Endothelium dependent

Three years later Robert F Furchgott discov ered that the relaxing of smooth muscles such as blood vessel walls was stimulated by an unknown substance produced in the lining of the blood vessels (the endothelium) He called this substance the endothelium-dependent relaxing factor or EDRF and in 1986 showed that EDRF was NO Louis J Ignarro reached the same conclusion at about the same time Further support was provided by Salvador Moncada who showed that endothelial cells did in deed produce NO and that the l arginine to l citrulline conversion was responsible... 

In addition to the effects on blood lipids, it has been suggested that soy consumption has a beneficial action on arterial function and improves antioxidant status (Lichtenstein, 1998 and refs therein). Genistein and daidzein were shown to have antioxidant properties in vitro (Kerry and Abbey, 1998), to enhance endothelium-dependent vasodilation and to reduce the development of atherosclerosis in monkeys (Honore et al, 1997 Wagner et al, 1997). 

Mu e, A., Elwell, J.H., Peterson, T.E., Hofmeyer, T.G., Heistad, D.D. and Harrison D.C. (1991). Chronic treatment with PEG-SOD partially restores endothelium dependent vascular relaxations in cholesterol fed rabbits. Circ. Res. 69, 1293-1300. 

Chin et al. (1992) have su ested that oxidized LDL and high-density lipoprotein (HDL) inactivate endothelial cell-derived NO. NO inactivation was due to the oxidized lipids within the lipoprotein particles and was thought to be explained by a chemical reaction between the lipoproteins and NO. Other investigators have shown that relaxation of vascular smooth muscle by acetylcholine or bradykinin (endothelium-dependent vasodilators) is inhibited by LDL (Andrews etal., 1987). The role of NO in the modification of LDL is discussed in full detail in Chapter 2. 

Andrews, Fi.E., Bruckdorfer, K.R., Dunn, R.C. and Jacobs, M. (1987). Low-density lipoproteins inhibit endothelium-dependent relaxation in rabbit aorta. Nature (Lond.) 327, 237-239. 

A relationship between polyol pathway activity and reduction in endothelium-dependent relaxation in aorta from chronic STZ-diabetic rats has recently been reported (Cameron and Cotter, 1992). In agreement with several previous studies (Oyama et al., 1986 Kamata et al., 1989), endothelial-dependent relaxation was defective in the diabetic rats but the deficit was prevented by prior treatment with an AR inhibitor. The mechanism underlying the defect has been speculated to be due to decreased production of endothelium-derived relaxing factor (EDRF) or nitric oxide, NO (Hattori et al., 1991). It has been speculated that these vascular abnormalities may lead to diminished blood flow in susceptible tissues and contribute to the development of some diabetic complications. NO is synthesized from the amino-acid L-arginine by a calcium-dependent NO synthase, which requires NADPH as a cofactor. Competition for NADPH from the polyol pathway would take place during times of sustained hyperglycaemia and... 

Superoxide dismutase recovers altered endothelium-dependent relaxation in diabetic rat aorta. Am. J. Physiol. 261, H1086-H1094. 

Kamata, K., Miyata, N. and Kasuya, Y. (1989). Impairment of endothelium-dependent relaxation and changes in levels of cyclic GMP in aorta from streptozocin-induced diabetic rats. Br. J. Pharmacol. 97, 614-618. 

Oyama, Y., Kawasaki, H., Flattori, Y. and Kanno, M. (1986). Attenuation of endothelium-dependent relaxation in aorta from diabetic rats. Eur. J. Pharmacol. 131, 75-78. 

Perticone F, Ceravolo R, Maio R, Ventura G, Zingone A, Perrotti N, Mat-tioli PL. Angiotensin-converting enzyme gene polymorphism is associated with endothelium-dependent vasodilation in never treated hypertensive patients. Hypertension 1998 31 900-905. 

The disturbance of balance between superoxide and nitric oxide occurs in a variety of common disease states. For example, altered endothelium-dependent vascular relaxation due to a decrease in NO formation has been shown in animal models of hypertension, diabetes, cigarette smoking, and heart failure [21]. Miller et al. [22] suggested that a chronic animal model atherosclerosis closely resembles the severity of atherosclerosis in patients. On the whole, the results obtained in humans, for example, in hypertensive patients [23] correspond well to animal experiments. It is important that endothelium-dependent vascular relaxation in patients may be improved by ascorbic acid probably through the reaction with superoxide. 

Sanders et al. [133] found that although quercetin treatment of streptozotocin diabetic rats diminished oxidized glutathione in brain and hepatic glutathione peroxidase activity, this flavonoid enhanced hepatic lipid peroxidation, decreased hepatic glutathione level, and increased renal and cardiac glutathione peroxidase activity. In authors opinion the partial prooxidant effect of quercetin questions the efficacy of quercetin therapy in diabetic patients. (Antioxidant and prooxidant activities of flavonoids are discussed in Chapter 29.) Administration of endothelin antagonist J-104132 to streptozotocin-induced diabetic rats inhibited the enhanced endothelin-1-stimulated superoxide production [134]. Interleukin-10 preserved endothelium-dependent vasorelaxation in streptozotocin-induced diabetic mice probably by reducing superoxide production by xanthine oxidase [135]. 

