Endothelial dysfunction in gestational hypertension induced by catechol‐O‐methyltransferase inhibition

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New Findings What is the central question of this study? Gestational hypertension is a major obstetric problem of placental origin, associated with reduced production of 2‐methoxyestradiol. In this study, we evaluated in rats the consequences of pharmacological inhibition of catechol‐O‐methyltransferase, the enzyme that produces 2‐methoxyestradiol from 2‐hydroxyestradiol. What is the main finding and its importance? The present study provides evidence that inhibition of catechol‐O‐methyltransferase in pregnant rats produces arterial hypertension and endothelial dysfunction due to reduced nitric oxide bioavailability. The results help us to understand gestational hypertension and support a possible new approach to early diagnosis and treatment of the disease. The present study evaluated whether catechol‐O‐methyltransferase inhibition in pregnant rats results in increased blood pressure and vascular endothelial dysfunction as a consequence of decreased nitric oxide bioavailability. Pregnant Sprague–Dawley rats were given entacapone (a catechol‐O‐methyltransferase inhibitor) by gavage from the 10th to the 20th day of pregnancy. Blood pressure was measured by plethysmography in the tail artery. Vascular endothelial function and NO release were assessed both in the absence and in the presence of tempol. Systolic blood pressure increased significantly in pregnant rats treated with entacapone compared with untreated pregnant rats on days 14 (143 ± 4 versus 122 ± 3 mmHg) and 19 of gestation (129 ± 4 versus 115 ± 5 mmHg). Both conductance (aortic rings) and resistance vessels (mesenteric small arterial vessels) from entacapone‐treated pregnant rats showed diminished relaxation in response to acetylcholine compared with vessels from vehicle‐treated pregnant and virgin rats. In mesenteric arterioles, this endothelial dysfunction was abolished in the presence of l‐NAME, indicating that it was caused by reduced NO availability, and it also improved in the presence of tempol, suggesting increased oxidative stress in hypertensive pregnant rats. Endothelial release of nitric oxide induced by calcium ionophore (A23187) was significantly greater in aortas from vehicle‐treated pregnant rats than in aortas from pregnant rats given entacapone. This endothelial dysfunction seen in hypertensive rats was prevented by addition of tempol. The present study provides evidence that catechol‐O‐methyltransferase inhibition in pregnant rats produces arterial hypertension and endothelial dysfunction due to reduced nitric oxide bioavailability.

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