SYMPATHOADRENERGIC OVERACTIVITY AND LIPID-METABOLISM

Epidemiological studies have identified high heart rates as a risk fac tor for coronary heart disease mortality, and heart rate was found to correlate with the severity of coronary atherosclerosis. Heart rate wa s positively correlated with serum concentrations of total cholesterol , triglycerides, and non-HDL cholesterol. Since heart rate responds se nsitively to sympathoadrenergic activity, it was hypothesized that cat echolamines play a crucial role in the unfavorable lipid alterations. In addition to influences on circulating lipids, the question arose wh ether catecholamines have more specific effects on molecular species o f structural lipids. Of particular importance is the question of the i nvolvement of catecholamines in the recently suggested correlation bet ween 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 s timulation. In swimming rats, linoleic acid was decreased by up to 40% in heart phospholipids, whereas stearic acid and arachidonic acid wer e increased. Similarly, chronic norepinephrine treatment in rats resul ted 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 d efine the action of catecholamines on structural lipids, isolated rat ventricular myocytes in culture were subjected four times to 30 minute s of isoproterenol (10(-6) M) stimulation over 48 hours. No changes in membrane lipid parameters were observed, although the beating rate wa s increased by 30% during the stimulation. When the cell membranes wer e 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 m embrane PUFAs. However, isoproterenol treatment again had no effect on the phospholipid fatty acid composition. Thus, the effect of catechol amines on membrane lipids observed in intact organism appears to be in direct and to involve most probably organs such as the liver and adipo se tissue. Catecholamines are expected to induce a lipolysis-linked qu antitative and qualitative alteration in circulating fatty acids, whic h in turn alter the heart membrane composition, similar to the composi tion changes elicited by diet lipid alterations. Since there is increa sing evidence that such fatty acid changes affect the activity of memb rane proteins, the possibility emerges that this mechanism may contrib ute to the catecholamine-linked cardiovascular mortality.