Vasodilatory Effect of the Stable Vasoactive Intestinal Peptide Analog RO 25-1553 in Murine and Rat Lungs

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.

CFTR and sphingolipids mediate hypoxic pulmonary vasoconstriction

“…Sphingolipids thus exert a dual action on TRPC6 in HPV, in that they both translocate (nSMase-derived ceramide) and activate (S1P) TRPC6 channels. CFTR inhibition or deficiency had no effect on basal perfusion pressures in the isolated lung, a finding that is in line with the virtual lack of basal vascular tone in this preparation (36). However, both interventions markedly reduced the HPV response in isolated mouse lungs.…”

Augmentation of the effects of vasoactive intestinal peptide aerosol on pulmonary hypertension via coapplication of a neutral endopeptidase 24.11 inhibitor

“…In our present study, the pulmonary vasodilative properties of VIP were preserved after its inhalation. This is in line with a recent study of Yin et al (33), who demonstrated that inhalation of a stable analog of VIP antagonizes acute hypoxic pulmonary vasoconstriction in an intact rat model.…”

“…This is comparable to previous data using a peptide preparation in this model (14) and discloses the difficulties that have to be taken into account when aerosolizing peptides to the lung. Therefore, stable analogs of VIP or liposomal-packed VIP have been suggested to prolong the biological activity of VIP when used as an aerosol (17,30,33).…”

Vasoactive intestinal peptide for diagnosing exacerbation in chronic obstructive pulmonary disease

“…In this study we did not observe increased VIP serum levels in COPD patients with PAH and did not find a correlation of VIP serum levels with low oxygen saturation as suggested by animal studies and in vitro models [45][46][47] . It is difficult to explain this discrepancy between studies in animal and human beings, as it may not necessarily be reproducible in COPD patients.…”