Sympathoadrenergic overactivity and lipid metabolism.

Grynberg A, Ziegler D*, Rupp H**

INRA, Unite de Nutrition Lipidique, Dijon, France, *Solvay Pharmaceuticals,
Hannover, Germany,  **Molecular Cardiology Laboratory, Department of
Internal Medicine and Cardiology, University of Marburg, Germany

Epidemiological studies have identified high heart rates as a risk factor for
coronary heart disease mortality, and heart rate was found to correlate with
the severity of coronary atherosclerosis. Heart rate was positively correlated
with serum concentrations of total cholesterol, triglycerides, and non-HDL
cholesterol. Since heart rate responds sensitively to sympathoadrenergic
activity, it was hypothesized that catecholamines play a crucial role in the
unfavorable lipid alterations. In addition to influences on circulating lipids,
the question arose whether catecholamines have more specific effects on
molecular species of structural lipids. Of particular importance is the
question of the involvement of catecholamines in the recently suggested
correlation between arachidonic acid and stroke mortality. It is therefore
attempted to delineate the possible effects of catecholamines on the fatty acid
composition of the phospholipids of heart muscle and vasculature. This was
achieved in rats by either catecholamine injection or by swimming, a condition
known to be associated with marked sympatho-adrenergic stimulation. In swimming
rats, linoleic acid was decreased by up to 40% in heart phospholipids, whereas
stearic acid and arachidonic acid were increased. Similarly, chronic
norepinephrine treatment in rats resulted in a net decrease in linoleic acid
and an increase in arachidonic acid and docosahexaenoic acid, which was
particularly pronounced when rats were fed an n-3 polyunsaturated fatty acid
(PUFA)-rich oil diet. Thus, catecholamines do affect the PUFA composition of
heart membranes, mainly through an increase in arachidonic acid content. To
further define the action of catecholamines on structural lipids, isolated rat
ventricular myocytes in culture were subjected four times to 30 minutes of
isoproterenol (10(-6) M) stimulation over 48 hours. No changes in membrane
lipid parameters were observed, although the beating rate was increased by 30%
during the stimulation. When the cell membranes were enriched in n-3 PUFAs (in
association with a decrease in arachidonic acid), the positive chronotropic
effect elicited by isoproterenol was raised to + 50%, indicating the modulation
of adrenergic function by membrane PUFAs. However, isoproterenol treatment
again had no effect on the phospholipid fatty acid composition. Thus, the
effect of catecholamines on membrane lipids observed in intact organism appears
to be indirect and to involve most probably organs such as the liver and
adipose tissue. Catecholamines are expected to induce a lipolysis-linked
quantitative and qualitative alteration in circulating fatty acids, which in
turn alter the heart membrane composition, similar to the composition changes
elicited by diet lipid alterations. Since there is increasing evidence that
such fatty acid changes affect the activity of membrane proteins, the
possibility emerges that this mechanism may contribute to the
catecholamine-linked cardiovascular mortality.