Background: There is evidence that factors, other than nitric oxide (NO), mediate endothelium-dependent vasodilation by hyperpolarizing vascular smooth muscle (VSM). EETs are endothelium-derived vasodilators formed from cytochrome P450 metabolism of arachidonic acid. It has been suggested that endothelial-derived hyperpolarizing factor (EDHF) is an EET. In cerebral, renal and coronary vessels, EETs are effective vasodilators in resistance vessels, but lack potency in large conduit vessels. The effect of EETs have not been described in the newborn pulmonary circulation. Objectives:(1) To determine whether 11,12-EET mediates vasodilation in pulmonary arteries(PA), veins (PV) and resistance vessels (PRV) isolated from newborn piglets.(2) To determine whether hyperpolarization of VSM is involved in the vasodilatory mechanism of 11,12-EET. Methods: PA and PV rings were mounted in organ chambers for measurement of isometric tension. PRV were cannulated and pressurized to 15 mm Hg for measurement of lumen diameter. Vessels were preconstricted with U46619, a thromboxane A2 analogue, or with KCl (50 mM) to depolarize the VSM, and a concentration-response profile(0.0001-1 μM) to 11,12-EET was recorded. Tetraethylammonium (TEA) (20 mM× 15 min) was used to determine if inhibition of medium and large conductance K+ channels blocks the relaxation response.Results: PA responded inconsistently to 11,12-EET. Only 5 of 14 PA from 6 piglets demonstrated significant relaxation to 11,12-EET while 17 of 17 PA responded to bradykinin (BK). Among responders, maximum relaxation was 83.7± 10.4% to 11,12-EET vs. 75.4 ± 11.7% to BK. PRV (n = 4) did not dilate to a maximal concentration (1 μM) of 11,12-EET. In contrast, among 20 PV from 5 piglets, 75% responded in a concentration-dependent fashion, relaxing 67.2 ± 14.3% to 1 μM 11,12-EET. The response was endothelial independent, as all denuded PV had intact dilatory responses. Preconstriction with KCl abolished the relaxation response, while treatment with TEA had no effect. Conclusion: 11,12-EET is an effective vasodilator in newborn piglet PV, but causes inconsistent or no vasodilation in PA and PRV. The mechanism of 11,12-EET-mediated dilation in PV does not involve TEA-sensitive calcium-dependent K+ channels, but may involve membrane hyperpolarization as the response was inhibited by depolarization with KCl. Further investigations are warranted to determine the role of NO-independent, cytochrome P450-dependent vasodilation in the newborn pulmonary circulation.
(Spon by: Steven M. Block)
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Journal of Applied Physiology (2017)