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Angiotensin II induces reactive oxygen species formation and augments 5‐HT‐induced vasoconstriction in isolated pulmonary arterioles

Accumulating evidence from our laboratories suggests that the renin‐angiotensin system (RAS) contributes to the development of some forms of pulmonary hypertension (PH) through the production of reactive oxygen species (ROS). Others have shown that the pulmonary vasoconstrictor response of 5‐hydroxytryptamine (5‐HT), another well known mediator of PH, is enhanced by superoxide. Therefore, we hypothesize that RAS contributes to PH through angiotensin II (Ang‐2)‐dependent ROS production and augmentation of 5‐HT‐induced pulmonary arteriolar (PA) constriction. We tested this hypothesis in isolated, pressurized (20 mmHg) rat PAs (int. dia. 252 ± 29 μm). Using confocal microscopy and the ROS‐sensitive fluorescent dyes, DCFH2‐DA and DHE, we found that exposure (1 hour) to Ang‐2 (10–8 M) induced the production of ROS without sustained vasoconstriction. Moreover, treatment with Ang‐2 induced a significant (n=4; P<0.05) left shift in 5‐HT sensitivity from a vasoconstriction EC50 of 3.00 ± 0.58 to 0.75 ± 0.08 μM that was not seen with repeated 5‐HT exposures (EC50 2.36 ± 0.86 μM). These data suggest that Ang‐2 promotes PA constriction by producing ROS that in turn potentiate the vasoconstrictor responses of 5‐HT. We propose that upregulation of the RAS in some forms of PH contributes to disease development by stimulating oxidative stress, potentiating vasoconstriction and inducing vascular remodeling.