Ziogas J, Vessey K
Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia.
Pharmacology. 2001;63(2):103-11. doi: 10.1159/000056120.
The aims of the present study were to determine the angiotensin II (AngII) receptor subtype(s) involved in vasoconstriction and enhancement of sympathetic neurotransmission in rat isolated mesenteric arteries. Vasoconstriction was assessed in mesenteric artery ring preparations suspended under 0.5 g of tension in a myograph. In control arteries, with an intact endothelium, AngII (1 nmol/l-3 micromol/l) caused a concentration-dependent contraction. The pEC(50) for AngII was 7.6 +/- 0.2 and the maximum response of 0.24 +/- 0.07 g was reached with 100 nmol/l. In the presence of indomethacin (3.0 micromol/l) and N(omega)-nitro-L-arginine (NOLA) (100 micromol/l) to remove the influence of endothelium-derived prostaglandins and nitric oxide, the maximum response evoked by AngII was increased to 0.48 +/- 0.1 g and the pEC(50) was 7.6 +/- 0.3. The AT1 receptor antagonist losartan (30 nmol/l) competitively blocked the AngII-induced contractions with an estimated pA(2) of 8.2 in both the control arteries and in arteries treated with indomethacin and NOLA. The AT2 receptor antagonist PD 123319 (1 micromol/l) did not affect AngII-induced contractions under either condition. Conventional intracellular microelectrode recording techniques were used to investigate the effects of AngII on excitatory junction potentials (EJP) evoked by stimulation of periarteriolar sympathetic nerves. Stimulation with trains of 10 pulses delivered at 0.9 Hz evoked EJP which were blocked by tetrodotoxin (0.1 micromol/l), guanethidine (30 micromol/l) and the P(2X) receptor desensitizing agent alpha,beta-methylene ATP (30 micromol/l) suggesting the EJP were mediated by ATP, or a related purine, released from sympathetic nerves. AngII (0.3- 100 nmol/l) did not affect the resting membrane potential or the amplitude of the first EJP, but did enhance the amplitude of the plateau EJP later in the train. A maximum 49.2 +/- 3.9% enhancement of the plateau EJP amplitude was elicited by 10 nmol/l AngII and the pEC(50) was 9.1 +/- 0.1. The facilitatory effect of AngII on EJP amplitude was not altered in the presence of indomethacin and NOLA. Losartan (30 nmol/l) competitively blocked the AngII-induced enhancement of plateau EJP amplitude, with an estimated pA(2) of 8.6. PD 123319 did not alter the enhancement of plateau EJP amplitude by AngII. The results from the present study show that both the vasoconstriction and enhancement of plateau EJP amplitude by AngII in rat mesenteric arteries are blocked by the AT1 receptor antagonist losartan and are unaffected by the AT2 receptor antagonist PD 123319.
本研究的目的是确定参与大鼠离体肠系膜动脉血管收缩和交感神经传递增强的血管紧张素II（AngII）受体亚型。在肌张力描记仪中，将肠系膜动脉环标本悬挂在0.5 g张力下，评估血管收缩情况。在具有完整内皮的对照动脉中，AngII（1 nmol/l - 3 μmol/l）引起浓度依赖性收缩。AngII的pEC(50)为7.6±0.2，100 nmol/l时达到最大反应0.24±0.07 g。在存在吲哚美辛（3.0 μmol/l）和N(ω)-硝基-L-精氨酸（NOLA）（100 μmol/l）以消除内皮衍生前列腺素和一氧化氮的影响时，AngII引起的最大反应增加到0.48±0.1 g，pEC(50)为7.6±0.3。AT1受体拮抗剂氯沙坦（30 nmol/l）在对照动脉以及用吲哚美辛和NOLA处理的动脉中，均以估计的pA(2)为8.2竞争性阻断AngII诱导的收缩。AT2受体拮抗剂PD 123319（1 μmol/l）在两种情况下均不影响AngII诱导的收缩。采用传统的细胞内微电极记录技术研究AngII对刺激动脉周围交感神经诱发的兴奋性接头电位（EJP）的影响。以0.9 Hz施加10个脉冲的串刺激诱发EJP，其被河豚毒素（0.1 μmol/l）、胍乙啶（30 μmol/l）和P(2X)受体脱敏剂α,β-亚甲基ATP（30 μmol/l）阻断，提示EJP由交感神经释放的ATP或相关嘌呤介导。AngII（0.3 - 100 nmol/l）不影响静息膜电位或第一个EJP的幅度，但在刺激串后期确实增强了平台期EJP的幅度。10 nmol/l AngII引起平台期EJP幅度最大增强49.2±3.9%，pEC(50)为9.1±0.1。在存在吲哚美辛和NOLA的情况下，AngII对EJP幅度的促进作用未改变。氯沙坦（30 nmol/l）竞争性阻断AngII诱导的平台期EJP幅度增强，估计pA(2)为8.6。PD 123319未改变AngII对平台期EJP幅度的增强作用。本研究结果表明，大鼠肠系膜动脉中AngII引起的血管收缩和平台期EJP幅度增强均被AT1受体拮抗剂氯沙坦阻断，且不受AT2受体拮抗剂PD 123319的影响。
