Remodeling of the cardiac pacemaker L-type calcium current and its β-adrenergic responsiveness in hypertension after neuronal NO synthase gene transfer

Daniel A. Heaton, Ming Lei, Dan Li, Simon Golding, Tom A. Dawson, Ravi M. Mohan, David J. Paterson

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Hypertension is associated with abnormal neurohumoral activation. We tested the hypothesis that β-adrenergic hyperresponsiveness in the sinoatrial node (SAN) of the spontaneously hypertensive rat occurs at the level of the L-type calcium current because of altered cyclic nucleotide-dependent signaling. Furthermore, we hypothesized that NO, a modulator of cGMP and cAMP, would normalize the β-adrenergic phenotype in the hypertensive rat. Chronotropic responsiveness to norepinephrine (NE), together with production of cAMP and cGMP, was assessed in isolated atrial preparations from age-matched hypertensive and normotensive rats. Right atrial/SAN pacemaking tissue was injected with adenovirus encoding enhanced green fluorescent protein (control vector) or neuronal NO synthase (nNOS). In addition, L-type calcium current was measured in cells isolated from the SAN of transfected animals. Basal levels of cGMP were lower in hypertensive rat atria. These atria were hyperresponsive to NE at all of the concentrations tested, with elevated production of cAMP. This was accompanied by increased basal and norepinephrine-stimulated L-type calcium current. Using enhanced green fluorescent protein, we observed transgene expression within both tissue sections and isolated pacemaking cells. Adenoviral nNOS increased right atrial nNOS protein expression and cGMP content. NE-stimulated cAMP concentration and L-type calcium current were also attenuated by adenoviral nNOS, along with the chronotropic responsiveness to NE in hypertensive rat atria. Decreased calcium current after cardiac nNOS gene transfer contributes to the normalization of β-adrenergic hyperresponsiveness in the SAN from hypertensive rats by modulating cyclic nucleotide signaling. © 2006 American Heart Association, Inc.
    Original languageEnglish
    Pages (from-to)443-452
    Number of pages9
    JournalHypertension
    Volume48
    Issue number3
    DOIs
    Publication statusPublished - Sept 2006

    Keywords

    • Nitric oxide synthase
    • Norepinephrine
    • Sinoatrial node

    Fingerprint

    Dive into the research topics of 'Remodeling of the cardiac pacemaker L-type calcium current and its β-adrenergic responsiveness in hypertension after neuronal NO synthase gene transfer'. Together they form a unique fingerprint.

    Cite this