Nonesterified fatty acids accumulate at sites of tissue injury and necrosis. In cardiac tissue the concentrations of oleic acid, arachidonic acid, leukotrienes, and other fatty acids increase greatly during ischemia due to receptor or nonreceptor-mediated activation of phospholipases and/or diminished reacylation. In ischemic myocardium, the time course of increase in fatty acids and tissue calcium closely parallels irreversible cardiac damage. We postulated that fatty acids released from membrane phospholipids may be involved in the increase ofintraceilular calcium. We report here that low concentrations (3-30 ,AM) of each long-chain unsaturated (oleic, linoleic, linolenic, and arachidonic) and saturated (paimitic, stearic, and arachidic) fatty acid tested induced multifold increases in voltage-dependent calcium currents (Ic.) in cardiac myocytes. In contrast, neither short-chain fatty acids (<12 carbons) or fatty acid esters (oleic and palmitic methyl esters) had any effect on IcS, indicating that activation of calcium channels depended on chain length and required a free carboxyl group. Inhibition of protein kinases C and A, G proteins, eicosanoid production, or nonenzymatic oxidation did not block the fatty acid-induced increase in Ica. Thus, long-chain fatty acids appear to directly activate Ica, possibly by acting at some lipid sites near the channels or directly on the channel protein itself. We suggest that the combined effects of fatty acids released during ishemla on Ica may contribute to ischemia-induced pathogenic events on the heart that involve calcium, such as arrhythmlas, conduction disturbances, and myocardial damage due to cytotoxic calcium overload.Considerable evidence suggests that the accumulation of membrane-derived free fatty acids and lysophospholipids are important in the pathogenic events caused by myocardial ischemia (1-8). The onset of disturbed membrane function, proceeding on to irreversible cardiac damage, closely parallels the time course of accumulation of fatty acids and an associated increase in tissue calcium (3,8). We postulated that the increase in fatty acids might be involved in the altered membrane function that leads to increased tissue calcium. We report that fatty acids have powerful effects on voltagedependent calcium currents (ICa) in cardiac cells, which could trigger ischemia-induced pathogenic actions on the heart that involve calcium-such as arrhythmias, coronary vasoconstriction, and cytotoxic calcium overload. MATERIALS AND METHODSThe effect of fatty acids on calcium currents was studied in single guinea pig ventricular myocytes using a standard whole-cell voltage-clamp technique. Ventricular myocytes were isolated as described (9). Only calcium-tolerant myocytes with clear striations were used. Cells with rapid rundown (>70%o decrease in ICa) during the 10-to 15-min control period were discarded. Whole-cell voltage-clamp experiments with myocytes were done at 320C with 2-to 3-MU glass pipettes (Narishige PB 7 puller). Dagan 3900A patch-clamp circui...

No abstract

No abstract

It is widely, but mistakenly, believed that ischemic heart disease (IsHD) and its complications are the sole and direct result of reduced coronary blood flow by obstructive coronary artery disease (CAD). However, cardiac angina, acute myocardial infarction (AMI), and sudden cardiac death (SCD) occur in 15%-20% of patients with anatomically unobstructed and grossly normal coronaries. Moreover, severe obstructive coronary disease often occurs without associated pathologic myocardiopathy or prior symptoms, ie, unexpected sudden death, silent myocardial infarction, or the insidious appearance of congestive heart failure (CHF). The fact that catecholamines explosively augment oxidative metabolism much more than cardiac work is generally underappreciated. Thus, adrenergic actions alone are likely to be more prone to cause cardiac ischemia than reduced coronary blood flow per se. The autonomic etiology of IsHD raises contradictions to the traditional concept of anatomically obstructive CAD as the lone cause of cardiac ischemia and AMI. Actually, all the signs and symptoms of IsHD reflect autonomic nervous system imbalance, particularly adrenergic hyperactivity, which may by itself cause ischemia as in rest angina. Adrenergic activity causing ischemia signals cardiac pain to pain centers via sympathetic efferent pathways and tend to induce arrhythmogenic and necrotizing ischemic actions on the cardiovascular system. This may result in ischemia induced metabolic myocardiopathy not unlike that caused by anatomic or spasmogenic coronary obstruction. The clinical study and review presented herein suggest that adrenergic hyperactivity alone without CAD can be a primary cause of IsHD. Thus, adrenergic heart disease (AdHD), or actually adrenergic cardiovascular heart disease (ACVHD), appears to be a distinct entity, most commonly but not necessarily occurring in parallel with CAD. CAD certainly contributes to vulnerability as well as the progression of IsHD. This vicious cycle, which explains the frequent parallel occurrence of arteriosclerosis and IHD, an association that appears to be linked by the same cause, comprises a common vulnerability to deleterious adrenergic actions on the myocardium, lipid metabolism, and vascular system alike, rather than viewing CAD and IsHD as having a putative cause and effect relationship as commonly thought. Adrenergic actions can also cause the abnormal lipid metabolism that is associated with CAD and IsHD by catecholamine-induced metabolic actions on lipid mobilization by activation of phospholipases. This may also be part of toxic catecholamine hypermetabolic actions by enhancing deleterious cholesterol and lipid actions in damaging coronary vessels by plaque formation as well as inducing obstructive coronary spasm and platelet aggregation. This may also cause direct toxic necrosis on the myocardium as well as atherosclerosis in blood vessels. In fact, drugs that inhibit adrenergic actions like propranolol, reserpine, and guanethidine all inhibit arteriosclerosis induced by hypercholestero...

No abstract