© 1997 American Heart Association, Inc.
Articles |
Nitric Oxide Can Increase Heart Rate by Stimulating the Hyperpolarization-Activated Inward Current, If
From the University Laboratory of Physiology (P.M., M.L., H.F.B., D.J.P.), Oxford, UK, and the Department of Cardiovascular Medicine (P.M., B.C.), John Radcliffe Hospital, Oxford, UK.
Correspondence to Piotr Musialek, MD, Department of Cardiovascular Medicine, John Radcliffe Hospital, Oxford OX3 9DU, UK. E-mail piotr.musialek{at}clinical-medicine.ox.ac.uk
Abstract We investigated the chronotropic effect of increasing concentrations of sodium nitroprusside (SNP, n=8) or 3-morpholinosydnonimine (SIN-1, n=6) in isolated guinea pig spontaneously beating sinoatrial node/atrial preparations. Low concentrations of NO donors (nanomolar to micromolar) gradually increased the beating rate, whereas high (millimolar) concentrations decreased it. The increase in rate was (1) enhanced by superoxide dismutase (50 to 100 U/mL, n=6), (2) prevented by the guanylyl cyclase inhibitors 6-anilino-5,8-quinolinedione (5 µmol/L, n=6) or 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (10 µmol/L, n=6), and (3) mimicked by 8-bromo-cGMP (n=6) with no additional positive chronotropic effect of SIN-1 (n=5). The response to 10 µmol/L SNP (n=28) or 50 µmol/L SIN-1 (n=16) was unaffected by ICa-L 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 4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino)pyrimidinium chloride (1 µmol/L). The effect on If was further evaluated in rabbit isolated patch-clamped sinoatrial node cells (n=21), where we found that 5 µmol/L SNP or SIN-1 caused a reversible Cs+-sensitive increase in this current (+130% at -70 mV and +250% at -100 mV). In conclusion, NO donors can affect pacemaker activity in a concentration-dependent biphasic fashion. Our results indicate that the increase in beating rate is due to stimulation of If via the NO-cGMP pathway. This may contribute to the sinus tachycardia in pathological conditions associated with an increase in myocardial production of NO.
Key Words: nitric oxide • nitrovasodilator • heart rate • hyperpolarization-activated inward current • sinoatrial node
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