Update: Präklinische Entwicklungen zur Therapie der pulmonalen arteriellen Hypertonie

Zusammenfassung

Die pulmonale arterielle Hypertonie (PAH) wird derzeit mit Substanzen behandelt, die primär eine Wiederherstellung der Balance des pulmonalvaskulären Tonus bewirken – namentlich die Prostanoide, Antagonisten des Endothelinrezeptors und die PDE-5-Inhibitoren – auch wenn diese Substanzen auch antiproliferative Effekte besitzen. Andere Substanzen, die direkt das Remodeling der Pulmonalarterien adressieren, werden derzeit nicht nur in präklinischen Tiermodellen, sondern auch bereits in klinischen Studien untersucht. Der Fokus der Grundlagenforschung liegt dabei sowohl auf der Ebene von Mediatoren und Rezeptoren, auf der Ebene von intrazellulären Signaltransduktionswegen und Transkriptionsfaktoren, sowie auf der Ebene der Effektoren.

Summary

Pulmonary arterial hypertension is a life-threatening, vasculoproliferative disease of the lung, which is characterized by vasoconstriction and remodeling of small pulmonary arteries. Drugs for the treatment of PAH mainly address the increased vascular tone. Substances like prostacyclin, endothelin-receptor-antagonists and phosphodiesterase-5-inhibitors have been approved for the treatment of PAH and represent the current therapeutic options. The development of a causal treatment aiming a normalization of the vessel wall structure is the current focus of research. The key events in disease progression are represented by increased proliferation, migration and a resistance to apoptosis of pulmonary vascular cells. Therefore, new non-vasoactive drugs are investigated in relevant preclinical animal models of pulmonary arterial hypertension. Some of these substances, like tyrosine kinase inhibitors, elastase inhibitors and phosphodiesterase-1-inhibitors, could not only attenuate (anti-remodeling) but reverse (reverse-remodeling) the disease. Additionally, new vasodilators, like soluble guanylate cyclase stimulators and activators, addressing well-known and new signaling pathways are currently under investigation. Taken together, with increasing insight into the pathology of PAH, several novel drug targets and treatments have emerged which may improve the management of patients and which efficacy is currently addressed in preclinical studies and clinical trials.

Schlüsselwörter

pulmonale arterielle Hypertonie - Gefäßremodeling - Vasokonstriktion

Keywords

pulmonary arterial hypertension - vascular remodeling - vasoconstriction

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