Myocyte Nitric Oxide Synthase 2 Contributes to Blunted β-Adrenergic Response in Failing Human Hearts by Decreasing Ca2+ Transients

Mark T. Ziolo, Lars S. Maier, Valentino Piacentino, Julie B C Bossuyt, Steven R. Houser, Donald M Bers

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

Background - Human heart failure (HF) usually exhibits blunted response to β-adrenergic receptor (AR) stimulation. Here, we examined whether expression of nitric oxide synthase-2 (NOS2, or inducible NOS) contributes to this loss of inotropic reserve in human HF. Methods and Results - Failing human hearts were obtained at transplantation. Contraction and [Ca2+] i measurements were performed in isolated cardiac myocytes and trabeculae. In HF myocytes and muscle, isoproterenol (ISO), a β-AR agonist, led to small inotropic and lusitropic responses. Specific inhibition of NOS2 by aminoguanidine (AG) or L-NIL dramatically increased the ISO-induced inotropy and lusitropy, such that the ISO+AG response in HF approached that seen with ISO alone in nonfailing human myocytes or muscles. Ca2+ transient data directly paralleled these results, indicating that altered cellular Ca 2+ handling is responsible. In nonfailing human hearts, NOS2 inhibition had no effects. In addition, NOS2 inhibition also had no effect in 30% of failing hearts, but in these myocytes and muscles, the ISO response alone was similar to that of nonfailing hearts. In line with these functional findings, NOS2 protein expression measured by Western blotting was induced in HF when AG/L-NIL had a functional effect but not when AG/L-NIL had no effect on contractility and Ca2+ transients. Conclusions - NOS2 expression strongly limited ISO-induced increases in contraction, twitch Δ[Ca 2+]i, and lusitropy in trabeculae and isolated myocytes from failing human hearts. Thus, the β-AR hyporesponsiveness in human HF is mediated in large part by NO (or related congeners) produced within cardiac myocytes via NOS2.

Original languageEnglish (US)
Pages (from-to)1886-1891
Number of pages6
JournalCirculation
Volume109
Issue number15
DOIs
StatePublished - Apr 20 2004
Externally publishedYes

Keywords

  • Calcium
  • Heart failure
  • Myocytes
  • Nitric oxide synthase
  • Receptors, adrenergic, beta

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Myocyte Nitric Oxide Synthase 2 Contributes to Blunted β-Adrenergic Response in Failing Human Hearts by Decreasing Ca<sup>2+</sup> Transients'. Together they form a unique fingerprint.

  • Cite this