ANitric oxide

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i a Nitric oxide is a diffusible, unstable or free radical gas. Having a low blood-gas g partition coefficient, it readily enters the gas phase. Nitric oxide is synthesised by r vascular endothelium from the terminal guanidine nitrogen of L-arginine in a y a single step reaction catalysed by nitric oxide synthase. It has a short half-life of

3 under 5 seconds, undergoing rapid oxidation to stable metabolic end-products, nitrate and nitrite. Toxic metabolites include methaemoglobin, nitrogen dioxide and peroxynitrite.

The actions, which may be paracrine or autocrine, include:

Intracellular: stimulation of guanosine 3'-5' monophosphate (cyclic GMP)-dependent kinase ion channels or phosphodiesterase.

Extracellular:

* Neurally mediated vascular smooth muscle relaxation. This is responsible for vasodilator tone, which helps regulate systemic blood pressure.

* Anterograde and retrograde signalling between pre- and postsynaptic units, regulating smooth muscle function in the stomach, small intestine and uterus. It is the major mediator of relaxation regulated by the noradrenergic, non-cholinergic system.

* Inhibition of platelet aggregation and adhesion, and of white blood cell aggregation.

* Regulation of cardiac contractility, via its negative inotropic effects.

* Neurotransmitter in the CNS and in the non-adrenergic non-cholinergic autonomic nervous system. In the CNS, it acts as a neurotransmitter at the presynaptic N-methyl-D-aspartate (glutamate) receptors which activate calcium channels.

* Modulation of immune cell defences, including stimulation of the formation of cytotoxic products by activated macrophages, thereby acting as an inflammatory mediator.

* Retinal phototransduction.

* Neuronal long-term potentiation and memory.

* Penile erection.

* Atherogenesis.

The synthesis of nitric oxide is catalysed by one of three isozymes of nitric oxide synthase, using nicotinamide adenine dinucleotide phosphate dehydro-genase (NADPH) as electron source and cofactors including tetrahydropterin and flavin nucleotides Flavine adenine mononucleotide (FMN), Flavine adenine dinucleotide (FAD). These enzymes are homodimeric cytochrome P450-like haemoproteins. The three types are neuronal, inducible and endothelial constitutive. Neuronal nitric oxide synthase is expressed by central and peripheral neurons. Inducible nitric oxide synthase is calmodulin-independent and cytokine-inducible. It is expressed by vascular smooth muscle cells, endothelial cells and inflammatory cells, including macrophages. Constitutive nitric oxide synthase is calcium/calmodulin and NADPH-dependent. It is expressed by endothelial cells and neurons.

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