© 2001 American Heart Association, Inc.
Integrative Physiology |
Upregulation of the Nitric Oxide–cGMP Pathway in Aged Myocardium
Physiological Response to l-Arginine
From the Department of Medicine (S.J.Z., G.G., G.O.R., K.V., K.M.R., J.M.H.), Cardiology Division, Johns Hopkins Medical Institutions, and Gerontology Research Center (E.G.L.), National Institute on Aging, Baltimore, Md.
Correspondence to Joshua M. Hare, MD, Cardiology Division, Johns Hopkins Hospital, 600 N Wolfe St, Carnegie 568, Baltimore, MD 21287-6568. E-mail jhare{at}mail.jhmi.edu
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 (
) 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
(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
(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.
Key Words: aging • cGMP • nitric oxide synthase • diastole • l-arginine
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