Biology Reference
In-Depth Information
Role of Phosphodiesterases in Adult-Onset
Pulmonary Arterial Hypertension
F. Murray, M.R. MacLean, and P.A. Insel
Contents
1 Pulmonary Arterial Hypertension .......................................................... 280
2 Role of Cyclic Nucleotides in PAH ........................................................ 282
3 Targeting Phosphodiesterases in PAH ..................................................... 283
3.1 Targeting PDEs in Pulmonary Artery Vasoconstriction and Remodeling .......... 284
3.2 Role of PDEs in the Right Ventricular Hypertrophy ................................ 293
3.3 Role of PDEs in the Inflammation Associated with PAH ........................... 295
4 Conclusion and the Future of PDEs in PAH ............................................... 296
References ....................................................................................... 297
Abstract Pulmonary arterial hypertension (PAH) is characterized by increased
mean pulmonary artery pressure (mPAP) due to vasoconstriction and structural
changes in the small pulmonary arteries (PAs); proliferation of pulmonary artery
smooth muscle cells (PASMCs) contributes to the remodeling. The abnormal
pathophysiology in the pulmonary vasculature relates to decreased cyclic nucleotide
levels in PASMCs. Phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP and
cGMP, thereby PDE inhibitors are effective in vasodilating the PA and decreasing
PASMC proliferation. Experimental studies support the use of PDE3, PDE5, and
PDE1 inhibitors in PAH. PDE5 inhibitors such as sildenafil are clinically approved to
treat different forms of PAH and lower mPAP, increase functional capacity, and
decrease right ventricular hypertrophy, without decreasing systemic arterial pressure.
New evidence suggests that the combination of PDE inhibitors with other therapies
F. Murray (
*
) and P.A. Insel
Department of Pharmacology and Department of Medicine, BSB 3073, University of California,
9500 Gilman Drive, La Jolla, San Diego, CA 92093-0636, USA
e-mail: fmurray@ucsd.edu
M.R. MacLean
Institute of Cardiovascular & Medical Sciences College of Medical, Veterinary and Life Sciences,
University of Glasgow, Glasgow G12 8QQ, Scotland, U.K
and
University of Glasgow, Glasgow, Scotland, UK
