Time course of alterations in phospholipid fatty acids and number of beta-adrenoceptors in the rat heart during adrenergic stimulation in vivo.

The purpose of this study was to test the hypothesis that catecholamine induced down-regulation of beta-adrenoceptors in cardiac muscle is facilitated by modifications of the lipid milieu in cellular membranes. The time course of down-regulation of beta -adrenoceptors and changes in the fatty acid composition of phospholipids was examined in the rat heart during adaptation to repeated epinephrine administration. By this we studied a possible relationship between modulation of the membrane phospholipids and the properties of beta-adrenoceptors during 7 days of epinephrine administration. The fatty acid composition of cardiac membrane phosphatidylcholine (PC) and phosphatidylethanolamine (PE) and Bmax and Kd of [3H]dihydroalprenolol binding to beta -adrenoceptors were measured in rats after 1, 2, 3, 5 and 7 days of epinephrine administration. The in vivo adrenergic stimulation led to a significant response of phospholipid fatty acyl chains. In both PC and PE the linoleic acid (18:2n-6) level decreased markedly. The docosahexanoic acid (22:6n-3) level increased in PE and the arachidonic acid (20:4n-6) level increased in PC. These fatty acid changes were all significant after 3-5 days of epinephrine administration. During the 7 day epinephrine administration, the polyunsaturated fatty acid levels in the phospholipids of purified cardiac sarcolemma changed in the same way as in the phospholipids of whole ventricular muscle. The number of binding sites of beta -adrenoceptors (Bmax) decreased as expected. The decrease in Bmax occurred later than the changes in their lipid environment and was only significant after 7 days of epinephrine administration. The conclusion is that during adaptation to epinephrine administration, the down-regulation of beta-adrenoceptors is preceded by alterations in the polyunsaturated fatty acid composition of phospholipids in heart muscle. This supports the concept of a regulatory role of membrane lipids in the response of beta-adrenoceptors to prolonged stimulation.

Regulation of beta-adrenoceptor properties and the lipid milieu in heart muscle membranes during stress.

UNLABELLED: The purpose of this study was to examine changes in fatty acyl chain composition of major cardiac phospholipids in relation to down-regulation of beta-adrenoceptors during various forms of stress or chronic adrenergic stimulation. Analysis of the fatty acid profile of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) in sarcolemma or cardiac muscle membranes showed partial replacement of 18:2n-6 by 20:4n-6 in PC and replacement of both 18:2n-6 and 20:4n-6 by 22:6n-3 in PE during daily administration of epinephrine or norepinephrine for 7 or 15 days, respectively. These changes in membrane PC and PE coincided with down-regulation or the decrease in Bmax of beta-adrenoceptors during adrenergic stimulation. Cardiac membrane response to other forms of stress or chronic adrenergic stimulation such as neonatal stress, restriction stress or restricted food intake was expressed in the same way, that is replacement of 18:2n-6 by 20:4n-6 in PC and replacement of 18:2n-6 and 20:4n-6 by 22:6n-3 in PE. CONCLUSION: Adaptation to stress includes a decrease in the density of binding sites or down-regulation of beta-adrenoceptors in sarcolemma synchronized with specific alterations in the fatty acyl chain composition with the membrane bilayer. The changes in the lipid milieu of the membrane may facilitate conformational changes in the transmembrane segment of the receptor forming the ligand binding sites of the beta-adrenoceptor.

Effects of ageing and adrenergic stimulation on alpha 1- and beta-adrenoceptors and phospholipid fatty acids in rat heart.

