Klein Thomas, Eltze Manfrid, Grebe Thomas, Hatzelmann Armin, Kömhoff Martin
Department of Biochemistry, ALTANA Pharma AG, D-78467 Konstanz, Germany.
Cardiovasc Res. 2007 Jul 15;75(2):390-7. doi: 10.1016/j.cardiores.2007.02.026. Epub 2007 Feb 28.
Celecoxib carries a smaller cardiovascular risk for myocardial infarction and hypertension than other cyclooxygenase-2 (COX-2)-selective non-steroidal anti-inflammatory drugs NSAIDs ("coxibs") and may ameliorate endothelial dysfunction. We aimed to determine which mechanism possibly accounts for the beneficial effect by investigating its vascular action in different in vitro preparations in comparison with other coxibs and reference phosphodiesterase-5 (PDE5) inhibitors.
To uncover potential effects on coronary flow, the effects of celecoxib in comparison with other NSAIDs and the PDE5 inhibitors, sildenafil and zaprinast, were investigated in guinea-pig Langendorff heart. This was supported by studies for vasorelaxation, interaction with the NO/cGMP pathway, and measurement of cyclic nucleotide amounts released from rat aortic rings, and inhibition of human PDE5 as well as PDE4 activity.
Bolus injections of sildenafil, celecoxib, and zaprinast (at 100 nmol) into the Langendorff heart increased coronary flow by approximately 100, 65, and 25%, respectively, while rofecoxib, lumiracoxib, parecoxib, and diclofenac, except valdecoxib (>100 nmol), failed to increase coronary flow up to 300 nmol. In rat aorta, sildenafil, celecoxib and zaprinast caused endothelium-dependent relaxation with -log[EC(50)]M values of 8.90, 6.66 and 5.56, respectively; their rank order of potency corresponds to their coronary dilatory effect. Celecoxib-induced relaxation of aorta was attenuated by the nitric oxide (NO) synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 10(-4) M) and by the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one (ODQ, 10(-5) M). In aortic rings, celecoxib (3x10(-5) M) caused a fivefold increase in the cGMP level and potentiated that induced by sodium nitroprusside (5x10(-7) M). Celecoxib and valdecoxib inhibited human PDE5A1 with an IC(50) of 1.6x10(-5) and 1x10(-4) M, respectively, whereas other coxibs were without inhibitory effect.
Celecoxib caused coronary vasodilatation in guinea-pig hearts and relaxation of rat aorta and had a potentiating effect on the NO/cGMP signaling pathway in rat aorta through specific blockade of PDE5. These unexpected findings clearly support the notion that celecoxib possesses an as yet undisclosed molecule-specific property that possibly compensates a decrease of prostacyclin-dependent cAMP generation by concomitantly increasing cGMP levels resulting from inhibition of PDE5.
与其他环氧化酶-2（COX-2）选择性非甾体抗炎药（NSAIDs，即“昔布类药物”）相比，塞来昔布导致心肌梗死和高血压的心血管风险较小，并且可能改善内皮功能障碍。我们旨在通过研究其在不同体外制剂中的血管作用，并与其他昔布类药物和参考磷酸二酯酶-5（PDE5）抑制剂进行比较，来确定可能导致这种有益作用的机制。
为了揭示对冠状动脉血流的潜在影响，在豚鼠Langendorff心脏中研究了塞来昔布与其他NSAIDs以及PDE5抑制剂西地那非和扎普司特的作用。对血管舒张、与一氧化氮/环磷酸鸟苷（NO/cGMP）途径的相互作用、从大鼠主动脉环释放的环核苷酸量的测量、对人PDE5以及PDE4活性的抑制等研究也支持了上述结果。
向Langendorff心脏一次性注射西地那非、塞来昔布和扎普司特（100 nmol）分别使冠状动脉血流增加约100%、65%和25%，而罗非昔布、卢米昔布、帕罗昔布和双氯芬酸（除伐地昔布>100 nmol外）在高达300 nmol时未能增加冠状动脉血流。在大鼠主动脉中，西地那非、塞来昔布和扎普司特引起内皮依赖性舒张，其-log[EC(5０)]M值分别为8.9０, 6.66和5.5６；它们的效价顺序与其冠状动脉扩张作用相对应。塞来昔布诱导的主动脉舒张被一氧化氮（NO）合酶抑制剂N(G)-硝基-L-精氨酸甲酯（L-NAME，10(-4) M）和鸟苷酸环化酶抑制剂1H-[1,2,4]恶二唑并[4,3-α]喹喔啉-1-酮（ODQ，10(-5) M）减弱。在主动脉环中，塞来昔布（3×10(-5) M）使cGMP水平增加了五倍，并增强了硝普钠（5×10(-7) M）诱导的cGMP水平升高。塞来昔布和伐地昔布抑制人PDE5A1的IC(5０)分别为1.6×10(-5)和1×10(-4) M，而其他昔布类药物则无抑制作用。
塞来昔布可使豚鼠心脏冠状动脉血管舒张，使大鼠主动脉松弛，并通过特异性阻断PDE5对大鼠主动脉中的NO/cGMP信号通路产生增强作用。这些意外发现明确支持了以下观点，即塞来昔布具有一种尚未被揭示的分子特异性特性，该特性可能通过抑制PDE5导致cGMP水平升高，从而补偿前列环素依赖性cAMP生成的减少。
Zotero 插件