Endothelial Dysfunction Providing the Basis for the Treatment of Pulmonary Hypertension: Endothelin-1

11 Jun
2014

Experimentally, in isolated pig lungs, we have demonstrated that the exhaled NO level falls when L-NAME is added to the perfusate and that ACh increases and hypoxia reduces exhaled NO in this preparation. The pulmonary vascular resistance rose and fell with the NO level. These results and those of other workers suggest that the pulmonary endothelium of resistance blood vessels contributes to exhaled NO.
In accord with these findings, we measured levels of exhaled NO in PPH patients. Part of the exhaled NO is derived from close to the alveoli. In PPH patients, there is a reduction in number of the precapillary resistance arteries together with a reduced capillary volume. We found that while the exhaled NO levels were reduced in PPH patients in absolute terms, when corrected for reduction in the lung diffusion coefficient (KCO), normal subjects and PPH patients had equivalent levels (Fig 3).
Using immunostaining for NOS III and in vitro hybridization together with Northern blotting, it has proved possible to localize and quantify the amount of NOS III in normal and diseased lung pulmonary endothelium. There remains some controversy between those reporting a general reduction of expression and those suggesting normal expression. Recently, an explanation has been found in that there is in diseased lungs a patchy distribution of NOS III compared with normal subjects so online asthma inhalers. Of note is the enhanced expression of NOS III in the plexiform lesions of a PPH patient’s lungs. The suggestion is that diseased arteries lose NOS III expression while the plexiform lesions have enhanced expression. Perhaps this facilitates the new vessel formation of these lesions.
Endothelin-1
Enhanced Expression of ET-1 in Pulmonary Hypertension:
In contrast to the use of PGI2 and inhaled NO, where treatment with the agents preceded the research into their roles in the pathogenesis, the study of the pathogenesis of ET-1 occurred before the introduction of therapies to block its production.
In both primary and secondary pulmonary hypertension, the levels of immunoreactive ET 1 are elevated, Immunostaining for ET-1 and in situ hybridization for messenger RNA of pre-pro ET-1 show increased expression in the pulmonary endothelium of the lungs of patients with pulmonary hypertension compared with control subjects.

Figure 3. Regression of rate of production of NO against predicted KCO in primary pulmonary hypertension (closed circles) and control (open circles) groups.

Figure 3. Regression of rate of production of NO against predicted KCO in primary pulmonary hypertension (closed circles) and control (open circles) groups.

 

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