The purpose of this study was to examine the influence of ageing on the alterations in binding characteristics of adrenoceptors and membrane phospholipid fatty acids in rat heart following repeated administration of epinephrine. The maximal number of binding sites (Bmax) and dissociation constant (Kd) of [3H]prazosin and [3H]dihydroalprenolol binding to alpha 1- and beta-adrenoceptors, respectively, changed significantly during ageing. The downregulation of alpha 1- and beta-adrenoceptors after repeated epinephrine administration for one week, did not differ with age, but the response of the affinity (1/Kd) of both alpha 1- and beta-adrenoceptors to epinephrine treatment was age dependent. In 3-month-old rats the affinity of alpha 1-adrenoceptors was decreased after epinephrine treatment but the affinity of beta-adrenoceptors was unchanged. In 10- and 23-month-old rats the affinity of beta-adrenoceptors decreased after epinephrine treatment but the affinity of alpha 1-adrenoceptors did not change. During ageing the linoleic acid (18:2(n-6)) level decreased in phosphatidylcholine and the arachidonic acid (20:4(n-6)) level increased in phosphatidylcholine and phosphatidylethanolamine. After epinephrine administration the 18:2(n-6) level decreased and the docosahexaenoic acid (22:6(n-3)) level increased in phosphatidylcholine and phosphatidylethanolamine and those changes were not age dependent. The 20:4(n-6) level increased in phosphatidylcholine after epinephrine administration, but that increase was smaller in old than in young rats. The results show that both ageing and epinephrine administration simultaneously modify the fatty acid composition of membrane phospholipids and the binding properties of alpha 1- and beta-adrenoceptors in rat heart.

Coregulation of adrenoceptors and the lipid environment in heart muscle during repeated adrenergic stimulation.

The purpose of this study was to examine changes in binding properties of alpha 1-adrenoceptors, beta-adrenoceptors and L-Ca channels in rat heart muscle in relation to changes in the lipid environment within the membrane, i.e. fatty acyl chain composition of membrane phospholipids, occurring during repeated adrenergic stimulation. The effect of daily administration of epinephrine for seven days upon the maximum number of binding sites of adrenoceptors and upon the fatty acyl chain composition of phosphatidylcholine and phosphatidylethanolamine was examined in 10 months old rats. Decrease in Bmax of adrenoceptors during repeated adrenergic stimulation coincided with remodeling of the membrane phospholipids, with replacement of 18:2n-6 by 20:4n-6 in phosphatidylcholine and by 22:6n-3 in phosphatidylethanolamine, respectively. The effect of repeated adrenergic stimulation was also examined in rats fed different dietary fats and oils, i.e. butter, corn oil or cod liver oil, in hearts with markedly different levels of 18:2n-6, 20:4n-6 and 22:6n-3. The binding properties of the adrenoceptors and L-Ca channels did not relate to the fatty acyl chain composition of bulk phospholipids, but the epinephrine induced decrease in Bmax of the receptors was always accompanied by replacement of 18:2n-6 by 20:4n-6 in phosphatidylcholine and by 22:6n-3 in phosphatidylethanolamine, regardless of the initial level of these fatty acyl chains in the phospholipids. It is concluded that adaption to repeated adrenergic stimulation may include coregulation of the lipid environment within the membrane and the binding properties of adrenoceptors, and possibly other functionally coupled proteins such as L-Ca channels, residing in the membrane.

Combined effects of age and dietary fat on beta 1-receptors and Ca2+ channels in rat hearts.

Male Wistar rats were fed a standard diet or diets supplemented with 10% butter, 10% corn oil, or 10% cod liver oil from the age of 2 mo. At 7 and 24 mo of age, the fatty acid composition of total phospholipids was determined in ventricular crude sarcolemma preparations; binding capacity and affinity (1/Kd) of [3H]dihydroalprenolol and [3H]nitrendipine binding were also determined. The arachidonic acid level was significantly higher at 24 mo than at 7 mo of age in the membrane phospholipids in rats fed no extra fat, but in rats fed fat-supplemented diets, age had no effect. Affinity of Ca2+ channels for [3H]nitrendipine decreased significantly in all dietary groups between 7 and 24 mo of age, whereas the affinity of beta 1-receptors for [3H]dihydroalprenolol increased in corn oil-fed rats. Density of beta 1-receptors decreased significantly in corn oil- and butter-fed rats and rats fed no extra fat between 7 and 24 mo of age, whereas the density of Ca2+ channels decreased significantly in corn oil-fed rats. We conclude that the antagonist binding properties of Ca2+ channels and beta 1-adrenergic receptors in rat hearts may change with age depending on the dietary fat.

Effects of n-3 polyunsaturated fatty acids on coronary heart disease.

