Characterization of cardioprotection mediated by AT2 receptor antagonism after ischemia-reperfusion in isolated working rat hearts.
BACKGROUND
Whether cardioprotection induced by the angiotensin II (AngII) type 2 receptor (AT(2)R) antagonist PD123,319 (PD) after ischemia-reperfusion (IR) is influenced by the concentration of PD, presence of AngII, timing of exposure, or inhibition of proton production from glucose metabolism is not known.


RESULTS
We examined these factors in isolated working rat hearts subjected to IR injury, no treatment (control), or treatment with N(6)-cyclohexyl adenosine (CHA, 0.5 micromol/L), an adenosine A(1) receptor agonist that induces cardioprotection by decreasing protons ("positive" control). Compared with control, 1 micromol/L PD present throughout IR improved recovery of left ventricular work (73 +/- 5 vs. 40 +/- 8%) to the level with CHA (82 +/- 5%), but 0.1 micromol/L PD did not (58 +/- 6 vs. 40 +/- 8%). AngII (1 nmol/L) did not effect postischemic recovery associated with 1 micromol/L PD (73 +/- 7%) but improved that associated with 0.1 micromol/L PD (86 +/- 3%). PD (1 micromol/L), present solely during reperfusion, enhanced postischemic left ventricular recovery to 72 +/- 5%. Also, PD (1 micromol/L) did not affect glycolytic rates or proton production in nonischemic or IR hearts.


CONCLUSIONS
PD-induced cardioprotection is 1) PD concentration-dependent, 2) AngII-sensitive, 3) mediated during reperfusion, and 4) independent of proton production, suggesting that reduction in IR injury and indirect AT(1)R stimulation might be involved.
Ford
W R
WR
Cardiology Division of the Department of Medicine and the Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada.
Clanachan
A S
AS
Jugdutt
B I
BI
D000804:Angiotensin II / Q000494:pharmacology* / Q000627:therapeutic use; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D017494:Proton Pumps / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016277:Ventricular Function, Left / Q000187:drug effects* / Q000502:physiology
D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D017494:Proton Pumps; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C073402:PD 123319