Nitric oxide and the cardiovascular system

Our perception of the cardiovascular system has changed over recent decades, from one of a rigid system of conducting pipes predominantly acted upon by vasoconstrictors, to one of a highly flexible tree under constant regulation by vasoconstrictor and vasodilator forces. We now know that in the testing state the vascular system is under a profound, constant vasodilator influence. 

Pre-menopausal women suffer less cardiovascular disease than men do. This protection disappears, however, after the menopause, and hormone replacement therapy in post-menopausal women reduces cardiovascular mortality. Animal work suggests that oestrogens dilate blood vessels by an endothelium-dependent mechanism, but as yet there is no direct evidence to show that NO generation is different between men and women. This is an area of considerable interest, particularly as women have greater longevity than men and suffer less ischaemic heart disease. Abnormal NO production may occur in hypercholesterolaemia and may be related to subsequent development of atherosclerosis. There is now a body of experimental data to suggest that an abnormality in NO production or function may be causal, or at least an amplifying factor, in both hypercholesterolaemia and atherosclerosis. 

There have been suggestions that nitroglycerin can substitute for defective NO production in atherosclerosis. There are important differences, however, between nitroglycerin and endogenous, endothelium-derived NO. Whereas endogenous NO and a number of other NO-donor drugs dilate all classes of coronary microvessels, nitroglycerin has only minor effects on coronary microvessels less 

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Horowitz, J.D., Nitrovasodilators, in Nitric Oxide and the Cardiovascular System, edited by Loscalzo, J., Vita, J.A., Humana Press Totowa, NJ 2000, p.383-409... 

Loscalzo, L Welch, G. Nitric oxide and the cardiovascular system. Prog. Cardiovasc. Dis. 1995, 38, 87-104. 

Loscalzo J, Vita J, eds. 2000. Nitric Oxide and the Cardiovascular System. To-towa, NJ Humana Press... 

Fedisdi M (1991) Ihe action and metabolism of organic nitrates and their similarity with endothelium-derived rdaxing fa (EDRF). hi Moncada S, Higgs EA, Berrazueta IR eds. Clinical rdevance of nitric oxide in the cardiovascular system, Edioomplet Madrid, pp. 29-43... 

Sartori C, Lepori M, Scherrer U. Interaction between nitric oxide and the cholinergic and sympathetic nervous system in cardiovascular control in humans. Pharmacol Ther. 2005 106 209-220. 

Physiological sites proposed for nitric oxide action include the immune system, where nitric oxide acts as a cytostatic agent, is tumoricidal, and can inhibit viral replication. In the cardiovascular system, nitric oxide is the biological mediator of vasodilator responses to agents such as acetylcholine and bradykinin, which act as receptors on endothelial cells to activate NOS and stimulate nitric oxide production. Diffusible nitric oxide then activates guanylate cyclase in vascular smooth muscle cells, leading to the production of cyclic guano-sine monophosphate (GMP) and vasodilation. In the brain, stimulation of A-methyl-o-aspartate receptors on... 

The physiological importance of nitric oxide should also be mentioned. It plays an important role in smooth muscle relaxation, platelet inhibition, neurotransmission, immune regulation, and penile erection (Nobel Prize in 1998 for the discovery of its role in the cardiovascular system). The importance of NO in biological systems stimulated the development of electrochemical sensors and the investigation of the electrochemical behavior of that compound. 

Garlic has been shown to have significant effects on the cardiovascular system. Such areas include improvement in lipids, modest effects on blood pressure, platelet inhibition, antioxidant effects, and a decrease in fibrinolytic activity. In vitro studies have shown garlic possesses specific antiatherosclerotic effects such as reducing inducible nitric oxide synthase (iNOS) mRNA expression (10), inhibition of oxidized low-density lipoprotein (LDL)-induced lactate dehydrogenase (LDH) release and inhibition of oxidized LDL-induced depletion of glutathione (11). 

J. Loscaizo and G. Welch Nitric oxide and its role in the cardiovascular system. Progress in Cardiovascular Diseases 38,87 (1995). 

Fig. 10.2 Cellular response to LPA and SIP in different organ systems. Examples of receptor-mediated cellular responses to LPA and SIP. Cytoskeletal reorganization, migration, survival, and proliferation operate in many biological systems particularly within the nervous system, the cardiovascular system, the immune system, and the female reproductive system. IL-2, interleukin-2 VEC, vascular endothelial cells VSMCs, vascular smooth muscle cells eNOS, endothelial nitric oxide synthase...

The discoverers of nitric oxide as a signal transmitter in the mediation of a variety of important cellular functions, in particular in the cardiovascular system, R. F. Furchgott, F. Murad, and L. J. Ignarro, were awarded the 1998 Nobel Prize in Physiology and Medicine. 

The same cardiovascular control system regulates blood distribution and blood pressure by affecting the small arterioles of the peripheral blood vasculature. The entrance to each of these vessels is surrounded by a sphincter muscle (a ring of involuntary muscle that surrounds the arteriolar aperture) with sympathetic, and in some cases, parasympathetic, nerve fibers. The sphincter is usually contracted. When the signal comes for the muscle to relax, the neuron produces nitric oxide at the neuromuscular junction, and this gas relaxes the sphincter. When the sphincter muscle expands, it increases the area through which blood flows and decreases its resistance. With decreased resistance, blood pressure falls. 

Research into the role played by NO in biological systems is an active area, and in 1992, Science named NO Molecule of the Year . The 1998 Nobel Prize in Physiology or Medicine was awarded to Robert F. Furchgott, Louis J. Ignarro and Ferid Murad for their discoveries concerning nitric oxide as a signalling molecule in the cardiovascular system (http //www.nobel.se/medicine/laureates/1998/press.html). 

Numerous studies indicate that regular intake of polyphenol-rich food and beverages such as red wine is associated with a protective effect on the cardiovascular system. In addition to the antioxidant property, polyphenols may also induce a beneficial effect on the cardiovascular system by several other mechanisms including the improvement of the vascular function. Indeed, experimental and chnical studies indicate that polyphenols are potent inducers of two major endothelial vasoprotective mechanisms, the formation of nitric oxide (NO) and the induction of endothelium-derived hyperpolarization (EDH). 

Nitric oxide (NO) displays potent activities in the cardiovascular system as well as in the central and peripheral nervous systems. NO and its co-product L-citruUine are produced by the oxidation of L-arginine (28) by nitric oxide synthase (NOS) (Scheme 13.4). Selective modulation of NO biosynthesis offers the opportunity for therapeutic intervention of neurodegenerative diseases, among others. Based on the mechanism proposed for NO biosynthesis, two boronic acid analogues (29 and 30, Figure 13.7) of... 

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