Systemic NO synthase inhibition blunts the chronotropic, but not the inotropic response to isoprenaline in man.
There is evidence that nitric oxide (NO) is involved in the chronotropic, the inotropic, and the vasodilator response to beta-adrenoceptor agonists. In the present study we hypothesized that inhibition of NO synthase may modulate the systemic vascular and cardiac effects of isoprenaline, a beta-adrenoceptor agonist, in healthy subjects. Subjects received stepwise increasing doses of isoprenaline (0.1-0.8 microg/min) in the absence or presence of systemic NO-synthase inhibition using two intravenous doses of N-monomethyl-L-arginine (L-NMMA; dosage 1, 3.0 mg/kg over 5 min, followed by 30 microg/kg/min over 75 min; dosage 2, 6.0 mg/kg over 5 min, followed by 60 microg/kg/min over 75 min) or peripheral vasoconstriction using exogenous endothelin-1 (ET-1; 5.0 ng/kg/min for 80 min). The chronotropic (RR interval) and the inotropic (QS2c) responses were assessed by noninvasive measurement of systolic time intervals. L-NMMA alone did not influence QS2c, but did increase the RR interval (P < 0.001) and the mean arterial blood pressure (P = 0.003). L-NMMA did not attenuate the blood pressure and the QS2c responses to isoprenaline, but significantly and dose-dependently blunted the heart rate response to beta-adrenoceptor stimulation (P = 0.029). ET-1 decreased the RR interval (P < 0.001) and increased the mean arterial blood pressure (P = 0.028). Our results indicate that beta-adrenoceptor mediated effects on the heart rate are much more susceptible to NOS inhibition than inotropic responses. This indicates that NO has an important role in heart rate control during beta-adrenoceptor stimulation.
Schmetterer
L
L
Department of Clinical Pharmacology, Vienna University, Austria. Leopold.Schmetterer@univie.ac.at
Dallinger
S
S
Polak
K
K
Eichler
H G
HG
Wolzt
M
M
D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D001944:Breath Tests; D018592:Cross-Over Studies; D003971:Diastole / Q000187:drug effects; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009569:Nitric Oxide / Q000032:analysis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D010919:Placebos; D011674:Pulse; D012016:Reference Values; D013599:Systole / Q000187:drug effects; D019323:omega-N-Methylarginine / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D010919:Placebos; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D007545:Isoproterenol