Hypertension, which is characterized by multiple alterations in the structure and function of the cell membrane, is often associated with important metabolic abnormalities including those concerning lipid metabolism. Dyslipidemia accompanying essential hypertension consists of elevated plasma triglycerides, low HDL cholesterol, and increased levels of atherogenic LDL cholesterol particles. The altered membrane microviscosity seen in hypertensive subjects reflects the changes of membrane lipid composition resulting from intensive exchange between circulating and membrane lipids, as well as from abnormal cellular lipid synthesis and metabolism. The changes of membrane microviscosity are known to modulate the activity of proteins involved in ion transport, signal transduction, cell Ca 2؉ handling, intracellular pH regulation, etc. Alterations in plasma or membrane lipids are indeed closely associated with ion transport abnormalities as well as with impaired control of cytosolic Ca 2؉ T here is no doubt that essential hypertension is associated with multiple membrane alterations, including changes in membrane microviscosity, receptor function, signal transduction, ion transport, calcium mobilization, intracellular pH regulation, and so on. Lipids, as an integral part of the cell membrane, play a decisive role in the modulation of the membrane properties mentioned. Specific lipid-lipid and lipid-protein interactions result in a highly dynamic but precisely controlled architecture of membrane components. Major regulators of membrane architecture are membrane potential, intracellular Ca 2ϩ and pH, lipid composition, cell-to-cell contact, and membrane coupling with the cytoskeleton or extracellular matrix. Intermolecular associations in the membrane and at the membrane-cytoskeleton interface are further selectively controlled by specific phosphorylation and dephosphorylation cascades involving both proteins and lipids. This is regulated by the extracellular matrix as well as by the binding of growth factors and hormones to their specific receptors. 1,2The aim of this review is to outline some interrelationships between abnormal lipid metabolism and altered membrane structure or function in human and experimental hypertension, and to evaluate whether abnormal lipid metabolism, which is responsible for a great part of membrane abnormalities found in hypertension, might be an integral part of its pathogenetic mechanisms. BLOOD PRESSUREMultiple metabolic abnormalities often accompany essential hypertension. Decreased high-density lipoproteins (HDL) together with increased plasma levels of low-density (LDL) and very low-density lipoproteins (VLDL), as well as hypertriglyceridemia, hypercholesterolemia, and insulin resistance, were found in many hypertensive patients. 3,4 There is increasing evidence for a genetic basis for the association of hypertension with insulin resistance and dyslipidemia. The genetic locus associated with dyslipidemia accompanying hypertension or diabetes seems to be closely linked to the LDL recept...

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The causal relationships between cytosolic free-Ca2+ concentration ([Ca2+]i) increases and production of nitric oxide (NO) have been investigated mostly with indirect methods and remain unclear. Here we demonstrate, by direct real-time measurements of [NO] with a porphyrinic microsensor, that Ca2+ entry, but not an increase in [Ca2+]i, is required for triggering of NO production in human endothelial cells. Histamine, ranging from 0.1 to 100 microM, increased both NO production and [Ca2+]i when given in a single dose. However, histamine caused increased NO release but induced progressively smaller [Ca2+]i changes when cumulatively added. In the absence of a transmembrane Ca2+ gradient, no significant NO release was detectable, despite the marked Ca2+ peak induced by histamine. Inhibition of Ca2+ entry by SK&F 96365 abolished histamine-elicited NO production but only reduced the transient [Ca2+]i rise. The suppression of the sustained [Ca2+]i response under these two conditions suggests that NO release was closely associated with Ca2+ entry from the extracellular space. In addition, membrane depolarization, achieved by increasing the extracellular K+ concentration from 5 to 130 mM, reduced both the amplitude of histamine-induced sustained [Ca2+]i elevation and NO production. These results lead us to propose that the availability of numerous Ca2+ ions around the internal side of the plasma membrane would promote the association between nitric oxide synthase and calmodulin, thereby activating the enzyme.

