Intervening with the Nitric Oxide Pathway to Alleviate Pulmonary Hypertension in Pulmonary Vein Stenosis.

Duin Duin,Merkus Merkus,Uitterdijk Uitterdijk,Bartelds Bartelds,Duncker Duncker,Stam Stam,Danser Danser,Reiss Reiss

doi:10.3390/jcm8081204

Abstract

Pulmonary hypertension (PH) as a result of pulmonary vein stenosis (PVS) is extremely difficult to treat. The ideal therapy should not target the high-pressure/low-flow (HP/LF) vasculature that drains into stenotic veins, but only the high-pressure/high-flow (HP/HF) vasculature draining into unaffected pulmonary veins, reducing vascular resistance and pressure without risk of pulmonary oedema. We aimed to assess the activity of the nitric oxide (NO) pathway in PVS during the development of PH, and investigate whether interventions in the NO pathway differentially affect vasodilation in the HP/HF vs. HP/LF territories. Swine underwent pulmonary vein banding (PVB; n = 7) or sham surgery (n = 6) and were chronically instrumented to assess progression of PH. Pulmonary sensitivity to exogenous NO (sodium nitroprusside, SNP) and the contribution of endogenous NO were assessed bi-weekly. The pulmonary vasodilator response to phosphodiesterase-5 (PDE5) inhibition was assessed 12 weeks after PVB or sham surgery. After sacrifice, 12 weeks post-surgery, interventions in the NO pathway on pulmonary small arteries isolated from HP/LF and HP/HF territories were further investigated. There were no differences in the in vivo pulmonary vasodilator response to SNP and the pulmonary vasoconstrictor response to endothelial nitric oxide synthase (eNOS) inhibition up to 8 weeks after PVB as compared to the sham group. However, at 10 and 12 weeks post-PVB, the in vivo pulmonary vasodilation in response to SNP was larger in the PVB group. Similarly, the vasoconstriction to eNOS inhibition was larger in the PVB group, particularly during exercise, while pulmonary vasodilation in response to PDE5 inhibition was larger in the PVB group both at rest and during exercise. In isolated pulmonary small arteries, sensitivity to NO donor SNP was similar in PVB vs. sham groups irrespective of HP/LF and HP/HF, while sensitivity to the PDE5 inhibitor sildenafil was lower in PVB HP/HF and sensitivity to bradykinin was lower in PVB HP/LF. In conclusion, both NO availability and sensitivity were increased in the PVB group. The increased nitric oxide sensitivity was not the result of a decreased PDE5 activity, as PDE5 activity was even increased. Some vasodilators differentially effect HP/HF vs. HP/LF vasculature.

Highlights

Pulmonary hypertension (PH) is a chronic disease characterised by a mean pulmonary arterial pressure >25 mmHg at rest [1]
The pulmonary vasculature draining into the stenotic pulmonary veins experiences a high pressure with a relatively low flow (HP/LF), while the pulmonary vasculature draining into the remaining unaffected pulmonary veins experiences a high pressure with a relatively high flow (HP/HF) because of flow redistribution [13]
Pulmonary vein banding resulted in an increased Total pulmonary vascular resistance index (tPVRi) as early as 6 weeks after banding (Table 1, 132 ± 4 vs. 107 ± 9 mmHg L−1 min kg in sham (p ≤ 0.05))

Summary

Introduction

Pulmonary hypertension (PH) is a chronic disease characterised by a mean pulmonary arterial pressure (mPAP) >25 mmHg at rest [1]. The use of PAH vasodilation therapy, can be perilous in group II PH, as vasodilation increases flow, while the outflow remains hampered, potentially resulting in an increase in capillary pressure and pulmonary oedema. Use of first-line vasodilator therapies like inhaled nitric oxide (NO), administration of NO donors or phosphodiesterase-5 (PDE5) inhibitors may increase dyspnoea by causing pulmonary oedema [12]. To this day, crucial information about the effects of these therapies in PH due to PVS is lacking. The ideal therapy would target only the HP/HF vasculature, lowering PAP with no detrimental effects associated with increased flow To date, it is unclear whether vasodilator therapies differentially affect these two different lung regions. Since exercise testing allows detection of perturbations in cardiopulmonary function that may not be apparent under resting conditions, which facilitates the assessment of disease severity [18], we performed measurements both at rest and during graded treadmill exercise

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