Merkel L A, Rivera L M, Perrone M H, Lappe R W
Rhône-Poulenc Rorer Central Research, King of Prussia, PA 19406.
Eur J Pharmacol. 1992 May 27;216(1):29-35. doi: 10.1016/0014-2999(92)90205-i.
We have examined the interaction of zaprinast, a selective inhibitor of cGMP phosphodiesterase, with guanylate cyclase activators on vascular smooth muscle relaxation in vitro and in vivo. Isolated porcine coronary arterial rings precontracted with prostaglandin F2 alpha (PGF2 alpha) were relaxed dose dependently by the guanylate cyclase activators nitroglycerin and nitroprusside, the cGMP phosphodiesterase inhibitor zaprinast and the endothelium-dependent agent bradykinin. A 1 h pretreatment with 0.5 mM nitroglycerin shifted the dose-response curve to nitroglycerin to the right by a factor of 90, reflecting the development of tolerance. The dose-response curve to sodium nitroprusside was also affected, albeit to a much lesser degree (9-fold increase in IC50). Both zaprinast and bradykinin remained unaffected by nitroglycerin pretreatment. A 30 min pretreatment of rings with zaprinast (1 microM) had no effect on nitroglycerin- or nitroprusside-induced relaxation in control rings, but enhanced vasorelaxation to both nitrovasodilators 7- and 2-fold, respectively, in tolerant rings. Similarly, a 30 min pretreatment of rings with 0.1 microM nitroprusside enhanced zaprinast-induced vasorelaxation 4- and 8-fold, respectively, in control and tolerant rings. Similar observations were made in vivo in anesthetized spontaneously hypertensive rats where zaprinast (0.1-3.0 mg/kg i.v.), caused dose-dependent reductions in mean arterial pressure. This effect was enhanced when rats had been pretreated with nitroprusside (1 micrograms/kg per min). In comparison, in zaprinast-pretreated rats the magnitude of depressor responses to nitroprusside (0.5-5.0 micrograms/kg) was not altered, but the duration of hypotensive response to the highest dose of nitroprusside was enhanced by zaprinast. These data demonstrate an enhanced vasodilatory response of nitrocompounds in combination with peak I-selective phosphodiesterase inhibitors.
我们研究了cGMP磷酸二酯酶的选择性抑制剂扎普司特与鸟苷酸环化酶激活剂在体外和体内对血管平滑肌舒张的相互作用。用前列腺素F2α（PGF2α）预收缩的离体猪冠状动脉环，可被鸟苷酸环化酶激活剂硝酸甘油和硝普钠、cGMP磷酸二酯酶抑制剂扎普司特以及内皮依赖性药物缓激肽剂量依赖性地舒张。用0.5 mM硝酸甘油预处理1小时，使硝酸甘油的剂量-反应曲线右移90倍，反映出耐受性的产生。硝普钠的剂量-反应曲线也受到影响，尽管程度小得多（IC50增加9倍）。扎普司特和缓激肽均不受硝酸甘油预处理的影响。用扎普司特（1 microM）预处理环30分钟，对对照环中硝酸甘油或硝普钠诱导的舒张无影响，但在耐受性环中，分别使两种硝基血管扩张剂的血管舒张增强7倍和2倍。同样，用0.1 microM硝普钠预处理环30分钟，在对照环和耐受性环中分别使扎普司特诱导的血管舒张增强4倍和8倍。在麻醉的自发性高血压大鼠体内也有类似的观察结果，扎普司特（0.1 - 3.0 mg/kg静脉注射）可使平均动脉压呈剂量依赖性降低。当大鼠用硝普钠（1微克/千克每分钟）预处理后，这种作用增强。相比之下，在扎普司特预处理的大鼠中，对硝普钠（0.5 - 5.0微克/千克）的降压反应幅度未改变，但扎普司特可增强对最高剂量硝普钠的降压反应持续时间。这些数据表明，硝基化合物与I型选择性磷酸二酯酶抑制剂联合使用时，血管舒张反应增强。
