Published online before print April 9, 2007, doi: 10.1161/CIRCULATIONAHA.106.643536
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(Circulation. 2007;115:2159-2167.)
© 2007 American Heart Association, Inc.
Molecular Cardiology |
Compartmentalization of Cardiac ß-Adrenergic Inotropy Modulation by Phosphodiesterase Type 5
From the Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Md.
Correspondence to Dr David A. Kass, Ross Research Building 835, Johns Hopkins University Hospital, 720 Rutland Avenue, Baltimore, MD 21205. E-mail dkass{at}jhmi.edu
Received June 2, 2006; accepted February 16, 2007.
Background— Recent cell-based studies have found that cGMP synthesis and hydrolysis by phosphodiesterase (PDE) appear compartmentalized, with nitric oxide synthase–derived and/or PDE type 5 (PDE-5)–hydrolyzable cGMP undetected at the sarcolemmal membrane in contrast to cGMP stimulated by natriuretic peptide. In the present study, we determine the functional significance of such compartments with a comparison of ß-adrenergic modulation by PDE-5 inhibition to that of natriuretic peptide stimulation in both cardiomyocytes and intact hearts. The potential role of differential cGMP and protein kinase G stimulation by these 2 modulators was also studied.
Methods and Results— Intact C57/BL6 mouse hearts were studied with pressure-volume analysis, and adult isolated myocytes were studied with fluorescence microscopy. PDE-5 inhibition with 0.1 to 1 µmol/L sildenafil (SIL) suppressed isoproterenol (ISO)-stimulated contractility, whereas 10 µmol/L atrial natriuretic peptide (ANP) had no effect. ISO suppression by SIL was prevented in cells pretreated with a protein kinase G inhibitor. Surprisingly, myocardial cGMP changed little with SIL+ISO yet rose nearly 5-fold with ANP, whereas protein kinase G activation (vasodilator-stimulated protein phosphorylation; ELISA assay) displayed the opposite: increased with SIL+ISO but unaltered by ANP+ISO. PDE-5 and ANP compartments were functionally separated, as inhibition of nitric oxide synthase by Nw-nitro-L-arginine methyl ester eliminated antiadrenergic effects of SIL, yet this was not restorable by co-stimulation with ANP.
Conclusions— Regulation of cardiac ß-adrenergic response by cGMP is specifically linked to a nitric oxide–synthesis/PDE-5–hydrolyzed pool signaling via protein kinase G. Natriuretic peptide stimulation achieves greater detectable increases in cGMP but not protein kinase G activity and does not modulate ß-adrenergic response. Such disparities likely contribute to differential cardiac regulation by drugs that modulate cGMP synthesis and hydrolysis.
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