Acute Cardiopulmonary Hemodynamic Effects of Brain Natriuretic Peptide in Patients With Pulmonary Arterial Hypertension*

Boston University, Boston, Massachusetts, United States
Chest (Impact Factor: 7.48). 01/2006; 128(6 Suppl):618S-619S. DOI: 10.1378/chest.128.6_suppl.618S-a
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Available from: Nicholas S Hill
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    ABSTRACT: Phosphodiesterase-5 (PDE5) inhibitors and other agents that modulate intracellular cGMP are now emerging as promising, safe, and easy to administer therapies for pulmonary hypertension, with relatively few side effects. Recent studies have shown that PDE5 inhibitors are potent acute pulmonary vasodilators in experimental models that partially reverse established pulmonary arterial hypertension and blunt chronic pulmonary hypertension. In addition, studies on animals reveal that PDE5 inhibitors work in concert with nitric oxide and/or natriuretic peptide levels by enhancing intracellular cGMP and cGMP-mediated vasodilator effects. Further, the combination of PDE5 inhibitors and agents that increase cGMP or cAMP also yields additive beneficial effects on pulmonary hemodynamics in patients with pulmonary arterial hypertension.
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    ABSTRACT: Despite reports of the efficacy of phosphodiesterase 4 (PDE4) inhibitors in some Phase III clinical trials of asthma and chronic obstructive pulmonary disease, the presence of dose-limiting side effects continue to hamper their development. Consequently, new approaches are required to improve the therapeutic ratio and the safety of these compounds. One option might lie in the synthesis of small molecules with a broader PDE specificity. The development of dual-specificity compounds that inhibit PDE4 and PDE1, PDE3, PDE5 or PDE7 could be beneficial for the treatment of chronic inflammatory lung diseases and are currently being investigated.
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    ABSTRACT: 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.
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