Oral contraceptive pill phase alters mechanisms contributing to cutaneous microvascular function in response to local heating

The purpose of this study was to investigate the effect of oral contraceptive pill (OCP) phase on in vivo microvascular endothelium-dependent vasodilation and contributions of nitric oxide (NO), cyclooxygenase (COX), and endothelial-derived hyperpolarizing factors (EDHFs). Participants completed two experimental visits in random order, during the <i>1</i>) low and <i>2</i>) high hormone phase of the OCP cycle. Endothelium-dependent dilation was assessed in the cutaneous microvasculature via local heating at four intradermal microdialysis sites treated with: <i>1</i>) lactated Ringer's (control), <i>2</i>) 10 mM ketorolac (Keto, COX inhibitor), <i>3</i>) 50 mM tetraethylammonium (TEA, calcium-activated potassium channel inhibitor), and <i>4</i>) 10 mM ketorolac + 50 mM TEA (Keto + TEA). Perfusion of 20 mM <i>N</i>^ω-nitro-l-arginine methyl ester (l-NAME) at each site was used to quantify the l-NAME-sensitive component of dilation, suggesting NO contribution. There was no effect of OCP phase on endothelium-dependent dilation (<i>P</i> = 0.75) or the l-NAME-sensitive component of the response (<i>P</i> = 0.09, <i>d</i> = 0.7) at control sites. Inhibition of COX increased baseline blood flow regardless of OCP phase (all <i>P</i> < 0.01). Control and Keto sites elicited greater endothelium-dependent dilation than TEA and Keto + TEA sites in both phases (all <i>P</i> < 0.0001). During the low hormone phase, the l-NAME-sensitive component was greater at control compared with TEA sites (<i>P</i> < 0.01). During the high hormone phase, the l-NAME-sensitive component was greater at Keto compared with TEA sites (<i>P</i> < 0.01). Within-participant differences between control and Keto sites support a phase-dependent restraint of NO activity via COX pathways (<i>P</i> = 0.01). These findings demonstrate that the OCP phase affects underlying mechanistic pathways contributing to cutaneous microvascular endothelial function.<b>NEW & NOTEWORTHY</b> This study investigates the effect of OCP phase on in vivo microvascular endothelium-dependent vasodilation and explores underlying mechanisms. Present findings suggest OCP phase does not affect overall microvascular endothelium-dependent dilation but does affect the underlying mechanisms. In women using OCP, there is a robust reliance on EDHF pathways and the COX pathway moderates basal microvascular blood flow and demonstrates a phase-dependent restraint of the NO pathway.