Phosphodiesterase inhibitors for the treatment of pulmonary hypertension

Abstract

The pulmonary vascular bed is both a source of and target for a number of vasoactive factors. Among the most important for pulmonary vascular homeostasis are factors that utilise cyclic guanosine monophosphate (cGMP) as an intracellular second messenger. These include nitric oxide and the natriuretic peptide family (atrial, brain and C-type natriuretic peptides). In the search for therapeutic strategies that engage the cGMP signalling pathway for the treatment of pulmonary arterial hypertension (PAH), inhibition of cGMP metabolism by phosphodiesterase type 5 (PDE5)-targeted compounds has proven most successful to date. One PDE5 inhibitor, sildenafil, has been shown to improve pulmonary haemodynamics and exercise capacity in patients with PAH and is now an approved treatment. Others are under investigation.An interesting, although still tentative, observation is the potential of sildenafil to reduce pulmonary vascular resistance without adversely affecting ventilation-perfusion matching. Another is the expression of phosphodiesterase type 5 in the hypertrophied right ventricle. These data suggest that phosphodiesterase type 5 inhibitors may have effects that distinguish them from other treatments for pulmonary hypertension and merit further study.

Role of Oxidized Lipids in Pulmonary Arterial Hypertension

“…This has resulted in the advancement of many therapies targeting the endothelin 1, phosphodiesterase, nitric oxide, and prostacyclin pathways to slow the progression of the disease. [10][11][12][13][14] This review specifically focuses on the role of oxidative stress, lipid oxidation, and peroxidation as contributing factors in PAH. Finally, this review discusses the emerging potential of high-density lipoprotein (HDL) mimetic peptides, which bind to oxidized lipids with high affinity, as well as microRNA-193, which targets oxidized lipids, as novel therapeutics.…”

Pregnancy outcomes in pulmonary arterial hypertension in the modern management era

“…Several classes of substances including calcium channel blockers, prostacyclin derivatives, endothelin receptor antagonists and phosphodiesterase-5 inhibitors are now being widely used in a tailored approach resulting in improved haemodynamics, exercise capacity and outcome [6][7][8][9][10]. Although it is generally not possible to cure PAH with these medications, some patients achieve substantial improvement and long-term stabilisation with near-normal haemodynamics.…”

Role of Notch Signaling in Pulmonary Hypertension

“…It stimulates soluble guanylate cyclase (sGC) to produce cyclic guanosine monophosphate (cGMP) in PASMCs, exerting vasodilatory and anti--proliferative effects [25]. All forms of PH are believed to be associated with a state of reduced NO bioavailability, as an outcome of reduced NOS expression [26], oxidative stress [27] and/or inhibition of NO synthesis [28].…”

“…Phosphodiesterase--5 (PDE--5) inhibitors PDE--5, enzyme abundantly found in pulmonary vasculature, inactivates cGMP, the secondary messenger responsible for mediating the vasodilatory activity of NO [25]. Hence, PDE--5 inhibitor, Sildenafil, initially used for erectile dysfunction, has emerged as an important drug therapy for PAH [72,73].…”