Nitric oxide research
We study mediators such as nitric oxide to understand how cardiovascular, pulmonary and visceral functions are controlled, with the long-term goal of finding novel or improved treatments for diseases in these organs, such as in asthma.
Our research has the last 15 years dealt with nitric oxide (NO) and its role in regulation of vascular and pulmonary function, as well as the role of NO in regulation of visceral organs such as the gastrointestinal tract and the genitals.
|Sten Friberg||PhD student|
|Lars E Gustafsson||Professor, senior|
Nitric oxide in a breath
At the end of the 1980's, we conducted research on microvascular function and demonstrated that nitric oxide is an important regulator of basal flow in skeletal muscle. During these studies we discovered that animals become hypoxic when given a large dose of a nitric oxide synthase inhibitor.
This led to our suggestion that nitric oxide, NO, is necessary for a normal oxygenation of the blood by acting as a servo regulator of pulmonary hypoxic vasoconstriction - the important mechanism serving to match perfusion of the lungs against ventilation. In the course of these studies we discovered in 1991 that NO is present in exhaled breath. We developed the methodology for measurements of exhaled nitric oxide by the single breath method.
Through our research from 1991 to 1993 it became evident that NO is formed by the airways and is altered in experimental asthma. Several groups subsequently demonstrated that exhaled NO is increased in asthmatics, due to the increased formation of NO in the airways, which in turn is due to the asthmatic inflammation of the airways. We have continued this research in order to understand what role the increased NO formation might have in the asthmatic responses, and have found evidence that endogenous NO counteracts bronchial obstruction during acute airway challenge.
Exhaled NO is now coming into clinical use as an adjunct in diagnosis of asthma and for monitoring of the effect of asthma treatment, notably the effect of inhaled steroids. More than 1000 papers on exhaled NO are now in the literature.
Another way of stimulating pulmonary NO formation is stretching of the lungs during normal respiration. This stimulus might contribute to the ventilation-perfusion matching in the lungs. We have found evidence that NO is not the only mediator for stretch-induced pulmonary vasodilation, and of importance for the future is to find which other mediators are responsible for this effect. A better understanding of these mechanisms are of importance to delineate new treatments of acute respiratory distress e.g. in intensive care and in the neonatal period.
A special application of the research on NO in pulmonary function is the role of NO in ventilation-perfusion matching in microgravity (space flight). We are involved in a project sponsored by the European Space Agency, analysing how NO formation is altered by changes in g-forces. As a spin-off of this and the above projects we have found that pulmonary NO formation is markedly altered in pulmonary embolism.
Exhaled NO can also be used for measurement of NO release from NO-donating pharmaceuticals, and an ongoing project in our group deals with understanding the NO release mechanisms from such drugs and the reasons for tolerance development, notably to nitroglycerin. This research might lead to improved treatment in cardiovascular diseases.
In the gastrointestinal tract and in the urogenital organs NO is a signalling molecule in nitrergic nerves. We have ongoing projects studying the release of NO from such nerves and how the release of NO is regulated. A recent dissertation project from our group showed that NO can exert feedback effects on its own release, probably via cGMP-dependent modulation of NO synthesis. These studies might lead to improved treatments in disturbances of gastrointestinal motility and urogenital function.
In the course of the above studies we are also analysing whether novel mediators can be found in signaling to visceral smooth muscle.
Nerve-smooth muscle models, bioassay, exhaled NO measurements, perfused lung model, pulmonary mechanics and whole animal models for cardiovascular and pulmonary function, HPLC, photon counting microscopy.