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Published on: November 18, 2018
Inhaled Fasudil Lacks Pulmonary Selectivity in Thromboxane-Induced Acute Pulmonary Hypertension in Newborn Lambs
Shawn F L Hanson1, Michael H Terry2, Dafne T Moretta3
11 Department of Pediatrics, Division of Neonatology, Loma Linda University School of Medicine, Loma Linda, CA, USA.
Insights
Inhaled fasudil did not selectively reduce pulmonary artery pressure in lambs, unlike intravenous administration. Both methods decreased systemic pressure, indicating a lack of targeted pulmonary vasodilation with inhaled fasudil.
Area of Science:
- Pharmacology
- Cardiovascular Physiology
- Neonatal Medicine
Background:
- Pulmonary hypertension (PH) is a severe condition with limited treatment options.
- Fasudil, a Rho-kinase inhibitor, promotes vasodilation and reduces blood pressure.
- Investigating targeted drug delivery for PH is crucial.
Purpose of the Study:
- To compare the efficacy and selectivity of inhaled versus intravenous fasudil in treating pulmonary hypertension.
- To evaluate the impact of different fasudil administration routes on pulmonary and systemic hemodynamics.
Main Methods:
- Newborn lambs with induced acute pulmonary hypertension were studied.
- Fasudil was administered via intravenous infusion or inhaled aerosol.
- Hemodynamic parameters including pulmonary artery pressure and systemic arterial pressure were measured.
Main Results:
- Both intravenous and inhaled fasudil significantly reduced pulmonary artery pressure and pulmonary vascular resistance.
- However, both administration routes also caused comparable decreases in mean systemic arterial pressure and systemic vascular resistance.
- Peak plasma concentration of fasudil was higher with intravenous than inhaled delivery.
Conclusions:
- Inhaled fasudil did not demonstrate pulmonary selectivity compared to intravenous administration in this lamb model.
- These findings suggest that inhaled fasudil may not be a superior method for targeted pulmonary vasodilation in PH.
- Further research is needed to explore alternative delivery methods or dosages for selective pulmonary effects.
Introduction:
Pulmonary hypertension (PH) is a potentially deadly disease for infants and adults with few existing medical interventions and no cure. In PH, increased blood pressure in the pulmonary artery eventually leads to heart failure. Fasudil, an antagonist of Rho-kinase, causes vasodilation leading to decreased systemic artery pressure and pulmonary artery pressure (PAP). This study compared the effects of fasudil administered as either an intravenous infusion or inhaled aerosol in newborn lambs.
Hypothesis:
Inhaled aerosol delivery of fasudil will provide selective pulmonary vasodilation when compared with intravenous administration.
Methods:
Newborn lambs (∼11 days) were surgically instrumented and mechanically ventilated under anesthesia. A pulmonary artery catheter and ultrasonic flow probe were inserted to measure hemodynamics. Acute PH was pharmaceutically induced via continuous intravenous infusion of thromboxane. After achieving a 2- to 3-fold elevation of PAP, fasudil was administered either as intravenous infusion (2.5 mg/kg) or inhaled aerosol (100 mg of fasudil in 2 mL of saline). Changes in PAP, mean systemic arterial pressure (MABP), pulmonary vascular resistance (PVR), systemic vascular resistance (SVR), cardiac output, and heart rate were assessed. In addition, plasma concentrations of fasudil were measured.
Results:
Both routes of fasudil delivery produced significant decreases in PAP and PVR but also produced similar decreases in MABP and SVR. The Cmax for intravenous fasudil was greater than that for inhaled fasudil.
Conclusions:
These results suggest inhaled fasudil lacks pulmonary selectivity when compared with intravenous fasudil.
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