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Cardiovascular Research 2001 52(3):446-453; doi:10.1016/S0008-6363(01)00425-4
© 2001 by European Society of Cardiology
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Copyright © 2001, European Society of Cardiology

NO-cGMP pathway increases the hyperpolarisation-activated current, If, and heart rate during adrenergic stimulation

Neil Herringa,1, Lauren Riggb, Derek A Terrarb and David J Patersona,*

aUniversity Laboratory of Physiology, University of Oxford, Parks Road, Oxford OX1 3PT, UK
bDepartment of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK

* Corresponding author. Tel.: +44-1865-272-518; fax: +44-1865-282-170 david.paterson{at}physiol.ox.ac.uk

Objectives: The role of the nitric oxide (NO)-cGMP pathway in the autonomic modulation of cardiac pacemaking is controversial and may involve an interplay between the L-type calcium current, ICaL, and the hyperpolarisation activated current, If. We tested the hypothesis that following adrenergic stimulation, the NO-cGMP pathway stimulates phosphodiesterase 2 (PDE2) to reduce cAMP dependent stimulation of If and heart rate (HR). Methods: In the presence of norepinephrine (NE, 1 µM), the effects of the NO donor sodium nitroprusside (SNP) were evaluated in sinoatrial node (SAN)/atria preparations and isolated SAN cells from adult guinea pigs. Results: Contrary to our hypothesis, SNP (10 and 100 µM, n=5) or the membrane permeable cGMP analogue, 8Br-cGMP (0.5 mM, n=6) transiently increased HR by 5±1, 12±1 and 12±2 beats/min, respectively. The guanylyl cyclase inhibitor 1H-(1,2,4)-oxadiazolo-(4,3-a)-quinoxalin-1-one (ODQ, 10 µM, n=5) abolished the increase in HR to SNP (100 µM) as did the If blockers caesium chloride (2 mM, n=7) and 4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino)-pyrimidinium chloride (ZD7288, 1 µM, n=7). Addition of SNP (10 µM) also transiently increased If in SAN cells (n=5). After inhibition of PDE2 with erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA, 10 µM, n=5), the increase in HR to SNP in the presence of NE was significantly augmented and maintained. RT-PCR analysis confirmed the presence of PDE2 in addition to cGMP inhibited PDE3 mRNA in central SAN tissue. Conclusions: These results suggest that during adrenergic stimulation, activation of the NO-cGMP pathway does not decrease HR, but has a transient stimulatory effect that is If dependent, and is limited in magnitude and duration by stimulation of PDE2.

KEYWORDS Sinus node; Heart rate (variability); Chronotropic agents; Adrenergic(ant) agonists; Nitric oxide

1 All authors are affiliated to the University of Oxford, UK.


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