Bradykinin released during intense exercise inhibits the expression of gap junction protein in trained mouse hearts

TISCORNIA GISELA; AMORENA CARLOS; GARCIA GRAS EDUARDO

Buenos AIres

Congreso; World Congress of Cardiology 08; 2008

World Heart Federation

Physical exercise is contraindicated for individuals suffering from a number of cardiomyopathies (1) . For cardiomyopathies such as arrhythmogenic right ventricular cardiomyopathy (ARVC) or Dilated cardiomyopathy (DC), sudden death events tend to occur during or shortly after intense physical exercise (2, 3). A ventricular fibrillation (VF) episode during exercise could be attributed to the increased cardiac rhythm. However it is common for these events to occur after exercise, once the heart has returned to its resting rate (2, 3) . We propose an alternative mechanism that could explain the generation of arrhythmogenic substrate as a direct result of the physical exercise, but independently of the heart rate. Ischemic preconditioning (IP) is a well known phenomenon that has been described mainly in the heart, but was also observed in the brain, kidney, liver and skeletal muscle, indicating that IP is a general phenomenon (4). Moreover it has been shown that a brief ischemia in tissues other than the heart (such as mesenteric artery occlusion) results in remote IP (RIP) of the heart (5). This process is mediated by bradykinin secreted by the ischemic tissues (6).  A key event in RIP is the inhibition of connexin 43 (cx43) expression as well as a change in cx43 intracellular localization that reduces the total number of functional gap junctions (7). During intense physical exercise blood flow is diverted from the mesenteric plexus to the striated muscles, resulting in transient hypoxia and bradykinin secretion from the mesenteric plexus (8). We therefore hypothesized that intense physical exercise could result in a reduction of cx43 expression through a mechanism similar to that of RIP.  Sustained exercise training would increase bradykinin receptor expression in the heart which would make a trained individual more susceptible to bradykinin released during exercise. We used swim trained mice to evaluate connexin 43 expression. We trained mice for 7 weeks with two daily sessions of swimming, from Monday to Friday. Daily sessions were increased in duration 5 minutes a day from 10 minutes until they reached 60 minutes. On the day of the experiment mice swam 0, 15 or 60 minutes. Mice were sacrificed immediately after swimming and the hearts were processed for protein and RNA extraction. Connexin 43 expression was analyzed by semi-quantitative RT-PCR and Western blot. We observed significant differences in cx43 mRNA expression from the minute 15 and in cx43 protein from minute 60. A decrease in gap junctions number in a heart compromised by ARVC or DC, could reduce conductivity generating the substrate for arrhythmia, VT or VF. We conclude that this mechanism, alone or in combination with increased heart rate during exercise, could be responsible for triggering sudden deaths in athletes suffering from cardiomyopathies such as ARVC or DC which reduce per se the expression of cx43(9).