Mechanisms of alterations in cardiac membrane Ca2+ transport due to excess catecholamines.

Dhalla KS, Rupp H, Beamish RE, Dhalla NS

Division of Cardiovascular Sciences, St. Boniface General Hospital Research
Centre, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.

The occurrence of excessive catecholamine release is often associated with
stress due to the lifestyle of Western societies. Contrary to the general
thinking that excess catecholamines produce cardiotoxicity mainly via binding
to adrenoceptors, there is increasing evidence that catecholamine-induced
deleterious actions may also occur through oxidative mechanisms. In this
overview it is shown that a high dose of isoproterenol induces a biphasic
change in cardiac Ca2+ transport in the sarcolemma and in sarcoplasmic
reticulum. Both sarcolemmal and sarcoplasmic reticular Ca2+-transport
activities are initially increased to maintain Ca2+ homeostasis and then are
impaired, which may be associated with the occurrence of intracellular Ca2+
overload. On the other hand, mitochondrial Ca2+-transport activities exhibited
a delayed increase. Pretreatment with vitamin E partially prevented the
deleterious changes in cardiac membranes as well as the depressed energetic
status of the heart muscle cell. It is concluded that excess catecholamines
affect Ca2+-transport mechanisms primarily via oxidation reactions involving
free radical-mediated damage. Thus drug approaches that reduce circulating
catecholamines and/or prevent their oxidation should prove beneficial. A
combination therapy involving inhibitors of catecholamine release, blockers of
adrenoceptors, and antioxidants may be indicated for stress-induced heart
disease.