© 2001 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
NO-cGMP pathway increases the hyperpolarisation-activated current, If, and heart rate during adrenergic stimulation
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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