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NO-cGMP pathway increases the hyperpolarisation-activated current, I(f), and heart rate during adrenergic stimulation

N Herring1, L Rigg, D A Terrar

  • 1University Laboratory of Physiology, University of Oxford, Parks Road, OX1 3PT, Oxford, UK.

Cardiovascular Research
|December 12, 2001
PubMed

Insights

The nitric oxide (NO)-cGMP pathway transiently increases heart rate (HR) via the I(f) current during adrenergic stimulation. This effect is limited by phosphodiesterase 2 (PDE2) activity.

Area of Science:

  • Cardiovascular Physiology
  • Autonomic Nervous System Regulation
  • Cardiac Electrophysiology

Background:

  • The autonomic nervous system modulates heart rate (HR) through complex signaling pathways.
  • The role of the nitric oxide (NO)-cGMP pathway in cardiac pacemaking, particularly its interaction with the L-type calcium current (I(CaL)) and hyperpolarization-activated current (I(f)), remains controversial.
  • Understanding this pathway is crucial for comprehending cardiac autonomic control.

Purpose of the Study:

  • To investigate the hypothesis that the NO-cGMP pathway, following adrenergic stimulation, activates phosphodiesterase 2 (PDE2) to attenuate cAMP-dependent stimulation of I(f) and HR.
  • To elucidate the specific role of the NO-cGMP pathway in the autonomic modulation of sinoatrial node (SAN) function.

Main Methods:

  • Experiments were conducted on guinea pig SAN/atria preparations and isolated SAN cells in the presence of norepinephrine (NE).
  • The effects of the NO donor sodium nitroprusside (SNP) and 8Br-cGMP were assessed.
  • Pharmacological agents including guanylyl cyclase inhibitor (ODQ), I(f) blockers (CsCl, ZD7288), and PDE2 inhibitor (EHNA) were utilized.
  • RT-PCR was employed to confirm the presence of relevant phosphodiesterase (PDE) isoforms.

Main Results:

  • Contrary to the hypothesis, SNP and 8Br-cGMP caused a transient increase in HR.
  • This stimulatory effect on HR was dependent on the I(f) current, as it was abolished by I(f) blockers.
  • SNP also increased I(f) in isolated SAN cells, and inhibition of PDE2 augmented and prolonged the SNP-induced HR increase.
  • RT-PCR confirmed the expression of PDE2 and cGMP-inhibited PDE3 in SAN tissue.

Conclusions:

  • Activation of the NO-cGMP pathway during adrenergic stimulation leads to a transient, I(f)-dependent increase in HR, not a decrease.
  • The magnitude and duration of this stimulatory effect are regulated by PDE2 activity.
  • These findings clarify the role of the NO-cGMP pathway in cardiac pacemaking under adrenergic influence.
Abstract

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