Prostacyclin in PAH

Prostacyclin: A fundamental pathway in PAH

cAMP: cyclic adenosine monophosphate; cGMP: cyclic guanosine monophosphate; ET_A: endothelin receptor type A; ET_B: endothelin receptor type B; IP: prostacyclin receptor; PDE-5: phosphodiesterase type 5; pro-ET: pro-endothelin; sGC: soluble guanylate cyclase; SMCs: smooth muscle cells.

In pulmonary arterial hypertension (PAH), prostacyclin and nitric oxide levels are decreased, and endothelin levels are increased.⁵ Reduced levels of prostacyclin synthase are found in patients with idiopathic pulmonary arterial hypertension (IPAH).⁶ Based on animal data, imbalances in prostacyclin and endothelin levels have been implicated in the following:

• Vasoconstriction^6,8,9
• Cellular proliferation^8,9
• In situ thrombosis⁶
• Hypertrophy⁹

The clinical significance of prostacyclin deficit in humans is unknown. Animal data cannot imply a benefit in humans.

The prostacyclin pathway is a key treatment target in PAH.

• The reduced level of prostacyclin has been implicated as an important pathological feature of PAH⁵
• The addition of prostacyclin has been shown to play a critical role in the management of PAH^7,10

Frequency of positive PGI₂ (prostacyclin) synthase production in IPAH and normal lungs⁶

Frequency of positive PGI₂ synthase production in lungs of normal patients (n=7) and in patients with IPAH (n=12). Results shown are the mean percentages of positive vessels (p=0.015 for normal versus IPAH small vessels, and p=0.03 for normal versus IPAH medium-sized vessels; p-value=nonsignificant for normal versus PAH large vessels⁶).

VENTAVIS cellular effects

4-hour elevation of cAMP levels following single inhaled dose of VENTAVIS^® (iloprost) Inhalation Solution in 10 healthy adults²¹

The association between increased plasma cAMP levels and clinical outcomes in PAH has not been established.

Horizontal line = median value; box = middle quartiles; whiskers = minimum and maximum values.
^†p<0.05 vs baseline.²¹

Cyclic adenosine monophosphate (cAMP) is the main mediator of the vasodilatory and antiproliferative effects of prostacyclin, prostacyclin analogs, or nonprostanoid prostacyclin receptor agonists.^5,12 Prostacyclin acts through activation of the cAMP-dependent pathways.⁵