Gasotransmitters

There are many gaseous chemicals with effects/functions in the human body, however only three of these act as bona fide 'gasotransmitters' (or gaseous transmitters): nitric oxide (NO, a free-radical mediator), carbon monoxide (CO) and hydrogen sulfide (H₂S). These three regulate a variety of key biological functions and are also implicated in tumour biology. They can have endocrine, paracrine, and autocrine actions. They are produced enzymatically under tight regulation. They have varying biological half-lives, which affects their mode of transmitter action. NO has a very short half-life (seconds) restricting it to autocrine or paracrine action. H₂S survives for seconds to minutes, and CO has the longest half-life, maintaining activity for several minutes.

Nitric oxide is biosynthesized from the substrate L-arginine, using oxygen, and NADPH by various nitric oxide synthase (NOS) enzymes. Reaction products are L-citrulline and NO. The three NOS enzymes are neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS). As their names suggest nNOS is primarily expressed in the brain and neuronal tissue and eNOS is expressed predominantly in the endothelial layer of the vasculature. These two isoforms show subcellular localisation. They are both constitutive, low-output enzymes. This is in contrast to high-output iNOS which shows largely cytosolic expression in immune cells such as macrophages. In normal physiology, NO binds to the haem group of guanylyl cyclase to increase intracellular cyclic GMP levels, with downstream effects resulting from modulation of cGMP-dependent protein kinases (PKGs). It also opens ATP-dependent potassium channels and mediates S-nitrosylation based protein modifications. Adverse effects of supra-normal levels of NO include inhibition of mitochondrial enzymes and initiation of DNA damage.

Endothelial NO: NO in the endothelium has a potent vasodilatory effect. Nitroglycerin (glyceryl trinitrate) is converted to nitric oxide in the body, hence its vasodilatory action. The NO moiety of the vasodilating antihypertensive drug minoxidil may act as a NO agonist, explaining some of its molecular mechanism of action.

Neuronal NO: Whilst mainly expressed in central and peripheral nervous tissue, nNOS is also found tethered to dystrophin in skeletal muscle. In these tissues NO acts as a classical transmitter enabling cell communication.

Immune cell NO: iNOS in monocytes, macrophages, and neutrophils can be activated by proinflammatory cytokines such as interferon-gamma (IFN-γ) and tumor necrosis factor (TNF). In contrast, transforming growth factor-beta (TGF-β) potently inhibits iNOS. iNOS-derived NO is used to regulate inflammation and immune responses to pathogens. The large quantities of NO produced in response to proinflammatory cytokines facilitates reaction with superoxide to form toxic peroxynitrite, as part of the macrophage oxidative burst. iNOS is also expressed in the cardiovascular system, but its role in these tissues is less clear.

Modified arginine analogues are inhibitors of all three isoforms, with different analogues exhibiting different inhibitory profiles. For example L-NNA is selective for eNOS and nNOS over iNOS.

Carbon monoxide is produced endogenously by the haem oxygenase enzymes (HO1 and HO2), as a product of oxidative degradation of haem. Expression of HO1 is induced by factors including haem, oxidative stress, UV radiation, heat shock, hypoxia and NO. HO2 is constitutively expressed in the brain, kidney, liver and spleen. At low physiological concentrations CO has antiinflammatory, antiproliferative, anti-apoptotic and anticoagulative responses. Like NO, CO also binds to the haem group of guanylyl cyclase, albeit with lower affinity than NO. CO also activates ATP-dependent potassium channels, and activates kinase signalling pathways (e.g. the PI3K–AKT and p38 mitogen-activated protein kinase pathways). At high concentration CO displaces oxygen from haemoglobin causing hypoxia (CO poisoning). CO can also inhibit mitochondrial cytochrome c oxidase (the last enzyme in the respiratory electron transport chain), at least in vitro, which may contribute to CO poisoning.

Hydrogen sulphide is a physiological modulator of blood pressure in humans. It is produced by the action of several hydrogen sulphide synthesis enzymes. It activates ATP-dependent potassium channels to mediate vascular smooth muscle relaxation. H₂S in the CNS is implicated in Alzheimer's disease, epilepsy, stroke and Down's syndrome. Pharmacological enhancement of H₂S levels may provide beneficial effects against gastric ulcer and in inflammatory bowel disease. Chattopadhyay et al. (2016) have reported the beneficial effects of a hybrid molecule combining naproxen with NO- and H₂S-releasing properties in preclinical animal models, as a potential mechanism for overcoming the gastrointestinal limitations of naproxen use.