Antiadrenergic effects of adenosine in pressure overload hypertrophy.
In the present study, we sought to evaluate whether the antiadrenergic action of adenosine in the heart is altered in pressure overload hypertrophy produced in rats by suprarenal aortic banding. Epicardial and coronary effluent adenosine and inosine concentrations and release were significantly elevated in compensated pressure overload hypertrophy but not in hearts with left ventricular failure. In pressure overload hearts, the contractile response to beta-adrenergic stimulation was less inhibited by incremental concentrations of either adenosine or the selective A(1) receptor agonist chloro-N:(6)-cyclopentyl adenosine than in controls. Furthermore, the extent of desensitization to the antiadrenergic actions of adenosine in pressure overload hypertrophy appeared to be proportional to the extent of chamber dilation and dysfunction. A 60-minute infusion of adenosine produced a sustained antiadrenergic effect that lasted up to 45 minutes after the infusion was terminated in both controls and hearts with compensated hypertrophy. This effect was not observed in the decompensated left ventricular failure group. Subsequent infusion with adenosine of the A(2A) receptor antagonist 8-(3-chlorostyryl)-caffeine to counteract the proadrenergic effect of A(2A) receptor stimulation did not alter the decreased sensitivity to the antiadrenergic actions of adenosine in hypertrophied hearts. Finally, isolated myocytes from hypertrophied hearts demonstrated a decreased ability to suppress isoproterenol-elicited increases in [Ca(2+)](i) transients in the presence of adenosine and the A(2A) receptor antagonist compared with myocytes from control hearts. Myocardial adenosine concentrations increase during the compensated phase of pressure overload hypertrophy but then decrease when there is evidence of decompensation. The antiadrenergic actions of adenosine transduced via the myocardial A(1) receptor are diminished in pressure overload hypertrophied hearts. These factors may render these hearts more vulnerable to the detrimental effects of chronically increased sympathetic activity.
Department of Medicine, University of Massachusetts (Worcester), USA. meyert@ummhc.org
T E
TE
Meyer
E S
ES
Chung
S
S
Perlini
G R
GR
Norton
A J
AJ
Woodiwiss
M
M
Lorbar
R A
RA
Fenton
J G
JG
Dobson
D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D018674:Adrenergic Antagonists / Q000494:pharmacology*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure; D001835:Body Weight; D002110:Caffeine / Q000031:analogs & derivatives / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000209:etiology / Q000503:physiopathology*; D002478:Cells, Cultured; D003326:Coronary Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D004452:Echocardiography; D066298:In Vitro Techniques; D007288:Inosine / Q000378:metabolism; D007545:Isoproterenol; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D009929:Organ Size; D010477:Perfusion; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley
D018674:Adrenergic Antagonists; D000318:Adrenergic beta-Agonists; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; C081320:8-(3-chlorostyryl)caffeine; C058394:2-chloro-N(6)cyclopentyladenosine; D002110:Caffeine; D007288:Inosine; D000241:Adenosine; D007545:Isoproterenol; D002118:Calcium