Chronotropic effects of nitric oxide in the denervated human heart

Abstract

Nitric oxide synthase is expressed in the sino-atrial node and animal data suggests a direct role for nitric oxide on pacemaker activity. Study of this mechanism in intact humans is complicated by both reflex and direct effects of nitric oxide on cardiac autonomic control. Thus, we have studied the direct effects of nitric oxide on heart rate in human cardiac transplant recipients who possess a denervated donor heart. In nine patients, the chronotropic effects of systemic injection of the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) (3 mg kg(-1)) or increasing bolus doses of the nitric oxide donor, sodium nitroprusside (SNP), were studied. Injection of L-NMMA increased mean arterial pressure by 17 +/- 2 mmHg (mean +/- S.E.M.; P < 0.001) and also had a significant negative chronotropic effect, lengthening the R-R interval by 54 +/- 8 ms (P < 0.001). This bradycardia was not reflex in origin since injection of the non-NO-dependent vasoconstrictor, phenylephrine (100 microg) achieved a similar rise in mean arterial pressure (18 +/- 3 mmHg; P < 0.001) but failed to change R-R interval duration (Delta R-R = -3 +/- 4 ms). Furthermore, no change in levels of circulating adrenaline was observed with L-NMMA. Conversely, injection of sodium nitroprusside resulted in a positive chronotropic effect with a dose-dependent shortening of R-R interval duration, peak Delta R-R = -25 +/- 8 ms with 130 microg (P < 0.01). These findings indicate that nitric oxide exerts a tonic, direct, positive chronotropic influence on the denervated human heart. This is consistent with the results of animal experiments showing that nitric oxide exerts a facilitatory influence on pacemaking currents in the sino-atrial node.

Figure 1. Original recording of R-R interval duration and continuous arterial pressure for a 60-year-old denervated female transplant recipient during administration of SNP

A 100 μg bolus injection of SNP was completed at the point marked by the arrow.

Figure 2. Change in R-R interval duration with increasing doses of SNP bolus

Vehicle (5 % dextrose) injection (n = 9) is shown as 0 μg SNP. SNP injection was tolerated at the 50 μg dose for n = 9, at 70 μg n = 8, at 100 μg n = 8 and at 130 μg n = 6. †P = 0.07, **P < 0.01 vs. vehicle.

Figure 3. Change from baseline in mean arterial pressure with bolus injection of l-NMMA, phenylephrine (Phe) or saline

n = 9 for all doses. *** P < 0.001vs. change with saline.

Figure 4. Change from baseline in R-R interval duration with bolus injection of l-NMMA, phenylephrine 100 μg (Phe) or saline

n = 9 for all drugs. *** P < 0.001vs. saline, †††P < 0.001 vs. phenylephrine.

Figure 5. Representative haemodynamic response for an individual patient (50-year-old male, 6 months from transplant) to a bolus of l-NMMA (black line) given at time zero, in comparison to a continuous infusion of phenylephrine (grey line)

Continuous data are presented as a 30 beat moving average. A, the infusion rate of phenylephrine was titrated to match, over a period of 10 min, the rise from baseline in continuously recorded mean arterial pressure following l-NMMA. B, the resulting rise in R-R interval duration with l-NMMA was not reproduced with the control vasoconstrictor, phenylephrine.