Amplification of the pulmonary vasodilatory response to inhaled iloprost by subthreshold phosphodiesterase types 3 and 4 inhibition in severe pulmonary hypertension

Objective: Aerosolized iloprost causes specific pulmonary vasodilation for about 60 mins in patients with severe primary and secondary pulmonary hypertension. Repeated daily inhalations are currently in use for chronic treatment. The aim of the current study was to evaluate if phosphodiesterase type 3 and 4 inhibition might amplify the prostanoid effect on pulmonary vasodilatation by stabilization of intracellular second messenger cyclic adenosine monophosphate. Design: Uncontrolled clinical trial. Setting: Medical intensive care unit, Department of Internal Medicine, University Hospital, Giessen, Germany. Patients: A total of 11 patients with precapillary pulmonary hypertension (eight with primary pulmonary hypertension; one with pulmonary hypertension associated with calcinosis, Raynaud phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia [CREST syndrome]; one with pulmonary hypertension associated with systemic lupus erythematodes, and one with chronic pulmonary embolism) were included. All were classified as New York Heart Association class III or class IV. Interventions: During right heart catheterization, a single inhalation with iloprost (1.4 mug per inhalation) was performed, and hemodynamics and gas exchange variables were recorded for the next 2.5 hrs. After the iloprost effects had completely leveled off, the dual-selective phosphodiesterase types 3 and 4 inhibitor tolafentrine was infused in seven patients and aerosolized in five patients at doses that were per se ineffective (80 mg per 2.5 hrs intravenously; similar to0.8 mg deposited by aerosol), followed by a second iloprost inhalation procedure. Measurements: Decrease in pulmonary vascular resistance, duration of drug effect, safety, and tolerability of combined pharmacologic intervention. Results: The decrease in pulmonary vascular resistance to sole iloprost nebulization lasted for approximately 60 mins. This response was enhanced and prolonged to approximately 120 mins in the presence of both infused and aerosolized tolafentrine, without loss of pulmonary selectivity. No adverse events were observed. Conclusions: These data support the principle that subthreshold selective phosphodiesterase types 3 and 4 inhibition amplifies the lung vasodilatory response to inhaled iloprost, with minute doses being sufficient via the inhalative route.