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

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.

Impaired pulmonary vasomotor control in exercising swine with multiple comorbidities

“…Further downstream in the NO-pathway, PDE5i resulted in a pulmonary vasodilation in DM + HC + CKD and normalized PVR, whereas no effect of PDE5i was observed in Healthy swine. The absence of a pulmonary vasodilator effect of PDE5i in Healthy swine is different from previous observations in which we showed a modest pulmonary vasodilator effect of PDE5 inhibition in Healthy swine [56,58]. This difference is not readily explained, but may be the result of an age difference, as swine in the previous studies were younger than in the present study.…”

“…In the current study, the endogenous vasodilator influence of NO was unaltered in the pulmonary vasculature as NOSi resulted in a similar vasoconstrictor response in DM + HC + CKD and Healthy swine. These data are consistent with previous findings from our laboratory, showing that the response to NOSi was maintained in swine with PVD secondary to myocardial infarction [37,56] and even increased in PVD secondary to pulmonary vein stenosis [58]. In accordance with the maintained vasodilator influence of endogenous NO in the present study, eNOS mRNA, eNOS total protein, uncoupling and phosphorylation were unaltered in DM + HC + CKD.…”

“…Consistent with the increased ET-dependent vasoconstrictor influence on the pulmonary vasculature, circulating ET-1 levels were higher in swine with DM + HC + CKD as compared to Healthy controls suggesting either increased production or impaired clearance. The elevated ET-levels in our swine model are in accordance with human studies, showing elevated plasma ET-levels in HFpEF-PH patients correlating with PA pressures [7,36,41,53], as well as with studies from our laboratory showing that plasma ET-levels are elevated in type II PH in swine, secondary to myocardial infarction [25] or due to pulmonary vein stenosis [58]. Furthermore, wedge ET-1 levels were shown to be higher than pulmonary arterial ET-levels and correlated with PVR in patients with combined pre-and post-capillary but not isolated post-capillary HFpEF-PH [7,36], suggesting that the higher ET-1 levels in patients ET A and ET B receptors are expressed in the pulmonary circulation under both physiological and pathophysiological circumstances [15].…”

“…This difference is not readily explained, but may be the result of an age difference, as swine in the previous studies were younger than in the present study. Similar to the present study, an increased response to PDE5i has been demonstrated in different swine models of type 2 PH, either due to pulmonary vein stenosis [58] or myocardial infarction [56]. In the present study, we observed no difference in PDE5 mRNA expression, but did not measure PDE5 protein or activity.…”

The many faces and outcomes of pulmonary vein stenosis in early childhood

“…In a swine model of PVS, both endothelin receptor blockade (tezosentan) and PDE 5 inhibition (sildenafil) induced pulmonary arterial vasodilation, suggesting potential treatment options for PVS‐induced pulmonary hypertension 45,46 …”