Abstract
RationaleStable analogs of vasoactive intestinal peptide (VIP) have been proposed as novel line of therapy in chronic obstructive pulmonary disease (COPD) based on their bronchodilatory and anti-inflammatory effects. We speculated that VIP analogs may provide additional benefits in that they exert vasodilatory properties in the lung, and tested this hypothesis in both ex vivo and in vivo models.MethodsIn isolated perfused mouse lungs and in an in vivo rat model, pulmonary blood vessels were preconstricted by hypoxia and hemodynamic changes in response to systemic (ex vivo) or inhaled (in vivo) administration of the cyclic VIP analog RO 25-1553 were determined.ResultsIn mouse lungs, RO 25-1553 reduced intrinsic vascular resistance at normoxia, and attenuated the increase in pulmonary artery pressure in response to acute hypoxia. Consistently, inhalation of RO 25-1553 (1 mg·mL−1 for 3 min) caused an extensive and sustained (> 60 min) inhibition of the pulmonary arterial pressure increase in response to hypoxia in vivo that was comparable to the effects of inhaled sildenafil. This effect was not attributable to systemic cardiovascular effects of RO 25-1553, but to a lung specific reduction in pulmonary vascular resistance, while cardiac output and systemic arterial hemodynamics remained unaffected. No adverse effects of RO 25-1553 inhalation on pulmonary gas exchange, ventilation-perfusion matching, or lung fluid content were detected.ConclusionOur findings demonstrate that inhaled delivery of the stable VIP analog RO 25-1553 induces a potent and sustained vasodilatory effect in the pulmonary circulation with no detectable adverse effects. Therapeutic inhalation of RO 25-1553 may provide vascular benefits in addition to its reported anti-inflammatory and bronchodilatory effects in COPD, yet caution is warranted given the overall poor results of vasodilator therapies for pulmonary hypertension secondary to COPD in a series of recent clinical trials.
Highlights
Projections for 2020 indicate that chronic obstructive pulmonary disease (COPD) will become the third leading cause of death worldwide in comparison to ranking 6th in 1990 and fifth leading cause of years lost through early mortality or handicap as compared to ranking 12th in 1990 [1]
The biological actions of vasoactive intestinal peptide (VIP) are mediated by two type II G-protein coupled receptors, VIP/pituary adenylate cyclaseactivating polypeptide type I (VPAC1) and type II (VPAC2) [6], which are expressed on airway epithelia, macrophages, and in pulmonary arteries and veins [7,8]
Analyses of data from the ASPIRE (Assessing the Spectrum of Pulmonary Hypertension Identified at a Referral Centre) registry did not detect an association of compassionate therapeutic targeting of the pulmonary vasculature with a survival benefit in COPD patients with severe pulmonary hypertension (PH); a subset of patients who responded to pulmonary vascular treatment either by an improvement in WHO functional class or by a fall in Pulmonary vascular resistance (PVR) .20% showed an increased cumulative survival as compared to non-responders [18]. While these findings suggest that targeting PH may be of potential clinical benefit in at least a subset of responders, recent clinical trials demonstrate that systemic delivery of vasodilators such as sildenafil or bosentan failed to show clinical improvement but frequently further aggravated arterial hypoxemia in COPD patients with PH [19,20,21,22]
Summary
Projections for 2020 indicate that chronic obstructive pulmonary disease (COPD) will become the third leading cause of death worldwide in comparison to ranking 6th in 1990 and fifth leading cause of years lost through early mortality or handicap (disabilityadjusted life years) as compared to ranking 12th in 1990 [1]. Vasoactive intestinal peptide (VIP) is a vasodilatory peptide that was first isolated from the upper intestine [2] and that exerts prominent smooth muscle relaxant as well as anti-inflammatory and immunomodulatory properties [3]. VPAC agonists such as VIP and synthetic analogs thereof have emerged as promising novel line of therapy for the treatment of obstructive and inflammatory airway disease such as COPD. As compared to VIP, the second generation VIP analog RO 25-1553 [9,10] and the chemically related follow up molecule RO 50-24118 [11] are biologically more stable, and constitute potent and selective agonists of VPAC2. RO 50-24118 has been shown to have dual bronchodilatory and anti-inflammatory effects, in that it relaxes airway smooth muscle cells, inhibits bronchoconstriction and attenuates the influx of neutrophils and CD8+ T-cells in inflammatory lung disease [12]
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