Indomethacin enhances endothelial NO release — evidence for a role of PGI2 in the autocrine control of calcium-dependent autacoid production

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Abstract
Objective: We studied whether NO or prostacyclin (PGI2), which are continuously released by endothelial cells, have autocrine/paracrine effects on the calcium-dependent autacoid production by modulating the intracellular Ca2+ concentration ([Ca2+]i). Methods: Histamine(His)-induced [Ca2+]i increases (Fura 2-method) and NO-dependent cGMP increase were measured in human umbilical vein endothelial cells (HUVECs) before and after cyclooxygenase inhibition or application of cAMP- and cGMP-elevating drugs. Results: 0.3 μM His increased endothelial [Ca2+]i from 77±2 nM to 418±59 nM. The His-induced [Ca2+]i increases were significantly attenuated following treatment with PGI2 (by 23%) and forskolin (by 33%), both increasing the cAMP release from HUVECs (by 49% and 66%). The His-induced [Ca2+]i increases were inhibited by the protein kinase A-activator cBIMPS (by 61%) which also abolished the His-induced PGI2 release. Conversely, inhibition of the PGI2 production with indomethacin significantly augmented the His-induced [Ca2+]i increases (by 32%), resulting in a significantly augmented NO production as indicated by an enhanced LNNA-sensitive cGMP increase in HUVECs. In contrast, neither increases of cGMP (basal 0.4±0.1 pmol/mg) elicited by 10 μM SNP (21±2 pmol/mg) or 10 μM C-type natriuretic peptide (CNP, 4.6±1.6 pmol/mg) nor its reduction by 30 μM LNNA had any effect on the His-induced [Ca2+]i increases. Conclusion: PGI2 attenuates agonist-induced [Ca2+]i increases by a cAMP-dependent mechanism, thereby modulating not only its own synthesis via a negative feedback but also that of NO. Consequently, reduced PGI2 levels result in an increased NO production. NO which does not cause a negative feedback control by cGMP might therefore compensate for the lack of PGI2.

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