Rhinehart Kristie, Handelsman Corey A, Silldorff Erik P, Pallone Thomas L
Division of Nephrology, University of Maryland School of Medicine, Baltimore 21201-1595, USA.
Am J Physiol Heart Circ Physiol. 2003 Mar;284(3):H779-89. doi: 10.1152/ajpheart.00317.2002. Epub 2002 Nov 7.
We tested whether the respective angiotensin type 1 (AT(1)) and 2 (AT(2)) receptor subtype antagonists losartan and PD-123319 could block the descending vasa recta (DVR) endothelial intracellular calcium concentration (Ca(2+)) suppression induced by ANG II. ANG II partially reversed the increase in Ca(2+) generated by cyclopiazonic acid (CPA; 10(-5) M), acetylcholine (ACh; 10(-5) M), or bradykinin (BK; 10(-7) M). Losartan (10(-5) M) blocked that effect. When vessels were treated with ANG II before stimulation with BK and ACh, concomitant AT(2) receptor blockade with PD-123319 (10(-8) M) augmented the suppression of endothelial Ca(2+) responses. Similarly, preactivation with the AT(2) receptor agonist CGP-42112A (10(-8) M) prevented AT(1) receptor stimulation with ANG II + PD-123319 from suppressing endothelial Ca(2+). In contrast to endothelial Ca(2+) suppression by ANG II, pericyte Ca(2+) exhibited typical peak and plateau Ca(2+) responses that were blocked by losartan but not PD-123319. DVR vasoconstriction by ANG II was augmented when AT(2) receptors were blocked with PD-123319. Similarly, AT(2) receptor stimulation with CGP-42112A delayed the onset of ANG II-induced constriction. PD-123319 alone (10(-5) M) showed no AT(1)-like action to constrict microperfused DVR or increase pericyte Ca(2+). We conclude that ANG II suppression of endothelial Ca(2+) and stimulation of pericyte Ca(2+) is mediated by AT(1) or AT(1)-like receptors. Furthermore, AT(2) receptor activation opposes ANG II-induced endothelial Ca(2+) suppression and abrogates ANG II-induced DVR vasoconstriction.
我们测试了血管紧张素1型（AT(1)）和2型（AT(2)）受体亚型拮抗剂氯沙坦和PD - 123319是否能阻断血管紧张素II（ANG II）诱导的直小血管降支（DVR）内皮细胞内钙浓度（Ca(2+)）的降低。ANG II部分逆转了由环匹阿尼酸（CPA；10(-5) M）、乙酰胆碱（ACh；10(-5) M）或缓激肽（BK；10(-7) M）引起的Ca(2+)升高。氯沙坦（10(-5) M）阻断了该效应。当血管在用BK和ACh刺激前用ANG II处理时，同时用PD - 123319（10(-8) M）阻断AT(2)受体会增强对内皮Ca(2+)反应的抑制。同样，用AT(2)受体激动剂CGP - 42112A（10(-8) M）预激活可防止用ANG II + PD - 123319刺激AT(1)受体抑制内皮Ca(2+)。与ANG II对内皮Ca(2+)的抑制相反，周细胞Ca(2+)表现出典型的峰值和平台期Ca(2+)反应，该反应被氯沙坦阻断，但未被PD - 123319阻断。当用PD - 123319阻断AT(2)受体时，ANG II引起的DVR血管收缩增强。同样，用CGP - 42112A刺激AT(2)受体可延迟ANG II诱导的血管收缩的起始。单独使用PD - 123319（10(-5) M）未显示出类似AT(1)的作用来收缩微灌注的DVR或增加周细胞Ca(2+)。我们得出结论，ANG II对内皮Ca(2+)的抑制和对周细胞Ca(2+)的刺激是由AT(1)或类似AT(1)的受体介导的。此外，AT(2)受体激活可对抗ANG II诱导的内皮Ca(2+)抑制，并消除ANG II诱导的DVR血管收缩。