The purpose of this paper is to discuss the role of n-6 and n-3 polyunsaturated fatty acids in coronary heart disease (CHD). The level of n-6 and n-3 fatty acids in plasma and cardiac phospholipids was examined in relation to CHD in man. The fatty acid profile of cardiac phospholipids was also examined in relation to various risk factors of CHD, such as the composition of dietary fat, aging and stress. Life expectancy in Iceland is higher than in other Nordic countries, and the cardiovascular diseases mortality is lower in Iceland in the older age groups. There is a positive correlation between the level of arachidonic acid (AA) in plasma phospholipids (PL) in the normal population and cardiovascular disease mortality in Nordic countries. The level of AA in plasma PL is significantly higher in patients with CHD than in normal subjects. Dietary intake of fish or fish oil lowers cellular levels of AA and favorably influences eicosanoid metabolism in platelets and leukocytes. The roles of n-6 and n-3 fatty acids in heart muscle are less well understood. Rats fed diets containing either 10% butter, corn oil or cod liver oil showed markedly different fatty acid composition of individual phospholipids in sarcolemma. Dietary cod liver oil lowered the AA level in sarcolemmal phosphatidyl choline (PC) and phosphatidyl ethanolamine (PE) by 50% compared to butter or corn oil fed rats, replacing AA with docosahexaenoic acid (DHA). Adaptation to moderate to severe stress induced by repeated administration of catecholamines for 15 days resulted in marked but reversible alterations in the fatty acid profile of cardiac phospholipids. During severe stress the level of AA increased by 50% in PC replacing linoleic acid (LA), whereas in PE the DHA increased markedly replacing LA. Aging was accompanied by similar alterations in cardiac phospholipids, increased levels of AA in PC and increased DHA in PE. The incidence of ventricular fibrillation (VF) and sudden cardiac death induced by isoproterenol in adult rats fed different dietary fat was lowest in rats fed cod liver oil, with a low ratio of AA/DHA in cardiac phospholipids. Mortality due to VF was highest in rats fed corn oil with the highest ratio of AA/DHA. Sudden cardiac death in man was frequently associated with a higher ratio of AA/DHA than observed in people of the same age who died in accidents. The balance between n-6 and n-3 fatty acids in cellular phospholipids seems to play an important role in stress tolerance and survival.

Reversible alterations in fatty acid composition of heart muscle membrane phospholipids induced by epinephrine in rats fed different fats.

The effect of epinephrine on the fatty acid composition of heart muscle phospholipids was examined in rats fed diets containing 10% by weight of butter, corn oil, or cod liver oil. Repeated administration of epinephrine caused elevation of docosahexaenoic acid in phosphatidylcholine and phosphatidylethanolamine and a corresponding decrease in linoleic acid content. Arachidonic acid was increased in phosphatidylcholine and decreased or unaltered in phosphatidylethanolamine. These alterations were qualitatively similar despite different initial levels of fatty acids due to different dietary fats. The initial level of arachidonic acid in phosphatidylcholine and phosphatidylethanolamine was more than 50% lower in the rats fed cod liver oil than in rats fed butter and was partially replaced by the (n-3) fatty acids docosahexaenoic and eicosapentaenoic acid. Dietary corn oil produced less changes in fatty acid composition than cod liver oil compared to the reference diet, 10% butter. The results demonstrate that repeated administration of epinephrine caused significant alterations in fatty acid composition of major phospholipids in heart muscle of rats fed diets enriched with either butter, corn oil, or cod liver oil.

Modification of the fatty acid composition of rat heart sarcolemma with dietary cod liver oil, corn oil or butter.

The effect of dietary cod liver oil, corn oil or butter upon the lipid composition of cardiac sarcolemma and the activity of sarcolemmal Na+, K+ ATPase was examined in male Wistar rats. The cod liver oil diet caused significant changes in the fatty acid composition of the major phospholipids of sarcolemma, phosphatidyl choline and phosphatidyl ethanolamine. In both these phospholipids arachidonic acid, 20:4 (n - 6) was reduced by about 50% compared to rats fed butter or corn oil and was replaced by the (n - 3) fatty acids eicosapentaenoic and docosahexaenoic acids. The corn oil diet caused a significant diminution in the oleic acid content of phosphatidyl choline and elevation of linoleic acid in phosphatidyl ethanolamine. The phospholipid class composition, total phospholipid fatty acid content and cholesterol content of sarcolemma were not altered by the diets used. The activity of Na+, K+ ATPase in the cardiac sarcolemma was not significantly changed by the different diets.