Antagonism of the cardiodepressant effects of adenosine during acute hypoxia.
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.
Cummings
J
J
Department of Emergency Medicine, Albert Einstein Medical Center, Philadelphia, PA 19141, USA.
Kaplan
J L
JL
Gao
E
E
Clas
D
D
Dalsey
W C
WC
de Garavilla
L
L
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
D058915:Purinergic P1 Receptor Antagonists