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Cardiovascular Research 2004 63(3):528-536; doi:10.1016/j.cardiores.2004.03.004
© 2004 by European Society of Cardiology
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Copyright © 2004, European Society of Cardiology

Atrial natriuretic peptide modulates the hyperpolarization-activated current (If) in human atrial myocytes

Giuseppe Lonardoa, Elisabetta Cerbaia, Simona Casinia, Gabriele Giuntib, Massimo Bonacchib, Francesco Battagliab, Brenno Fioranib, Pier Luigi Stefanob, Guido Sanib and Alessandro Mugelli*,a

a Department of Preclinical and Clinical Pharmacology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy
bDepartment of Cardiosurgery, Azienda Ospedaliera Careggi, Viale Morgagni 85, 50134 Florence, Italy

* Corresponding author. Tel.: +39-55-427-1264; fax: +39-55-427-1285. Email address: alessandro.mugelli{at}unifi.it

Objectives: The relationship between atrial stretching and changes in cell excitability is well documented. Once stretched, human atrial myocytes (HuAM) release atrial natriuretic peptide (hANP). Receptors for hANP (NPR) are coupled to a guanylyl cyclase (GC) activity, and are present on HuAM, but the electrophysiological effects of hANP are largely unknown. We investigated the effect of hANP on If, the hyperpolarization-activated current present in HuAM, and the underlying intracellular pathway. Methods: HuAM were isolated from atrial appendages and utilized for patch-clamp recording. Results: hANP caused a significant and concentration dependent shift of the midpoint activation potential ({Delta}Vh) toward less negative potentials of 6.9±1.0 mV at 0.1 nM; 13.0±2.6 mV at 1 nM and 15.3±2.2 mV at 10 nM (p<0.001 for all); a parallel increase of If rate of activation occurred. The effect of hANP was completely blocked by isatin, a potent antagonist of NPR (p<0.01 vs. hANP). In the presence of the inhibitors of guanylyl cyclase (ODQ and LY83583), hANP caused a significantly smaller {Delta}Vh (p<0.01 vs. hANP for both). 8Br-cGMP mimicked the effect of hANP, both in the presence and absence of KT5823, a selective inhibitor of Protein kinase G. Pretreatment with pertussis toxin (PTX) did not change the effect of hANP, thus excluding a major role for the coupling of NPR with the Gi-Proteins system. Pretreating cells with cyclopentyladenosine (CPA), an A1-adenosine receptor agonist, completely blocked hANP effect. Adding hANP to maximal serotonin concentration produced an additive response. Conclusions: Our data demonstrate for the first time that ANP is able to increase If, likely through a modulation of intracellular cGMP and cAMP levels. This effect could have implications in the relationship between stretch and arrhythmogenesis in the human atrium.

KEYWORDS Atrial natriuretic peptide; Human atrial myocytes; Hyperpolarization-activated current; Patch-clamp; Signal transduction

Time for primary review 21 days


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