Rationale: Stable 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.
Methods: In 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.
Results: In 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.
Conclusion: Our 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.