Upregulation of the nitric oxide-cGMP pathway in aged myocardium: Physiological response to L-arginine

Susan J. Zieman, Gary Gerstenblith, Edward G. Lakatta, Gisele O. Rosas, Koenraad Vandegaer, Kelly M. Ricker, Joshua M. Hare

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Cardiovascular aging is associated with decreased endothelial vasoreactivity and prolonged diastolic relaxation. As diminished NO signaling contributes to age-associated endothelial dysfunction, we tested the hypothesis that impaired NO signaling or bioactivity also contributes to slowed ventricular relaxation with age. Accordingly, we measured myocardial NO synthase (NOS) enzyme activity, protein abundance, and cGMP production in old (22 to 25 months) and young adult (4 to 7 months) male Wistar rats. Both NOS3 protein abundance and calcium-dependent NOS activity were elevated in old compared with young adult hearts (7.2 ±1.1 versus 4.2 ±0.6 pmol/mg protein, respectively, P=0.03). However, NOS activity and protein abundance were similar in isolated myocytes, indicating that endothelial NOS likely explains the age difference. Cardiac effluent cGMP (enzyme immunoassay) was 4.8-fold higher (1794±373 fmol/min per mg heart tissue) in older versus younger hearts (P=0.003). To assess NO pathway responsiveness, we administered the NOS substrate L-arginine (100 μm) to isolated perfused rat hearts. Baseline isovolumic relaxation (τ) was prolonged in old (42.9±2.5 ms, n= 16) versus young hearts (36.0± 1.9 ms, n= 11, P=0.03). L-Arginine decreased τ (P<0.001) and left ventricular end-diastolic pressure in both old and young hearts. Supporting an NO/cGMP-mediating mechanism, the NO donor sodium nitroprusside reduced τ (maximal effect, -14±2%, n=5, P<0.001), and this lusitropic effect was attenuated by the soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo-[4,3,-a]quinoxalin-1-one (n=7, P<0.001). Thus, the NO-cGMP pathway is upregulated in the endothelial cells of aged hearts. L-Arginine, the NOS precursor, enhances ventricular relaxation in old and young hearts, indicating that the NOS pathway may be exploited to modulate diastolic function in aged myocardium.

Original languageEnglish (US)
Pages (from-to)97-102
Number of pages6
JournalCirculation research
Volume88
Issue number1
DOIs
StatePublished - Jan 19 2001

Keywords

  • Aging
  • CGMP
  • Diastole
  • L-arginine
  • Nitric oxide synthase

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Zieman, S. J., Gerstenblith, G., Lakatta, E. G., Rosas, G. O., Vandegaer, K., Ricker, K. M., & Hare, J. M. (2001). Upregulation of the nitric oxide-cGMP pathway in aged myocardium: Physiological response to L-arginine. Circulation research, 88(1), 97-102. https://doi.org/10.1161/01.RES.88.1.97