Inhalative application of soluble guanylyl cyclase stimulator BAY 41–8543 for treatement of pulmonary arterial hypertension

Background. Pulmonary arterial hypertension (PAH) is a devastating disease with a pure outcome. Recently, a new class of medicines has been proposed for treatment of the disease – soluble guanylyl cyclase stimulators. The possible drawback of the drugs is the potential of systemic arterial hypotension. Therefore, we sought to achieve the pulmonary selectivity of the BAY 41–8543 effects by inhalative application.

Methods. The model of monocrotaline (60kg/kg s.c.) induced PAH in rats was applied. Four weeks after monocrotaline injection, treatment for two weeks with vehicle, BAY 41–8543 10mg/kg peroral gavage (PO), 3mg/kg intratracheal instillation (IT), or 1mg/kg IT was started. Systemic arterial pressure (SAP) was measured continuously using invasive telemetry system. Heart function was assessed by echocardiography. After finishing the treatment course, rats undergo invasive hemodynamic measurements, after which tissue samples for molecular analysis and staining are collected.

Results. Monocrotaline injection induced severe PAH. Treatment with BAY 41–8543 10mg/kg PO and 3mg/kg IT reduced PAH, whereas 1mg/kg IT did not demonstrate any effect on pulmonary arterial pressure. All treatment regimens decreased degree of pulmonary vessel muscularisation and improved cardiac function. Per oral administration of BAY 41–8543 induced a transient decrease in SAP, which was absent after intra-tracheal drug administration.

Conclusion. Inhalative application of BAY 41–8543 for treatment of PAH is as effective as established method of per oral administration. Pulmonary selectivity of the vasodilating effect is achieved by inhalative application of the BAY 41–8543.