Kilter H, Lenz O, La Rosée K, Flesch M, Schwinger R H, Mädge M, Kuhn-Regnier F, Böhm M
Klinik III für Innere Medizin, Universität zu Köln, Germany.
Naunyn Schmiedebergs Arch Pharmacol. 1995 Sep;352(3):308-12. doi: 10.1007/BF00168562.
Nitric oxide (NO) has been reported to mediate several effects in response to muscarinic cholinergic stimulation in cardiovascular tissues. Recently, an attenuation of guinea pig cardiac myocyte contraction by NO has been described. The aim of the present study was to determine whether the indirect negative inotropic effect of M-cholinoceptor stimulation in human myocardium is in part due to an effect of endogenous NO. Therefore, the effect of carbachol was studied under control conditions and during inhibition of NO-synthase by pretreatment with NG-monomethyl-L-arginine (NMMA). Functional experiments were performed in isolated, electrically driven (1 Hz, 37 degrees C) left ventricular papillary muscle strips of human myocardium. Since cytokines have been reported to be increased in the serum of patients with heart failure and could induce NO-synthase activity in failing myocardium, we compared samples from nonfailing and terminally failing (classified as NYHA IV) hearts. The indirect negative inotropic effect of carbachol (10 mumol/l) was studied in the presence of the beta-adrenoceptor agonist isoprenaline (0.03 mumol/l). After stimulation with isoprenaline, carbachol significantly (P < 0.05) reduced force of contraction. This effect was diminished in failing myocardium compared to nonfailing, probably due to the diminished inotropic response most likely due to the lower cAMP levels in response to beta-adrenoceptor stimulation in the former condition. Pretreatment with NMMA (100 mumol/l) altered the antiadrenergic effect of carbachol neither in nonfailing nor in failing preparations. Furthermore, inhibition of guanylyl cyclase, the target enzyme of NO, by preincubation with methylene blue (10 mumol/l) for 30 min had no effect on the carbachol-induced decrease in force of contraction.(ABSTRACT TRUNCATED AT 250 WORDS)
据报道，一氧化氮（NO）在心血管组织中介导对毒蕈碱胆碱能刺激的多种效应。最近，有人描述了NO对豚鼠心肌细胞收缩的减弱作用。本研究的目的是确定M胆碱受体刺激对人心肌的间接负性肌力作用是否部分归因于内源性NO的作用。因此，在对照条件下以及用NG-单甲基-L-精氨酸（NMMA）预处理抑制NO合酶期间，研究了卡巴胆碱的作用。在分离的、电驱动（1Hz，37℃）的人心肌左心室乳头肌条上进行功能实验。由于据报道心力衰竭患者血清中细胞因子会增加，并且可能诱导衰竭心肌中的NO合酶活性，我们比较了非衰竭和终末期衰竭（分类为NYHA IV级）心脏的样本。在存在β肾上腺素能激动剂异丙肾上腺素（0.03μmol/L）的情况下，研究了卡巴胆碱（10μmol/L）的间接负性肌力作用。在用异丙肾上腺素刺激后，卡巴胆碱显著（P<0.05）降低了收缩力。与非衰竭心肌相比，这种作用在衰竭心肌中减弱，可能是由于前者条件下对β肾上腺素能刺激的正性肌力反应减弱，最有可能是由于cAMP水平降低。用NMMA（100μmol/L）预处理在非衰竭和衰竭制剂中均未改变卡巴胆碱的抗肾上腺素能作用。此外，用亚甲蓝（10μmol/L）预孵育30分钟抑制NO的靶酶鸟苷酸环化酶，对卡巴胆碱诱导的收缩力降低没有影响。（摘要截断于250字）
