Evidence against a role of nitric oxide in the indirect negative inotropic-effect of M-cholinoceptor stimulation in human ventricular myocardium.
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)
Kilter
H
H
Klinik III für Innere Medizin, Universität zu Köln, Germany.
Lenz
O
O
La Rosée
K
K
Flesch
M
M
Schwinger
R H
RH
Mädge
M
M
Kuhn-Regnier
F
F
Böhm
M
M
D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects*; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D010210:Papillary Muscles / Q000187:drug effects; D011950:Receptors, Cholinergic / Q000502:physiology*; D019323:omega-N-Methylarginine
D011950:Receptors, Cholinergic; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D002217:Carbachol; D001120:Arginine; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP; D007545:Isoproterenol