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

被引:43
作者
Bolz, SS [1 ]
Pohl, U [1 ]
机构
[1] Univ Mainz, Inst Physiol & Pathophysiol, D-55099 Mainz, Germany
关键词
HUVECs; histamine; cAMP; cGMP; feedback;
D O I
10.1016/S0008-6363(97)00197-1
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective: We studied whether NO or prostacyclin (PGI,), 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 mu M 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 PGI(2) (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 PGI, release. Conversely, inhibition of the PGI, 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 mu M SNP (21 +/- 2 pmol/mg) or 10 mu M C-type natriuretic peptide (CNP, 4.6 +/- 1.6 pmol/mg) nor its reduction by 30 mu M LNNA had any effect on the His-induced [Ca2+](i) increases. Conclusion: PGI(2) 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 PGI(2) 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 PGI(2). (C) 1997 Elsevier Science B.V.
引用
收藏
页码:437 / 444
页数:8
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