P2Y receptors that are found on endothelial cells elicit a Ca2+-dependent release of endothelium-dependent relaxing factor (EDRF) and vasodilation. A secondary activation of a Ca2+-sensitive phospholipase A2 increases the synthesis of endothelial prostacyclin, which limits the extent of intravascular platelet aggregation following vascular damage and platelet stimulation. The P2Y-mediated vasodilation opposes a vasoconstriction evoked by P2X receptors located on vascular smooth muscle cells. The latter elicit an endothelial-independent excitation (i.e. constriction). P2Y receptors are also found on adrenal chromaffin cells and platelets, where they modulate catecholamine release and aggregation respectively. 

Christopher TA, Lopez BL, Stillwagon JC, Gao F, Gao E, Ma XL, Ohlstein EH, Yue TL (2002) Idoxifene causes endothelium-dependent, nitric oxide-mediated vasorelaxation in male rats. Eur J Pharmacol 446(1-3) 139-143... 

Rapoport RM, Draznin MB, Murad F (1983) Endothelium-dependent relaxation in rat aorta may be mediated through cyclic GMP-dependent protein phosphorylation. Nature 306 174-176... 

Mixed evidence, however, has been described in women. Raloxifene improved flow-mediated, endothelium-dependent vasodilation in postmenopausal women (Sarrel et al. 2003) to an extent similar to that of HT (Colacurci et al. 2003 Saitta et al. 2001). Other investigators, however, have been unable to detect any effect of raloxifene (Ceresini et al. 2003 Griffiths et al. 2003). Flow-mediated vasodilation has been described for droloxifene (Herrington et al. 2000), while a neutral effect on vascular reactivity has been described for ospemifene, a more recent SERM (Ylikorkala et al. 2003). 

Ceresini G, Marchini L, Rebecchi I, Morganti S, Bertone L, Montanari I, Bacchi-Modena A, Sgarabotto M, Baldini M, Denti L, Ablondi F, Ceda GP, Valenti G (2003) Effects of raloxifene on carotid blood flow resistance and endothelium-dependent vasodilation in postmenopausal women. Atherosclerosis 167 121-127... 

Idoxifene causes endothelium-dependent, nitric oxide-mediated vasorelaxation in male rats. Eur J Pharmacol 446 139-143... 

Griffiths KA, Sader MA, Skilton MR, Harmer JA, Celermajer DS (2003) Effects of raloxifene on endothelium-dependent dilation, lipoproteins, and markers of vascular function in postmenopausal women with coronary artery disease. J Am Coll Cardiol 42 698-704... 

Kugiyama K, Kerns SA, Morrisett JD, Roberts R, Henry PD (1990) Impairment of endothelium-dependent arterial relaxation by lysolecithin in modified low-density lipoproteins. Nature 344 160-162... 

Saitta A, Altavilla D, Cucinotta D, Morabito N, Frisina N, Corrado F, D Anna R, Lasco A, Squadrito G, Gaudio A, Cancellieri F, Arcoraci V, Squadrito F (2001) Randomized, double-blind, placebo-controlled study on effects of raloxifene and hormone replacement therapy on plasma no concentrations, endothelin-1 levels, and endothelium-dependent vasodilation in postmenopausal women. Arterioscler Thromb Vase Biol 21 1512-1519... 

Raeymaekers The data indicate that it is SERCA3 that fills the stores that are involved in the endothelium-dependent relaxation. At face value, the separate data indicate that this store could be connected to TRPC4. 

While several studies reported that PLB was present in smooth muscle, very little was known about its role in Ca2+ handling. Some evidence suggested that in addition to A-kinase pathway phosphorylation, activation of the G -kinase pathway was associated with PLB phosphorylation. The latter was of particular interest to vascular smooth muscle, for which endothelium-dependent relaxation via nitric oxide (NO) made the mechanism of G-kinase-mediated relaxation of considerable physiological significance (Karczewski et al 1998). 

Liu LH, Paul RJ, Sutliff RL et al 1997 Defective endothelium-dependent relaxation of vascular smooth muscle and endothelial cell Ca2+ signaling in mice lacking sarco(endo)plasmic reticulum Ca2+-ATPase isoform 3. J Biol Chem 272 30538—30545... 

Mulsch, A., Busse, R., Bassenge. E., Desensitization of guanylate cyclase in nitrate tolerance does not impair endothelium-dependent responses. Eur. J.Pharmacol. 158 (1988),... 

Dysregulation of the vascular endothelium has emerged as a critical component of most thrombotic disorders [10, 21]. Often without any anatomical sign of atherosclerosis, many cardiovascular diseases express a vasomotor abnormality termed endothelial dysfunction, indexed clinically as impaired endothelium-dependent vasodilation [31]. Although its mechanism is multifactorial, endothelial dysfunction is characterized by diminished vascular NO production and/or bioavailability [32]. The... 

Sorensen, K. E., Celermajer, D. S., Georgakopoulos, D., Hatcher, G., Betteridge, D. J., and Deanfield, J. E., Impairment of endothelium-dependent dilation is an early event in children with familial hypercholesterolemia and is related to the lipoprotein(a) level. J. Clin. Invest. 93, 50-55 (1994). 

Kang, S. Y., Kim, S. H., Schini-Kerth, V. B., and Kim, N. D. (1995a). Dietary ginsenosides improve endothelium-dependent relaxation in the thoratic aorta of hypercholesterolemic rabbit. Gen. Pharmacol. 26, 483—487. 

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