Abboud K, Bassila J-C, Ghali-Ghoul R, Sabra R
Department of Pharmacology and Therapeutics, American University of Beirut Faculty of Medicine, Beirut, Lebanon.
Am J Physiol Heart Circ Physiol. 2009 Aug;297(2):H836-45. doi: 10.1152/ajpheart.00102.2009. Epub 2009 Jun 19.
The aims of this study were to study the influence of the duration of diabetes, the role of endothelial-derived vasodilators, and the role of phosphodiesterase (PDE) isoform activity in the early changes in vascular reactivity of aortic rings from diabetic rats. Diabetes mellitus was induced in female rats by intravenous streptozotocin (85 mg/kg). Two or 4 wk later, thoracic aortic rings from control and diabetic rats were isolated, and vascular responses to acetylcholine (ACh), S-nitroso-N-acetylpenicillamine (SNAP) [nitric oxide (NO) donor], DMPPO (PDE5 inhibitor), and phenylephrine (PE) were obtained in the presence and absence of endothelium or other drugs. PDE isoform activity was also measured. At 2 wk, responses to ACh and DMPPO were enhanced, whereas those to PE were attenuated in diabetic rats relative to controls. Indomethacin and SQ-29548 (a thromboxane A(2) receptor antagonist), but not N(G)-nitro-L-arginine methyl ester, corrected these differences. The responses to SNAP, and cAMP and cGMP hydrolytic activities, were similar in the two groups. In contrast, at 4 wk, ACh, DMPPO, and PE produced similar responses in the two groups: N(G)-nitro-L-arginine methyl ester rendered the response to PE lower in the diabetic group, and this was corrected by indomethacin, but not SQ-29548, treatment. The response to SNAP was greater in the diabetic group, and this was corrected by DMPPO. Activity of all PDEs was decreased at 4 wk. We conclude that, at 2 wk, there is modulation of thromboxane A(2) production, but no change in the NO system or PDE isoform activities. At 4 wk, a reduction in NO activity is superimposed; at this stage, PDE activity is reduced, together with increased production of vasodilating prostaglandins, possibly as a compensatory mechanism to maintain normal vascular reactivity.
本研究的目的是探讨糖尿病病程的影响、内皮源性血管舒张剂的作用以及磷酸二酯酶(PDE)同工酶活性在糖尿病大鼠主动脉环血管反应性早期变化中的作用。通过静脉注射链脲佐菌素(85mg/kg)诱导雌性大鼠患糖尿病。两周或四周后,分离对照大鼠和糖尿病大鼠的胸主动脉环,在有或无内皮或其他药物存在的情况下,检测血管对乙酰胆碱(ACh)、S-亚硝基-N-乙酰青霉胺(SNAP)[一氧化氮(NO)供体]、DMPPO(PDE5抑制剂)和去氧肾上腺素(PE)的反应。同时也测定了PDE同工酶活性。在两周时,与对照组相比,糖尿病大鼠对ACh和DMPPO的反应增强,而对PE的反应减弱。吲哚美辛和SQ-29548(血栓素A2受体拮抗剂)可纠正这些差异,但N(G)-硝基-L-精氨酸甲酯不能。两组对SNAP的反应以及cAMP和cGMP水解活性相似。相比之下,在四周时,两组对ACh、DMPPO和PE的反应相似:N(G)-硝基-L-精氨酸甲酯使糖尿病组对PE的反应降低,吲哚美辛治疗可纠正这一现象,但SQ-29548治疗无效。糖尿病组对SNAP的反应更大,DMPPO可纠正这一现象。四周时所有PDE的活性均降低。我们得出结论,在两周时,血栓素A2的产生受到调节,但NO系统或PDE同工酶活性没有变化。在四周时,NO活性降低;此时,PDE活性降低,同时血管舒张前列腺素的产生增加,这可能是维持正常血管反应性的一种代偿机制。