Endothelium-dependent relaxation inhibition

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. 

Buckley, C, Bund SJ, McTaggart F et al. Oxidized low-density lipoproteins inhibit endothelium-dependent relaxations in isolated large and small rabbit coronary arteries. J. Auton. Pharmacol. 16,... 

T Murohara, K Kugiyama, M Ohgushi, S Sugiyama, Y Ohta, H Yasue. LPC in oxidized LDL elicits vasocontraction and inhibits endothelium-dependent relaxation. Am J Physiol 267 H2441-H2449, 1994. 

Recent findings [117] suggest that native LDL and Ox-LDL directly inactivate EDRF but do not attenuate formation of EDRF in cultured and native endothelial cells after short-term exposure. A direct inactivation of EDRF by the lipoproteins rather than an effect on the target-organ smooth muscle has been involved [117]. It has been reported that contractions to native LDL are due to its oxidation in the organ chamber, and that Ox-LDL, but not native LDL, inhibits endothelium-dependent relaxations to 5HT. In fact, the native-LDL molecule is known to be unstable after its isolation from the blood, is readily auto-oxidised in the presence of air, and is highly sensitive to metal-catalyzed oxidation [118],... 

ABSTRACT In mammals, nitric oxide (NO) is a reactive free radical involved in diverse physiological functions. NO and its redox-related forms NO+ and NO react with di(oxygen) and its derivatives, with metalloproteins and thiol-containing proteins. NO-mediated nitrosation of proteins represents an important cellular regulatory mechanism. Biosynthesis of NO is catalysed by nitric oxide synthase (NOS). Three isoenzymes representing distinct gene products have been identified the inducible NOS isoform, the constitutive neuronal and endothelial isoforms. Inducible and constitutive NOSs have the same structural features, but their activities differ in their dependence to calcium and the rate of NO produced. The principal NO-mediated functions in mammals are endothelium-dependent relaxation, neurotransmission and immune response. The role of NO in the antitumor immune response comprises both regulatory and effector functions at the intra- or inter-cellular level. The first function includes inhibition of lymphocyte proliferation or participation in different transduction pathways. The second fiinction includes pro- or anti-tumoral effects and NO-mediated cell toxicity or cell resistance to apoptosis. 

We evaluated whether the Mn(ii)-based SOD mimics could potentiate the levels of nitric oxide, a potent vasorelaxant. Superoxide reacts with nitric oxide in a diffusion-controlled manner to produce peroxynitrite. By catalyzing the dismu-tation of superoxide, SOD mimics would be expected to increase nitric oxide levels. The SOD mimic SC-52608 enhanced nitric oxide levels (as assessed by cyclic GMP activity) in rat lung fibroblasts in a dose-dependent manner. SC-52608 induced the relaxation of preconstricted rat aortic rings. The aortic ring relaxation was endothelium-dependent and inhibitable by a nitric oxide synthase inhibitor. Intravenous administration of SC-52608 into conscious rats resulted in a transient, dose-dependent decrease in blood pressure. The results are consistent with the SOD mimic SC-52608 potentiating levels of nitric oxide, which causes the observed relaxation of the aortic rings and the decrease in blood pressure. 

Plane, F., Jacobs, M., McManus, D., and Bnickdorfer, K. R., 1993, Probucol and other antioxidants prevent the inhibition of endothelium-dependent relaxation by low density lipoproteins, Atherosclerosis 103 73-79. 

In rabbits, vascular ACE activity was significantly increased by atherogenic diet with significant correlation between vascular ACE activity and plaque area, however, contractile responses of the femoral arteries to AI and All in the atherogenic diet-fed animals were not different from those of the normal diet-fed animals (273). ACE inhibition improves vascular compliance, NO production, vascular relaxation, plasma markers of relaxation, oxidative stress, and thrombosis (reviewed in ref. 274). On the other hand, hypercholesterolemia in rabbits resulted in atherosclerosis, loss of endothelium-dependent relaxation, increased ATI in aortic tissues with enhanced constrictor response to All (275). 

Andrews HE Bruckderfer KR, Dunn RC et al. LDL inhibits endothelium dependent relaxation in rabbit aorta. Nature 1987 327 237-239. 

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. 

Fig. 9.1 Nitric oxide mediated inhibition of platelet activation. Abbreviations used NO, nitric oxide EDRF, endothelium-derived relaxing factor GC, guanylyl cyclase PDE, phosphodiesterase cGMP-PK, GMP-dependent protein kinase Raplb, small GTPase Raplb ...

Vascular and hematologic effects Ginkgo exerts vascular effects through at least two mechanisms inhibition of platelet-activating factor (PAF) and nitric oxide mechanisms. Ginkgo extract relaxes the porcine basilar artery in a concentration-dependent and partly endothelium-dependent manner (Chen et al. 1997). It also enhances vasorelaxation created by transmural nerve stimulation in arteries with and without the endothelium intact, and is prevented by nitro-L-arginine, indicating that the effect is mediated by nitric oxide. 

The oxidation hypothesis of atherosclerosis states that the oxidative modification of LDL (or other lipoproteins) is important and possibly obligatory in the pathogenesis of the atherosclerotic lesion thus, it has been suggested that inhibiting the oxidation of LDL will decrease or prevent atherosclerosis and clinical sequelae. LDL oxidation also has important implications for vascular health function. High concentrations of LDL may inhibit arterial function in terms of the release of nitric oxide from the endothelium and many of these effects are mediated by lipid oxidation products. Furthermore, oxidized LDL inhibits endothelium-dependent nitric oxide-mediated relaxations in isolated rabbit coronary arter-... 

Relaxation of blood vessels appears to be at least partially under the control of endothelial cells and their secreted products, especially endothelium-derived relaxation factor (EDRF). Oxidized LDL directly inhibits the endothelial cell-associated vessel relaxation. The generation of increased reactive oxygen species in association with elevated levels of blood cholesterol has also been reported. One of these reactive oxygen species, superoxide (O2), may interact with vasoactive EDRF (nitric oxide) locally in the artery wall, preventing endothelial cell-dependent vasodilation. In addition, a product of the reaction of nitric oxide and superoxide, the reactive peroxynitrite, may act to stimulate lipoprotein oxidation, which, as noted above, is regarded as an early step in atherosclerotic plaque generation. 

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