Increased kallikrein expression protects against cardiac ischemia.
Multiple indirect lines of evidence point at a cardioprotective role for enhanced bradykinin formation. In particular, the inhibition of angiotensin-converting enzyme, also known as kininase II, can protect against cardiac ischemia, putatively via accumulation of bradykinin. To address whether an increase in kinin formation is sufficient to protect against cardiac ischemia, we studied transgenic rats harboring the human tissue kallikrein gene TGR(hKLK1) under the control of the metallothionein promoter, which drives expression of the transgene in various organs including the heart. We subjected the isolated hearts from transgenic rats and their transgene negative littermates to ex vivo regional cardiac ischemia and reperfusion. During the experiment, the hearts were treated with either vehicle or the specific bradykinin type 2 receptor antagonist HOE 140 (10-9 M). In the transgenic rats, overflow of nucleotide breakdown products upon reperfusion was significantly less (455 +-54 nmol/min/g in transgene negative rats vs. 270+-57 nmol/min/g in the transgenic rats, P.
Pinto
Y M
YM
Departments of Cardiology and Clinical Pharmacology, University Hospital Groningen, Groningen, The Netherlands.
Bader
M
M
Pesquero
J B
JB
Tschöpe
C
C
Scholtens
E
E
van Gilst
W H
WH
Buikema
H
H
D000818:Animals; D030801:Animals, Genetically Modified; D001920:Bradykinin / Q000031:analogs & derivatives / Q000096:biosynthesis* / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D007610:Kallikreins / Q000096:biosynthesis* / Q000235:genetics; D023421:Models, Animal; D017202:Myocardial Ischemia / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D011687:Purines / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016277:Ventricular Function, Left
D065168:Bradykinin Receptor Antagonists; D011687:Purines; C065679:icatibant; D007610:Kallikreins; D001920:Bradykinin