糖尿病大鼠主动脉和膀胱中肾上腺素能受体及毒蕈碱受体相关前列环素合成的差异变化

Differential changes of adrenoceptor- and muscarinic receptor-linked prostacyclin synthesis by the aorta and urinary bladder of the diabetic rat.

作者信息

Jeremy J Y, Thompson C S, Mikhailidis D P

机构信息

Department of Chemical Pathology and Human Metabolism, Royal Free Hospital and School of Medicine, University of London.

出版信息

Br J Pharmacol. 1993 Apr;108(4):1131-6. doi: 10.1111/j.1476-5381.1993.tb13516.x.

DOI:10.1111/j.1476-5381.1993.tb13516.x

PMID:8485622

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1908128/

Abstract

The effect of experimental diabetes mellitus (DM; hyperglycaemic, non-ketototic; 2 months duration) in the rat on receptor-linked prostacyclin (PGI2) synthesis (measured as 6-oxo-PGF1 alpha by radioimmunoassay) was studied in the aorta and urinary bladder using adrenaline, angiotensin II (AII) and acetylcholine (ACh). Signal transduction systems were studied via stimulation of PGI2 synthesis with phorbol ester dibutyrate (PDBU; a protein kinase C activator [PKC]), Ca2+ ionophore A23187 (A23187) and thapsigargin (both elevate intracellular Ca2+, activating phospholipase A2 [PLA2]) and arachidonate (AA; substrate for PGI2 synthesis). 2. In response to adrenaline, AII and phorbol ester, aortic PGI2 release was markedly reduced (all > 75%) in diabetic rats compared to controls. EC50s of the dose-response curves for adrenaline, AII and PDBU were also markedly increased in aortae from DM rats compared to controls. Although there was decreased output of PGI2 in response to A23187 by aortae from diabetic rats compared to controls, there was no difference in the EC50s (mean +/- s.e. mean: diabetic, 2.7 +/- 0.2 x 10(-6) M; controls 2 +/- 0.18 x 10(-6) M). There were no differences in PGI2 release (or in the EC50s) in response to thapsigargin or AA between aortae from diabetic and control rats. 3. In the urinary bladder, there was a marked increase in PGI2 output in response to ACh and a marked decrease in EC50s for the ACh-PGI2 dose-response curves in diabetic rats (EC50 = 5.8 +/- 0.32 x 10(-7) M) compared to controls (EC50 = 2.2 +/- 0.15 x 10(-6) M). Although there was an increase in PGI2 output in the urinary bladders from diabetic rats in response to A23187, there were no differences in the EC50s (control, 1.8 +/- 0.2 x 10-6 M; diabetic, 1.1 +/- 0.15 X 10-6 M). In the urinary bladders, there were no differences in PGI2 output (or the EC50s) in response to PDBU, thapsigargin or AA between diabetic or control rats.4. These data indicate that: (i) reduced PGI2 synthesis coupled to adrenoceptors and AII receptors in the aortae of diabetic rats may be due to diminished PKC activity and not to changes in receptor density and/or affinity, Ca2+ stores, PLA2, cyclo-oxygenase or PGI2 synthase; (ii) the diametrically opposite effect of DM on ACh-stimulated PGI2 synthesis is not due to an increase in PKC activity, but possibly to an increase in muscarine receptor number and/or affinity; (iii) changes in receptor-linked PGI2 synthesis are not ubiquitous in experimental DM and may be organ-specific.

摘要

采用肾上腺素、血管紧张素II（AII）和乙酰胆碱（ACh），研究了实验性糖尿病（DM；高血糖、非酮症；病程2个月）大鼠的主动脉和膀胱中与受体相关的前列环素（PGI2）合成（通过放射免疫分析法测定6-氧代-PGF1α）。通过用佛波酯二丁酸酯（PDBU；一种蛋白激酶C激活剂[PKC]）、Ca2+离子载体A23187（A23187）和毒胡萝卜素（二者均可升高细胞内Ca2+，激活磷脂酶A2[PLA2]）以及花生四烯酸（AA；PGI2合成的底物）刺激PGI2合成来研究信号转导系统。2. 与对照组相比，糖尿病大鼠对肾上腺素、AII和佛波酯的反应中，主动脉PGI2释放显著减少（均>75%）。糖尿病大鼠主动脉中肾上腺素、AII和PDBU剂量反应曲线的半数有效浓度（EC50）也比对照组显著增加。虽然与对照组相比，糖尿病大鼠主动脉对A23187的反应中PGI2输出减少，但EC50没有差异（平均值±标准误平均值：糖尿病组，2.7±0.2×10-6M；对照组，2±0.18×10-6M）。糖尿病大鼠和对照大鼠主动脉对毒胡萝卜素或AA的反应中，PGI2释放（或EC50）没有差异。3. 在膀胱中，与对照组（EC50 = 2.2±0.15×10-6M）相比，糖尿病大鼠对ACh的反应中PGI2输出显著增加，且ACh-PGI2剂量反应曲线的EC50显著降低（EC50 = 5.8±0.32×10-7M）。虽然糖尿病大鼠膀胱对A23187的反应中PGI2输出增加，但EC50没有差异（对照组，1.8±0.2×10-6M；糖尿病组，1.1±0.15×10-6M）。在膀胱中，糖尿病大鼠和对照大鼠对PDBU、毒胡萝卜素或AA的反应中，PGI2输出（或EC50）没有差异。4. 这些数据表明：（i）糖尿病大鼠主动脉中与肾上腺素能受体和AII受体相关的PGI2合成减少可能是由于PKC活性降低，而非受体密度和/或亲和力、Ca2+储存、PLA2、环氧化酶或PGI synthase的变化；（ii）DM对ACh刺激的PGI2合成的截然相反的作用不是由于PKC活性增加，而是可能由于毒蕈碱受体数量和/或亲和力增加；（iii）实验性DM中与受体相关的PGI2合成变化并非普遍存在，可能具有器官特异性。