Adenosine A1 antagonism attenuates beta-adrenergic-resistant sudden hypoxic cardiac insufficiency.

Abstract

OBJECTIVES:

In states such as hypoxia, shock, and cardiac arrest, compromised systemic oxygenation or perfusion appears to induce cardiac insufficiency that can be resistant to beta-adrenergic drugs. Elevated levels of adenosine may mediate such beta-adrenergic-resistant cardiac insufficiency via the adenosine A(1) receptor (A(1)AdoR). The objective of this study was to test the hypothesis that selective A(1)AdoR antagonism attenuates hypoxic cardiac insufficiency more efficaciously than beta(1)-adrenergic agonism or nonselective adenosine antagonism.

METHODS:

Rats were paralyzed and ventilated to a pCO(2) level of 35-40 mm Hg. Ten minutes before hypoxia (inspired o(2) concentration = 5%), rats were treated intravenously with one of the following: 0.1 mg/kg BG-9719 (n = 9), 10 mg/kg NPC-205 (n = 10; BG-9719 and NPC-205 are selective A(1)AdoR antagonists, with durations of action of 30-60 minutes and 60-90 minutes, respectively), 10 mg/kg aminophylline (n = 12), 5 microg/kg/min dobutamine (n = 11), or control solutions. These drug doses maximized survival duration in dose-response studies.

RESULTS:

Before hypoxia, cardiac work was increased more by aminophylline and dobutamine than by BG-9719. Mean (+/-SEM) duration of survival (in minutes) after hypoxia increased from <13 (control solutions) to 13.8 (+/-1.4) (dobutamine), 20.0 (+/-1.6) (aminophylline), 31.7 (+/-4.6) (BG-9719), and 40.5 (+/-7.5) (NPC-205) (p < 0.0001). Heart rate and dP/dt decreased rapidly after hypoxia, but decreases were attenuated with BG-9719 and NPC-205 compared with dobutamine (p < 0.05) and tended toward attenuation with aminophylline.

CONCLUSIONS:

BG-9719 and NPC-205 improved survival duration, heart rate, and left ventricular contractility during hypoxia more efficaciously than dobutamine and possibly aminophylline. Selective A(1)AdoR antagonists warrant further study as alternatives to beta-adrenergic agonists in hypoxia, shock, and cardiac arrest, in which compromised systemic perfusion or oxygenation impairs cardiac output.

• Authors: Erhe Gao, Justin L Kaplan, Michelle S Victain, William C Dalsey, Lawrence de Garavilla
• Journal: Academic emergency medicine : official journal of the Society for Academic Emergency Medicine (Acad Emerg Med) Vol. 12 Issue 5 Pg. 389-95 (May 2005) ISSN: 1553-2712 [Electronic] United States
• PMID: 15860691 (Publication Type: Comparative Study, Journal Article)

Chemical References

• 1,3-dipropyl-8-(2-(5,6-epoxy)norbornyl)xanthine
• Adenosine A1 Receptor Antagonists
• Adrenergic beta-Agonists
• Cardiotonic Agents
• Xanthines
• Aminophylline
• Dobutamine

Topics

• Acute Disease
• Adenosine A1 Receptor Antagonists
• Adrenergic beta-Agonists (therapeutic use)
• Aminophylline (therapeutic use)
• Animals
• Cardiotonic Agents (therapeutic use)
• Disease Models, Animal
• Dobutamine (therapeutic use)
• Dose-Response Relationship, Drug
• Heart Diseases (drug therapy)
• Hemodynamics (drug effects)
• Hypoxia (drug therapy)
• Male
• Pilot Projects
• Rats
• Rats, Sprague-Dawley
• Survival Analysis
• Treatment Outcome
• Xanthines (therapeutic use)