The Na+ and K+ electrochemical gradients across cell membranes are believed to be maintained by the action of a Na+, K+-pump. In human erythrocytes this pump exchanges internal Na+ for external K+ in approximately a 1.5 ratio. Thus, when Na+-loaded/K+-depleted erythrocytes are incubated in physiological conditions they tend to recover their original low Na+/high K+ content. Surprisingly, in erythrocytes from healthy donors the net Na+ extrusion/K+ influx ratio exceeds the 1.5 ratio predicted for Na+, K+-pump-mediated fluxes whereas it is similar to this value in erythrocytes from essential hypertensive patients and some of their descendants. We now report that this difference is due to the presence of a Na+, K+-co-transport system in normal erythrocytes which extrudes both internal Na+ and K+ and is functionally deficient in erythrocytes of essential hypertensive patients and some of their descendants. No difference in passive Na+ permeability could be detected between normotoensive and hypertensive subjects.

Abstract-Recent studies have demonstrated that, unlike cholesterol, cholesterol oxidized at position 7 can reduce the maximal endothelium-dependent relaxation of isolated rabbit aortas (Circulation. 1997;95:723-731). The aim of the current study was to determine whether cholesterol oxides reduce the release of nitric oxide (NO) from human umbilical vein endothelial cells (HUVECs). The amount of NO released by histamine-stimulated HUVECs was determined by differential pulse amperometry using a nickel porphyrin-and Nafion-coated carbon microfiber electrode. The effects of cholesterol (preserved from oxidation by butylated hydroxytoluene), 7-ketocholesterol, 7␤-hydroxycholesterol, 5␣,6␣-epoxycholesterol, 19-hydroxycholesterol (60 g/mL), and ␣-lysophosphatidylcholine (10 g/mL) were compared. Pretreatment of HUVECs with cholesterol, 5␣,6␣-epoxycholesterol, or 19-hydroxycholesterol did not alter histamineactivated NO production. In contrast, pretreatment with 7-ketocholesterol or 7␤-hydroxycholesterol significantly decreased NO release. The inhibitory effect of 7-ketocholesterol was time and dose dependent and was maintained in the presence of L-arginine. In the absence of serum, lysophosphatidylcholine also reduced NO production. In ionomycin-stimulated cells, pretreatment with 7-ketocholesterol did not inhibit NO release. These results demonstrate that cholesterol derivatives oxidized at the 7 position, the main products of low density lipoprotein oxidation, reduce histamine-activated NO release in HUVECs. Such an inhibitory effect of cholesterol oxides may account, at least in part, for the ability of oxidized low density lipoprotein to reduce the endothelium-dependent relaxation of arteries. Key Words: human endothelial cells Ⅲ cholesterol oxides Ⅲ histamine Ⅲ NO production T he endothelium of blood vessels regulates vascular tone by releasing endothelium-derived relaxing and contracting factors.1-3 In particular, it has now been clearly established that the endothelium-dependent relaxation of arteries induced by acetylcholine or histamine involves the release of endothelium-derived relaxing factor, 1,4 identified as NO. 5,6 Recent studies have demonstrated that alterations in vascular reactivity can be associated with cardiovascular disorders [7][8][9][10] and that arteries from hypercholesterolemic and atherosclerotic patients exhibit marked attenuation of endothelium-dependent relaxation. 7,11,12 Although the impairment of arterial relaxation at an early stage of the atherosclerotic process may constitute a crucial step in disease progression, the related molecular mechanisms remain unclear. Several studies have demonstrated that LDLs, rather than native LDLs, can mimic the impairment of arterial relaxation observed in hyperlipidemia. [13][14][15][16] Whereas in some previous studies the inhibition of endothelium-dependent relaxation was attributed to LPC, 14,15,17 other studies did not support this view. 16,18 In particular, no significant relationship between the LPC content of LDLs and their ability to reduc...

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