: L
authors.initials: L
authors.lastname: de Garavilla
mesh_terms: D000818:Animals; D001784:Blood Gas Analysis; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D000860:Hypoxia / Q000503:physiopathology*; D011446:Prospective Studies; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D016019:Survival Analysis
chemical_list: D058915:Purinergic P1 Receptor Antagonists