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Nitric oxide can increase heart rate by stimulating the hyperpolarization-activated inward current, I(f)
1University Laboratory of Physiology, Oxford, UK. piotr.musialek@clinical-medicine.ox.ac.uk
Circulation Research
|July 1, 1997
Summary
Nitric oxide (NO) donors like SNP and SIN-1 affect heart rate in a biphasic manner. Low NO concentrations increase heart rate by stimulating the I(f) current via the NO-cGMP pathway.
Area of Science:
- Cardiovascular Physiology
- Pharmacology
- Cellular Electrophysiology
Background:
- Nitric oxide (NO) plays a role in cardiovascular regulation.
- The precise mechanisms by which NO donors influence cardiac pacemaker activity are not fully elucidated.
Purpose of the Study:
- To investigate the chronotropic effects of NO donors, sodium nitroprusside (SNP) and 3-morpholinosydnonimine (SIN-1), on isolated guinea pig sinoatrial node preparations.
- To determine the underlying cellular mechanisms, particularly the involvement of the hyperpolarization-activated inward current (I(f)) and the NO-cGMP pathway.
Main Methods:
- Isolated spontaneously beating sinoatrial node/atrial preparations from guinea pigs were used.
- Concentration-response curves for SNP and SIN-1 were established.
- Effects of guanylyl cyclase inhibitors, superoxide dismutase, 8-bromo-cGMP, nifedipine, and I(f) blockers (Cs+, ZD-7154) were assessed.
- Patch-clamp electrophysiology was performed on rabbit sinoatrial node cells to directly measure I(f).
Main Results:
- NO donors exhibited a concentration-dependent biphasic effect on beating rate: nanomolar to micromolar concentrations increased rate, while millimolar concentrations decreased it.
- The rate increase was potentiated by superoxide dismutase, inhibited by guanylyl cyclase blockers, and mimicked by 8-bromo-cGMP.
- The positive chronotropic effect was independent of L-type calcium channel (IcaL) blockade but was abolished by I(f) current blockade.
- SNP and SIN-1 directly increased I(f) in sinoatrial node cells in a Cs+-sensitive manner.
Conclusions:
- NO donors modulate cardiac pacemaker activity in a concentration-dependent biphasic manner.
- The stimulatory effect on heart rate is mediated by the NO-cGMP pathway leading to the activation of the I(f) current.
- This mechanism may contribute to sinus tachycardia in conditions with increased myocardial NO production.