The anti-infarct effect of an adenosine A1-selective agonist is diminished after prolonged infusion as is the cardioprotective effect of ischaemic preconditioning in rabbit heart.
Our aim was to determine whether adenosine A1 receptor-mediated protection could be maintained for a prolonged period of time by a continuous infusion of an A1-selective agonist. To produce myocardial infarction a branch of the left coronary artery of rabbit hearts was occluded for 30 min and reperfused for 3 h. Infarct size was determined with tetrazolium staining. Prior to the 30 min ischaemia, rabbits were subjected to one of the following six protocols: (1) 6 h i.v. saline infusion; (2) 6 h i.v. CCPA (0.043 mg/kg/h) infusion; (3) 72 h saline infusion; (4) 72 h CCPA infusion; (5) 72 h CCPA infusion plus preconditioning with 5 min ischaemia followed by 10 min reperfusion; (6) 72 h saline infusion plus preconditioning. The 6 h CCPA infusion group had significantly smaller infarct sizes than the 6 h vehicle group. 16.2 +/- 2.9% infarction of the ischaemic region v 39.5 +/- 2.6%, P < 0.01. Infarction in the 72 h CCPA infusion group (37.7 +/- 2.7%) was the same as in the 72 h vehicle group (35.2 +/- 3.1%). Ischaemic preconditioning could not limit infarct size in 72 h CCPA animals (%infarction; 29.1 +/- 4.6%) but did protect animals given vehicle for 72 h (8.4 +/- 1.2%, P < 0.01). After 72 h infusion of CCPA, both the cardioprotective effect of adenosine A1-selective agonist and ischaemic preconditioning were attenuated. These findings indicate that: (1) the myocytes become desensitized to the protective effect of CCPA with prolonged exposure; and (2) ischaemic preconditioning is no longer protective when tachyphylaxis to CCPA occurs.
Tsuchida
A
A
Department of Physiology, University of South Alabama, Mobile 36688.
Thompson
R
R
Olsson
R A
RA
Downey
J M
JM
D000109:Acetylcholine / Q000494:pharmacology; D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology / Q000502:physiology* / Q000627:therapeutic use; D000818:Animals; D001919:Bradycardia / Q000139:chemically induced; D004361:Drug Tolerance; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D007022:Hypotension / Q000139:chemically induced; D007262:Infusions, Intravenous; D008297:Male; D009124:Muscle Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control*; D017202:Myocardial Ischemia / Q000503:physiopathology*; D009206:Myocardium / Q000473:pathology; D009336:Necrosis; D058915:Purinergic P1 Receptor Antagonists; D011817:Rabbits; D011976:Receptors, Muscarinic / Q000187:drug effects; D018047:Receptors, Purinergic P1 / Q000502:physiology
D009124:Muscle Proteins; D058915:Purinergic P1 Receptor Antagonists; D011976:Receptors, Muscarinic; D018047:Receptors, Purinergic P1; C058394:2-chloro-N(6)cyclopentyladenosine; D000241:Adenosine; D000109:Acetylcholine