Vasoactive peptides and the pathogenesis of pulmonary hypertension: role and potential therapeutic application

Pulmonary hypertension (PH) is a debilitating disease with a dismal prognosis. Recent advances in therapy (e.g. prostacyclin analogues, endothelin receptor antagonists and phosphodiesterase 5 inhibitors), whilst significantly improving survival, simply delay the inexorable progression of the disease. An array of endogenous vasoconstrictors and vasodilators coordinates to maintain pulmonary vascular homeostasis and morphological integrity, and an imbalance in the expression and function of these mediators precipitates PH and related lung diseases. The vasodilator peptides, including natriuretic peptides, vasoactive intestinal peptide, calcitonin gene-related peptide and adrenomedullin, trigger the production of cyclic nucleotides (e.g. cGMP and cAMP) in many pulmonary cell types, which in tandem exert a multifaceted protection against the pathogenesis of PH, encompassing vasodilatation, inhibition of vascular smooth muscle proliferation, anti-inflammatory and anti-fibrotic effects and salutary actions on the right ventricle. This coordinated beneficial activity underpins a contemporary perception that to advance treatment of PH it is necessary to offset multiple disease mechanisms (i.e. the pulmonary vasoconstriction, pulmonary vascular remodelling, right ventricular dysfunction). Thus, there is considerable potential for harnessing the favourable activity of peptide mediators to offer a novel, efficacious therapeutic approach in PH.