Adenosine attenuates phorbol ester-induced negative inotropic and vasoconstrictive effects in rat hearts.
Phorbol esters reduce cardiac contractility and produce coronary vasoconstriction presumably by stimulating protein kinase C (PKC). We tested whether adenosine altered the response to phorbol 12-myristate 13-acetate (PMA) in isolated rat hearts. Hearts, perfused at constant flow and constant heart rate, were exposed to PMA (10 nM) for 30 min and then allowed 30 min of recovery. PMA reduced left ventricular developed pressure (LVDP) from 81 +/- 2 to 49 +/- 3 and 40 +/- 2 mmHg (51 +/- 3% of baseline LVDP) after 30 min infusion and 30 min recovery, respectively. PMA also increased coronary perfusion pressure to 224 +/- 13% of baseline after 60 min. The PKC inhibitor bisindolylmaleimide (0.5 microM) blocked the PMA-induced negative inotropy and vasoconstriction. Adenosine (100 microM) and the A1-agonist 2-chloro-N6-cyclopentyladenosine (CCPA, 0.1 microM) significantly attenuated the negative inotropic effect of PMA as LVDP was maintained at 81 +/- 4% and 99 +/- 7% of baseline, whereas CGS-21680, an A2-agonist, had no beneficial effect on function (54 +/- 4% of baseline). Adenosine and CGS-21680 (0.1 microM), but not CCPA, significantly attenuated PMA-induced coronary vasoconstriction. These results suggest that adenosine receptor activation may modulate myocardial PKC activity or attenuate the effects of increased PKC activity.
Lasley
R D
RD
Department of Surgery, University of Wisconsin, Madison 53792-0001.
Noble
M A
MA
Paulsen
K L
KL
Mentzer
R M
RM
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects*; D004075:Diglycerides / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects*; D010477:Perfusion; D010627:Phenethylamines / Q000494:pharmacology; D011312:Pressure; D051381:Rats; D017208:Rats, Wistar; D018047:Receptors, Purinergic P1 / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*
D004075:Diglycerides; D007211:Indoles; D008301:Maleimides; D010627:Phenethylamines; D018047:Receptors, Purinergic P1; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C058394:2-chloro-N(6)cyclopentyladenosine; D000241:Adenosine; C088060:bisindolylmaleimide; D013755:Tetradecanoylphorbol Acetate; C013965:diolein