Plasma from Normal Pregnant Women Diminishes Endothelium-Derived Hyperpolarizing Factor (EDHF) Production in Cerebral Arteries Ödül A. Amburgey MD, Shane A. Reeves MD, Ira M. Bernstein MD and Marilyn J. Cipolla, PhD Depts. of Ob/Gyn, Neurology, and Pharmacology, University of Vermont, Burlington, VT Objective Circulating factors during pregnancy can have significant effects on endothelium, altering vascular resistance to promote either normal or pathologic adaptation. We investigated the effect of circulating factors during pregnancy on myogenic tone (MT) and endothelial vasodilator production of the posterior cerebral artery (PCA) by perfusing vessels from nonpregnant (NP) rats with plasma from NP or normal pregnant (P) women. We also investigated how cerebrovascular adaptation to pregnancy affected the vasoactive response to P plasma by comparing PCAs from late-pregnant (LP) and NP animals. Methods Third-order branches of PCAs from virgin and timed late- pregnant SD rats (d20) were dissected, mounted in an arteriograph chamber, and perfused with plasma (20% in buffer) pooled from nonpregnant or normal, non-laboring pregnant women (mean GA 33.4 ± 1.6 wks). Lumen diameter and MT were measured in response to increased intravascular pressure ( mm Hg), after which the nitric oxide synthase (NOS) inhibitor L-NNA (0.1 mM) and the cyclooxygenase (COX) inhibitor indomethacin (10 -5 mM) were added to the bath. Changes in diameter were used as a measure of basal NO and prostacyclin production, respectively. In the presence of NOS / COX inhibition, calcium ionophore A23187 was cumulatively added to the bath to measure EDHF response. Summary and Conclusions Circulating factors in pregnant plasma cause increased myogenic activity and decreased EDHF activity in NP vessels, responses that were ameliorated in LP vessels. There was no effect of pregnant plasma on basal NO or prostacyclin production in NP or LP vessels Pregnancy provides a unique and adaptive response to the vasoconstricting properties of P plasma, and returns myogenic reactivity / tone towards a nonpregnant state. Results Myogenic activity and vessel tone: effect of pregnant plasma PCAs perfused with both types of plasma demonstrated considerable myogenic activity as demonstrated by the amount of vasoconstriction measured in response to increased intravascular pressure. NP vessels perfused with NP plasma dilated at pressures below the myogenic pressure range, from 25 – 50 mm Hg, but then constricted, developing MT as the pressure was increased to 75 mm Hg. Tone was maintained up to 150 mm Hg. However, NP vessels perfused with P plasma had diameters that were significantly smaller and developed greater MT at lower pressures, suggesting P plasma has a vasoconstricting effect in these vessels. Adaptation of LP vessel to P plasma perfusate To determine if the vascular adaptation to pregnancy affected the reactivity of vessels to P plasma, the response to P plasma was compared in NP and LP vessels. NP PCAs constricted and developed MT that was maintained to 150 mm Hg while LP PCAs constricted less and developed less tone. MT in LP vessels perfused with P plasma was similar to what was seen with NP vessels perfused with NP plasma, suggesting these vessels adapt to the vasoconstricting influence of P plasma. Vasodilator production: L-NNA caused a similar response of vasoconstriction independent of vessel type or perfusate. Vessels had minimal response to indomethacin. Addition of A23187 in the presence of NOS / COX inhibition caused dilation in all vessels indicating an EDHF response; however, EDHF dilation was diminished in NP PCAs exposed to P plasma vs. NP PCAs exposed to NP plasma. EDHF activity was then compared in vessels from NP vs. LP animals perfused with P plasma. PCAs from LP animals had greater EDHF activity indicating that vascular adaptation to pregnancy influenced the reactivity to P plasma. These vessels had EDHF activity similar to NP vessels with NP plasma perfusate. We would like to gratefully acknowledge the support of the NINDS NS (to MJC), AHA EI (to MJC), the Preeclampsia Foundation Vision Grant (to LOA) and NIH RO1 HL (IMB) for their financial support of this work. Arteriograph Chamber PCA mounted on two glass cannulas above the optical window. Pressure vs. Diameter Curves Myogenic Tone NO / ProstacyclinEDHF Endothelial Vasodilator Production Pressure vs. Diameter Curves Myogenic Tone * * * *