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

Cardiovascular aging is associated with decreased endothelial vasoreactivit y and prolonged diastolic relaxation. As diminished NO signaling contribute s 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 m onths) 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, respec tively, P=0.03), However, NOS activity and protein abundance were similar i n isolated myocytes, indicating that endothelial NOS likely explains the ag e difference. Cardiac effluent cGMP (enzyme immunoassay) was 4.8-fold highe r (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 sub strate L-arginine (100 mum) to isolated perfused rat hearts. Baseline isovo lumic relaxation (7) was prolonged in old (42.9+/-2.5 ms, n=16) versus youn g hearts (36.0+/-1.9 ms, n=11, P=0.03). L-Arginine decreased tau (P<0.001) and left ventricular end-diastolic pressure in both old and young hearts. S upporting an NO/cGMP-mediating mechanism, the NO donor sodium nitroprusside reduced <tau> (maximal effect, -14+/-2%, n=5, P<0.001), and this lusitropi c 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 pa thway is upregulated in the endothelial cells of aged hearts. L-Arginine, t he NOS precursor, enhances ventricular relaxation in old and young hearts, indicating that the NOS pathway may be exploited to modulate diastolic func tion in aged myocardium.