AT(1) and AT(2) receptor expression and blockade after acute ischemia-reperfusion in isolated working rat hearts.
We assessed ANG II type 1 (AT(1)) and type 2 (AT(2)) receptor (R) expression and functional recovery after ischemia-reperfusion with or without AT(1)R/AT(2)R blockade in isolated working rat hearts. Groups of six hearts were subjected to global ischemia (30 min) followed by reperfusion (30 min) and exposed to no drug and no ischemia-reperfusion (control), ischemia-reperfusion and no drug, and ischemia-reperfusion with losartan (an AT(1)R antagonist; 1 micromol/l), PD-123319 (an AT(2)R antagonist; 0.3 micromol/l), N(6)-cyclohexyladenosine (CHA, a cardioprotective adenosine A(1) receptor agonist; 0.5 micromol/l as positive control), enalaprilat (an ANG-converting enzyme inhibitor; 1 micromol/l), PD-123319 + losartan, ANG II (1 nmol/l), or ANG II + losartan. Compared with controls, ischemia-reperfusion decreased AT(2)R protein (Western immunoblots) and mRNA (Northern immunoblots, RT-PCR) and impaired functional recovery. PD-123319 increased AT(2)R protein and mRNA and improved functional recovery. Losartan increased AT(1)R mRNA (but not AT(1)R/AT(2)R protein) and impaired recovery. Other groups (except CHA) did not improve recovery. The results suggest that, in isolated working hearts, AT(2)R plays a significant role in ischemia-reperfusion and AT(2)R blockade induces increased AT(2)R protein and cardioprotection.
Xu
Yi
Y
Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada T6G 2R7.
Kumar
Dinender
D
Dyck
Jason R B
JR
Ford
William R
WR
Clanachan
Alexander S
AS
Lopaschuk
Gary D
GD
Jugdutt
Bodh I
BI
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000693:Anaerobiosis; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism; D015773:Enalaprilat / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000502:physiology; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D019808:Losartan / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015425:Myocardial Reperfusion; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D051381:Rats; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000235:genetics* / Q000502:physiology; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
D000316:Adrenergic alpha-Agonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000889:Anti-Arrhythmia Agents; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; C027513:N(6)-cyclohexyladenosine; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D015773:Enalaprilat; D006152:Cyclic GMP; D019808:Losartan; D000241:Adenosine