The involvement of endothelin-1 (ET-1) in the pathobiology of pulmonary arterial hypertension is well-established and has led to the successful clinical development of endothelin receptor antagonists for patients affected by the disease. Natriuretic peptides, on the other hand, exert a number of effects which in many instances oppose those of ET-1. Thus, natriuretic peptides have a vasodilatory action, especially in the pulmonary arterial vasculature, but they also produce beneficial long-term structural effects in the context of cardiovascular diseases, including pulmonary hypertension, by virtue of their anti-proliferative, anti-inflammatory, and anti-fibrotic properties.
ET-1 is formed from a biologically inactive precursor by endothelin converting enzyme(s) (ECE). Natriuretic peptides are degraded by the neutral endopeptidase (NEP) which is closely related to ECE and shares similar features in its catalytic site. Therefore, both types of enzymes can be targeted by single small drug molecules exhibiting dual ECE/NEP inhibitory activity. Such inhibitors are able to simultaneously prevent the formation of ET-1 (by blocking ECE) and the degradation of natriuretic peptides (by blocking NEP), thus combining two pharmacological principles which are applicable to pulmonary hypertension.
The present chapter reviews the experimental evidence in favor of using this novel therapeutic concept for the treatment of pulmonary arterial hypertension, and possibly also other forms of pulmonary hypertension, and discusses the potential advantages in comparison to existing pharmacological treatments.
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