Better blood circulation, lower blood pressure and a stronger heart beat, who wouldn’t want this? This has been a long sought goal of pharmaceutical companies as well. One biomolecule, called nitroxyl (HNO), offers all 3 in 1. However, the mechanisms of its formation in the body and its actions were elusive until recently. In their study recently published in “Nature Communication”, Eberhardt and colleagues answer all this and a bit more, offering a promise for patients with advanced cardiovascular problems.
Gaseous molecules produced in our body join their forces
Our body produces several small gaseous molecules with important bodily functions. One such molecule is nitric oxide (NO). This is the active molecule of nitroglycerine, for example, and for the discovery of its role in blood pressure control the Nobel Prize was awarded in 1998. The other such gas is a less expected one, hydrogen sulphide (H2S), a toxic gas responsible for the smell of rotten eggs. However, H2S seems to have a similar potency in controlling the blood pressure. The study led by Dr Milos Filipovic and professor Peter Reeh showed in fact that in our body these two molecules join their forces forming a new molecule, the above-mentioned nitroxyl (HNO). This is facilitated by the cellular proximity of the enzymes that produce the two gasses.
How does nitroxyl work: a surprising role of the wasabi receptor
Nitroxyl is known to oxidize cysteine residues of proteins, so it did not come as a surprise when its activity on cells and animals was completely prevented if only one protein was knocked-down, TRPA1, also known as a wasabi or mustard oil receptor. TRPA1 is expressed in sensory neurons and rich in influential cysteines. In their study that spans from basic chemistry to experiments on humans, Eberhardt and colleagues show that H2S and NO react directly to form HNO which then activates the TRPA1 channel to admit Ca2+ into the cells which then causes the release of a vasoactive peptide called CGRP (calcitonin gene-related peptide). CGRP is the strongest known vasodilator produced in our body that possesses all the above-mentioned effects: It lowers the blood pressure but increases the contractility of the heart. A century after the demonstration that the classical TRPA1 agonist mustard oil acts as a strong vasodilator, the ion channel responsible for this action could be considered as a co-mediator of an endogenous ligand, HNO, that widens blood vessels and strengthens the heart.
“The zest of the discovery is that it shows how two small gaseous molecules, both capable of controlling blood pressure by themselves, react together to form HNO which has more desirable cardiovascular effects. In addition, “HNO could be one of the long sought endogenous activators of TRPA1 channels,” Dr Filipovic says.
Future drug development
The discovery of H2S+NO/HNO/TRPA1/CGRP signalling cascade offers new approaches for drug design. Development of HNO releasing drugs has already been one of the goals of the pharmaceutical industries. The recent study offers a simpler approach where drugs would only need to release NO and H2S together and the two of them will suffice to generate HNO.
However, the researchers warn us: “Overstimulation of TRPA1 by nitroxyl could promote inflammation and pain. As always, it will be a matter of dosage” Prof Reeh says.
Dr. Milos R. Filipovic
Phone: +49 9131 8527391