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Prostacyclin in PAH

Prostacyclin is a fundamental pathway in the progression of PAH^†

• Reduced levels of prostacyclin are found in the pulmonary vasculature of patients with PAH

Frequency of positive PGI₂ synthase expression in IPAH and normal lungs¹

† Statements are based on observations reported from in vitro or animal trials. The clinical significance in humans is unknown.
Frequency of positive PGI₂ S expression in lungs of normal patients (n=7) and in patients with idiopathic pulmonary arterial hypertension (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=NS for normal versus PAH large vessels).⁸

Prostacyclin may play a role in1-10:

Action Potential benefit

Vasodilation Improved hemodynamics

Platelet aggregation inhibition Anticoagulation, inhibition of in situ thrombosis

Antiproliferation Improved pulmonary blood flow

Cardiac contractility Improved heart function

Anti-inflammatory Improved endothelial function

A system out of balance, with multifactorial pathology

Three principal pathways are implicated in the pathogenesis of PAH^{11, 12}

In PAH, prostacyclin and nitric oxide levels are decreased. Endothelin levels are increased.¹⁰

Imbalances in prostacyclin and endothelin levels have been implicated in^{1-3, 12-14}:

• Vasoconstriction
• Cellular proliferation
• In situ thrombosis
• Hypertrophy

Both the prostacyclin and endothelin pathways are key treatment targets in PAH^*

• The absence of prostacyclin has been implicated as a key pathological feature of PAH¹⁰
• The addition of prostacyclin has been shown to play a critical role in the management of PAH^2,3
• The interplay between the prostacyclin, nitric oxide, and endothelin pathways may have important treatment implications¹¹

"Importantly, the pathways interact…modulating the effect of any single pathway." McLaughlin W, McGoon MD. Circulation11

1. Tuder RM, Cool CD, Geraci MW, et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med. 1999;159:1925-1932.
2. Vane JR, Bottlin RM. Pharmacodynamic profile of prostacycline. Am J Cardiol. 1995;75:3A-10A.
3. Badesch DB, McLaughlin W, Delcroix M, et al. Prostanoid therapy for pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43:56-61.
4. Kerbaul F, Brimioulle S, Rondelet B, Dewachter C, Hubloue I, Naeije R. How prostacyclin improves cardiac output in right heart failure in conjunction with pulmonary hypertension. Am J Respir Crit Care Med. 2007;175:846-850.
5. Kemming G, Kisch-Wedel H, Flondor M, et al. Improved ventricular function during inhalation of PGI(2) aerosol partly relies on enhanced myocardial contractility. Eur Surg Res. 2005;37:9-17.
6. van Albada ME, Berger RM, Niggebrugge M, van Veghel R, Cromme-Dijkhuis AH, Schoemaker RG. Prostacyclin therapy increases right ventricular capillarisation in a model for flow-associated pulmonary hypertension. Eur J Pharmacol. 2006;549:107-116.
7. Pavlovic ´M, Petkovic´ D, Cvetkovic´ M, et al. The influence of prostacyclin (PGI2) on contractile properties of isolated right ventricle of rat heart. Experientia. 1995;51:941-944.
8. Pavlovic´M, Petkovic´ D, Cvetkovic´ M, Zdjelar K, Starcevic´ V, Bosnic´O. Study of the mechanism of prostacyclin (PGI2) action on myocardial contractility. Agents Actions Suppl. 1992;37:171-175.
9. Rose F, Hattar K, Gakisch S, et al. Increased neutrophil mediator release in patients with pulmonary hypertension-suppression by inhaled iloprost. Thromb Haemost. 2003;90:1141-1149.
10. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004;351:1425-1436.
11. McLaughlin W, McGoon MD. Pulmonary arterial hypertension. Circulation. 2006;114:1417-1431.
12. Braunwald E, Zipes DP, Libby P, eds. Heart Disease. 2 vols. 6th ed. Philadelphia, PA: WB Saunders Co; 2001:1912-1928.
13. Giald A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med. 1993;328:1732-1739.
14. Miyauchi T, Masaki T. Pathophysiology of endothelin in the cardiovascular system. Annu Rev Physiol. 1999;61:391-415.

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