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Changes in extracellular pH mediate the chronotropic responses to L-arginine.
UNLABELLED: We have recently shown that exogenous nitric oxide (NO) elicits a positive chronotropic response by stimulating the hyperpolarization activated current, I(f). 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 mumol/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 mumol/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 mumol/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-ArFB 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.
Vagus nerve stimulation decreases left ventricular contractility in vivo in the human and pig heart.
1. Studies of the effect of vagus nerve stimulation on ventricular myocardial function in mammals are limited, particularly in the human. 2. The present study was designed to determine the effect of direct electrical stimulation of the left vagus nerve on left ventricular contractile state in hearts paced at 10 % above the natural rate, in anaesthetised pigs and anaesthetised human subjects undergoing open chest surgery for coronary artery bypass grafting. 3. Contractility of the left ventricle was determined from a series of pressure-volume loops obtained from a combined pressure and conductance (volume) catheter placed in the left ventricle. From the measurements a regression slope of the end-systolic pressure-volume relationship was determined to give end-systolic elastance (Ees), a load-independent measure of contractility. 4. In six anaesthetised open chest pigs, stimulation of the peripheral cut end of the left cervical vagus nerve induced a significant decrease in Ees of 26 +/- 14 %. 5. In nine patients electrical stimulation of the left thoracic vagus nerve close to its cardiac branch resulted in a significant drop in Ees of 38 +/- 16 %. 6. The effects of vagal stimulation were blocked by the muscarinic antagonist glycopyrronium (5 mg kg(-1)). 7. Administration of the beta-adrenoreceptor antagonist esmolol (1 mg kg(-1)) also attenuated the effect of vagal stimulation, indicating a degree of interaction of vagal and sympathetic influences on contractility. 8. These studies show that in the human and pig heart the left vagus nerve can profoundly decrease the inotropic state of the left ventricular myocardium independent of its bradycardic effect.
Non-invasive imaging of cardiac electrophysiology
We present source formulations and computational/validation strategies currently in vogue for non-invasive imaging of cardiac eleetrophysiology.
Nitric oxide inhibits the positive chronotropic and inotropic responses to sympathetic nerve stimulation in the isolated guinea-pig atria.
This study was designed to determine whether nitric oxide (NO) modulates the positive chronotropic and inotropic (in paced atria) responses to cardiac sympathetic nerve stimulation (SNS) in the isolated guinea-pig double atrial/right stellate ganglion preparation. The ganglion was stimulated at 1, 2, 3 and 5 Hz at constant voltage and the changes in heart rate or force of contraction were measured. The selective neuronal NO synthase (nNOS) inhibitors TRIM (1-(2-trifluoromethylphenyl) imidazole; 100 microM) and 7-NiNa (Na+ salt of 7-nitroindazole; 100 microM) significantly enhanced the positive chronotropic and inotropic responses to SNS. Similar results for heart rate were seen with the non-isoform-selective NOS inhibitor N(omega)nitro-L-arginine (L-NA; 100 microM). All effects were reversed with L-arginine (1 mM). The NO donor sodium nitroprusside (SNP; 100 microM) increased baseline heart rate and force of contraction, and attenuated the positive chronotropic and inotropic responses to SNS. SNP also decreased the positive chronotropic response to bath-applied noradrenaline (NA; 1 microM). In contrast, 7-NiNa did not alter the increase in heart rate with bath-applied NA (0.1 or 1 microM). The guanylyl cyclase inhibitor ODQ (10 microM) enhanced (mimicking nNOS inhibition) and the cyclic GMP (guanosine 3':5'-cyclic monophosphate) analogue 8-Br-cGMP (8-bromoguanosine 3':5'-cyclic monophosphate; 1 mM) attenuated (mimicking exogenous NO) the positive inotropic response to SNS. Taken together, these results are consistent with endogenous NO, synthesized from nNOS, inhibiting the positive chronotropic and inotropic responses evoked by cardiac SNS via a cyclic GMP-dependent pathway.
Non-invasive electrical imaging of the heart
The performance of an electrical imaging procedure for the heart ideally needs to be validated against invasive electrical recordings made directly on the heart. We report here on an experimental and modelling program that is working towards obtaining the necessary in-vivo data required for model validation. We also present results illustrating the performance of a recently published activation imaging algorithm using some of the data obtained to date.
