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Increased kallikrein expression protects against cardiac ischemia
Author(s) -
Pinto Yigal M.,
Bader Michael,
Pesquero João B.,
Tschöpe Carsten,
Scholtens Egbert,
Gilst Wiek H.,
Buikema Hendrik
Publication year - 2000
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.99-1011fje
Subject(s) - bradykinin , transgene , bradykinin receptor , genetically modified mouse , kinin , ischemia , kallikrein , in vivo , medicine , endocrinology , antagonist , angiotensin ii , biology , receptor , chemistry , pharmacology , enzyme , gene , biochemistry , microbiology and biotechnology
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 <0.05). Systolic dP/dt at the end of ischemia was significantly higher ( P <0.05) in the transgenic rats than in the transgene negative controls, despite a similar reduction in total coronary flow during ischemia. These differences were abolished in the rat hearts where HOE140 was co‐infused. This finding suggests that a chronic increase in tissue kallikrein can increase bradykinin levels sufficiently to protect against cardiac ischemia and that this effect is brought about by a rapid mechanism, rather than by long term structural alterations.