PURPOSE:Both endogenous and exogenous estrogen attenuates pulmonary artery (PA) vasoconstriction. Whether these effects are mediated via estrogen receptor (ER)-α or ER-β, remains unknown. A better understanding may result in novel, nonhormonal treatment options for pulmonary hypertension. We hypothesized that administration of the selective ER-α agonist propylpyrazole-triol (PPT) and/or the selective ER-β agonist diarylpropiolnitrile (DPN) attenuates PA vasoconstriction induced by pharmacologic and hypoxic stimuli.
METHODS:PA rings (n=4–9/group) from adult male Sprague-Dawley rats were suspended in physiologic organ baths. Force displacement (FD) was continuously recorded. Vasoconstrictor responses to phenylephrine (10–8M –10–5M) and hypoxia (PaO2 35–45 mmHg) were determined. Endothelium-dependent (acetylcholine, 10–8M –10–4M) and -independent (sodium-nitroprusside, 10–9M –10–5M) vasorelaxation were also measured. PPT or DPN (10–9M –5x10–5M) or vehicle were added to the organ bath in presence or absence of the nitric oxide (NO)-synthase inhibitor L-NAME (10–4M). FD after phenylephrine was expressed as percent change from baseline tension. FD during hypoxic pulmonary vasoconstriction (HPV) was expressed as percent of phenylephrine-precontraction. Data (mean±SEM) were analyzed with two-way ANOVA with post-hoc Bonferroni test.
RESULTS:Selective ER-α activation (PPT, 5x10–5M) acutely (<10 min) attenuated phenylephrine-induced vasoconstriction (39.06±10.13% vs. vehicle: 116.92±29.14%; p<0.001). This effect was abolished by L-NAME (PPT&L-NAME: 73.52±5.59%; p<0.001 vs. PPT alone). PPT did not affect endothelium-dependent or –independent vasorelaxation. In contrast, selective ER-β activation (DPN, 5x10–5M) attenuated HPV (6.20±6.47% vs. vehicle: 54.47±9.39%; p<0.01). L-NAME prevented this effect (DPN&L-NAME: 78.87±25.31%, p<0.001 vs. DPN alone). Lower PPT or DPN concentrations were less effective. Interestingly, DPN did not affect phenylephrine-induced vasoreactivity, while PPT did not affect HPV.
CONCLUSION:Both, ER-α and ER-β significantly attenuate PA vasoconstriction in a dose-dependent manner. The rapid onset of action suggests a nongenomic mechanism. The contribution of specific ERs appears to be stimulus-specific: ER-α modulates phenylephrine-induced vasoconstriction, while ER-β mediates the attenuation of HPV. NO-inhibition eliminates these effects, suggesting a central role for NO in mediating the pulmonary vascular effects of ER-α and ER-β.
CLINICAL IMPLICATIONS:Selective ER-activation may allow for novel treatment options in pulmonary hypertension.
DISCLOSURE:Tim Lahm, No Financial Disclosure Information; No Product/Research Disclosure Information