Sarcoplasmic calcium release contributes substantially to the positive chronotropic effect of nitric oxide donors
Background: Nitric oxide (NO) exerts a positive chronotropic effect in vitro by stimulating the pacemaker current If without affecting ICaL. If activity is modulated by [Ca2+]i and recent evidence indicates that NO can activate ryanodine receptors in cardiac sarcoplasmic (SR) vesicles. The aim of this study was to test whether exogenous NO stimulates pacemaker activity by promoting SR Ca2+ release. Methods and Results: In isolated guinea-pig atria, we evaluated the chronotropic response to increasing concentrations (from 0.1 μmol/L to 1 mmol/L) of the NO donors SIN-1 (+superoxide dismutase 100 U/mL, n=6) or DEA/NO (n=8), (i) alone, or (ii) after pre-treatment (40min) with 2μmol/L ryanodine (n=7) to block the SR Ca2+ release or 60μmol/L cyclopiazonic acid (2h) to deplete SR Ca2+ stores (n=9). Ryanodine decreased heart rate (HR) from 169±7 to 125±7 bpm (mean± SEM, p<0.05). CPA caused a transient increase in HR (from 163±6 to 196±9 bpm) followed by a reduction to 133±6 bpm (p<0.05). SIN-1 or DEA/NO alone, progressively increased HR with a peak effect of +51±5 bpm and +41±5 bpm at 0.1 mmol/L (p<0.05). In contrast, after pre-treatment with ryanodine or CPA, the peak increase in HR was only +19±4 bpm with SIN-1 and +16±3 bpm with DEA/NO (p<0.05). In addition, we evaluated the intracellular Ca2+ transient (fluorescence with 5 μmol Indo-1 AM) in guinea pig isolated sinoatrial node cells (n=6) before and after application of sodium nitroprusside (SNP, 5 μmol/L). SNP significantly augmented diastolic Ca2+ (+13±9%), peak Ca2+ (+33±21%), and the amplitude of the Ca2+ transient (+102±49%) (Fig), and increased the spontaneous beating rate by 34±12% (p<0.05). Conclusion: Exogenous NO stimulates SR Ca2+ release in sinoatrial node cells. This pathway contributes substantially to the positive chronotropic effect of NO donors. (Graph Presented).
Does L-arginine increase heart rate independent of nitric oxide?
Background: The beneficial effects of L-Arginine (L-Arg) supplementation in patients with hypertension or heart failure have been ascribed to an increase in the synthesis of NO. It is, however, controversial whether NO synthesis can be enhanced by supplying exogenous L-Arg since intracellular concentrations of L-Arg are already very high (∼mM in endothelial cells). We have recently shown that NO donors have a direct chronotropic effect. The aim of this study was to determine whether L-Arg can affect heart rate (HR) through a No-dependent mechanism. Methods and Results: In isolated guinea-pig atria, with a basal (B/L) HR of 176±5 bpm (mean±SEM), we evaluated the chronotropic effect of increasing concentrations (1μM to 10 mM) of L-Arg alone (n=8), L-Arg after pre-treatment (30 min) with the inhibitor of NO synthase L-NMMA (100-500 μM, n=9), or D-Arg (which is not a biological precursor of NO, n=7). L-NMMA decreased B/L HR by 8±1% (p<0.05, ANOVA). Application of L-Arg, L-Arg on top of L-NMMA, or D-Arg caused a progressive, dose-dependent, positive chronotropic response at concentrations ≥ 0.5 mM (see Fig, * p<0.05). The increase in HR was similar in each group (at 10 mM +64±7 bpm with L-Arg, +66±6 bpm with L-Arg on top of L-NMMA, and +68±6 bpm with D-Arg) and could be reversed upon wash-out. In Conclusion:, (i) the 8% decrease in HR in response to L-NMMA is consistent with a small tonic positive chronotropic effect of endogenous NO, (ii) the increase in HR with L-Arg appears to be independent of NO. Our results point out the importance of excluding non-specific effects of L-Arg in studies where this amino acid is used as a substrate for NO synthesis. (Graph Presented).
Nitric oxide can increase heart rate by stimulating the hyperpolarization-activated inward current, if.
Background: Nitric oxide (NO) can modulate myocardial contractility and relaxation but it is not clear whether its effects on heart rate result from a direct action on the activity of the cardiac pacemaker or from a reflex response to the concurrent changes in arterial blood pressure. Methods and Results: In guinea pig isolated spontaneously beating atria we investigated the chronotropic effect of increasing concentrations of two NO donors (NOd): sodium nitroprusside (SNP, n=8) and 3-morpholino-sydnonimine (SIN-1, n=6). We found that exogenous NO modulates the beating rate in a concentration-dependent biphasic fashion, with a gradual increase in beating rate for low concentrations of NOd (nano- to micromolar) and a decrease in beating rate for high concentrations (millimolar). The positive chronotropic effect of 10 μmol/L SNP (n=28) or 50 μmol/L SIN-1 (n=16) was unaffected by ICaL antagonism with nifedipine (0.2 μmol/L) but was abolished after blockade of the hyperpolarization-activated inward current, If, by Cs+ (2 mmol/L) or ZD7288 (1 μmol/L). The involvement of If in the positive chronotropic response of exogenous NO was also tested in rabbit isolated patch-clamped SAN cells (n=17) where 5 μmol/L SNP caused a reversible, Cs+-sensitive, increase in this current (+ 130% at -70 mV and + 250% at -100 mV). Conclusions: Exogenous NO can directly affect pacemaker activity in a concentration-dependent biphasic fashion. The increase in beating rate with low doses of NOd is unaffected by ICaL antagonism but is abolished in the presence of If blockade. Direct recordings of If in SAN cells confirmed that this current is markedly increased by NOd. Our results suggest that stimulation of If by NO might play a part in the sinus tachycardia which accompanies pathological conditions associated with an increase in myocardial production of NO (e.g. heart failure and septic shock).