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1 Department of Physiology, University of South Alabama, Mobile, AL, USA
2 Department of Cell Biology and Neuroscience, University of South Alabama, Mobile, AL, USA
3 Department of Physiology, University of South Alabama, Mobile, AL, USA; Department of Medicine, University of South Alabama, Mobile, AL, USA
* To whom correspondence should be addressed. E-mail: mcohen{at}usouthal.edu.
Bradykinin mimics ischemic preconditioning by generating reactive oxygen species (ROS). To identify intermediate steps leading to ROS generation, rabbit cardiomyocytes were incubated in reduced MitoTracker Red that becomes fluorescent after exposure to ROS. Fluorescence intensity in treated cells was expressed as % of that in paired untreated cells. Bradykinin (500nM) caused 51±16% increase in ROS generation (p<0.001). Co-incubation with either bradykinin B2 receptor blocker HOE140 (5µM) or free radical scavenger N-(2-mercaptopropionyl) glycine (1mM) prevented this increase confirming the response was receptor-mediated and ROS were actually being measured. Closing mitochondrial KATP (mKATP)channels with 5-hydroxydecanoate (5HD, 1mM) prevented increased ROS generation. Bradykinin-induced ROS generation was blocked by L-NAME (200µM) implicating nitric oxide as an intermediate. Blockade of guanylyl cyclase with ODQ (10µM) aborted bradykinin-induced ROS generation, but not that from diazoxide, a direct opener of mKATP channels. The PKG blocker 8-Br-cGMPS (25µM) eliminated bradykinin's effect. Conversely, direct activation of PKG with 8-pCPT-cGMP (100µM) increased ROS generation (39±15%, p<0.004) similar to bradykinin. This increase was blocked by 5HD. Finally, the nitric oxide donor SNAP (1µM)increased ROS by 34±6%. This increase was also blocked by 5HD. In intact rabbit hearts bradykinin (400nM) decreased infarction from 30.5±3.0% of the risk zone in control hearts to 11.9±1.4% (p<0.01). This protection was aborted by either L-NAME (200µM) or ODQ (2µM)(35.4±5.7% and 30.4±3.0% infarction, resp., pNS vs control). Hence, bradykinin preconditions through receptor-mediated production of nitric oxide which activates guanylyl cyclase. The resulting cGMP activates PKG that opens mKATP. Subsequent release of ROS triggers cardioprotection.
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