Neurally-mediated increase in calcineurin activity regulates cardiac contractile function in absence of hypertrophy.
OBJECTIVE
The calcineurin pathway has been involved in the development of cardiac hypertrophy, yet it remains unknown whether calcineurin activity can be regulated in myocardium independently from hypertrophy and cardiac load.


METHODS
To test that hypothesis, we measured calcineurin activity in a rat model of infrarenal aortic constriction (IR), which affects neurohormonal pathways without increasing cardiac afterload.


RESULTS
In this model, there was no change in arterial pressure over the 4-week experimental period, and the left ventricle/body weight ratio did not increase. At 2 weeks after IR, calcineurin activity was increased 1.8-fold (P<0.05) and remained elevated at 4 weeks (1.7-fold, P<0.05). Similarly, the cardiac activity of calcium calmodulin kinase II (CaMKII) was increased significantly after IR, which confirms a regulation of Ca(2+)-dependent enzymes in this model. In cardiac myocytes, the increased activity of calcineurin was accompanied by a significant decrease in L-type Ca(2+) channel activity (I(Ca)) and contraction velocity (-dL/dt). Cardiac denervation prevented the activation of calcineurin after IR, which demonstrates that a neurohormonal mechanism is responsible for the changes in enzymatic activity. In addition, cardiac denervation suppressed the effects of IR on I(Ca) and -dL/dt, which shows that calcineurin activation is related to altered contractility. However, action potential duration, the densities of inward rectifier K(+) currents (I(K1)), and outward K(+) currents (I(to) and I(K)) were not altered in IR myocytes.


CONCLUSIONS
Calcineurin can be activated in the heart through a neural stimulus, which induces alterations in Ca(2+) currents and contractility. These effects occur in the absence of myocyte hypertrophy, electrophysiological changes in action potential, and K(+) channel currents.
D000818:Animals; D001012:Aorta, Abdominal; D001020:Aortic Stenosis, Subvalvular / Q000378:metabolism* / Q000503:physiopathology; D009320:Atrial Natriuretic Factor / Q000235:genetics; D017763:Autonomic Denervation; D001341:Autonomic Nervous System / Q000503:physiopathology*; D019703:Calcineurin / Q000032:analysis / Q000378:metabolism*; D020013:Calcium Signaling; D004594:Electrophysiology; D015151:Immunoblotting; D008297:Male; D023421:Models, Animal; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
D015221:Potassium Channels; D012333:RNA, Messenger; D009320:Atrial Natriuretic Factor; D019703:Calcineurin