© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
Changes in extracellular pH mediate the chronotropic responses to L-arginine
aDepartment of Cardiovascular Medicine, John Radcliffe Hospital, Oxford OX3 9DU, UK
bUniversity Laboratory of Physiology, Oxford, UK
* Corresponding author. Tel.: +44-1865-220-428 or +44-1865-220132; fax: +44-1865-768-844 piotr.musialek{at}clinical-medicine.ox.ac.uk barbara.casadei{at}cardiov.ox.ac.uk
We have recently shown that exogenous nitric oxide (NO) elicits a positive chronotropic response by stimulating the hyperpolarization activated current, If. Objective: To examine whether L-arginine (L-Arg) can mimic the chronotropic effect of NO by enhancing its endogenous production. Methods: In spontaneously beating guinea pig atria we evaluated the heart rate (HR) response to increasing concentrations of L-Arg (1 µmol/l to 10 mmol/l), and compared it with that for D-Arg or L-lysine (L-Lys) (all in free base (FB) or hydrochloride (HCl) formulation). Results: L-ArgFB >100 µmol/l caused a reversible dose-dependent increase in HR (peak effect +64±7 bpm at 10 mmol/l, P<0.05, n=8). However, a similar HR response occurred with D-ArgFB (n=7) or L-LysFB (n=6). All FB formulations increased the perfusate pH (peak [pH]o=8.61±0.03). Although alkalinization can stimulate NO release from the endothelium, this is unlikely to have contributed to HR changes in our preparation, since neither NG-methyl-L-arginine, (100–500 µmol/l, which per se reduced HR by 8±1%, P<0.05, n=9) nor NO scavenging (fresh 5% red blood cells, n=9) caused a rightward shift of the concentration–response curve to L-ArgFB. Furthermore, as opposed to FB formulations, L-ArgHCl, D-ArgHCl or L-LysHCl >1 mmol/l significantly decreased HR and [pH]o (n=17). The chronotropic effects of L-ArgFB or L-ArgHCl were reproduced by changing [pH]o with NaOH (n=8) or HCl (n=7), whereas the HR increase with L-ArgFB was prevented by clamping [pH]o at 7.42±0.07 (n=10). Conclusions: In vitro, L-Arg can markedly affect HR through a pH-mediated, NO-independent mechanism. Our data show that the opposing changes in [pH]o induced by different formulations of L-Arg can importantly confound the assessment of the biological effects of this amino acid.
KEYWORDS L-Arginine; Nitric oxide; Chronotropic agents; Heart rate
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