Nitric oxide and the mediation of the hemodynamic effects of growth hormone in humans.

Two major cardiovascular effects of growth hormone (GH) are peripheral vasodilation and increased myocyte growth. Many of the effects of GH on the vascular system are mediated by insulin-like growth factor (IGF)-I. There is abundant evidence that IGF-I stimulates endothelial nitric oxide (NO) synthesis and thereby induces endothelium-dependent vasodilation in experimental models as well as in humans. NO is synthesized by a family of enzymes named NO synthases (NOS), of which three major isoforms have been isolated, cloned and characterized. In endothelial cells, NOS III is a constitutively expressed isoform of NOS which releases small amounts of NO in a calcium-dependent manner. Endothelium-derived NO is an important vasodilator, inhibitor of platelet adhesion and aggregation, inhibitor of monocyte adhesion and inhibitor of vascular smooth muscle cell growth. These pleiotropic cardiovascular actions of NO have been summarized in the characterization of NO as an endogenous antiatherosclerotic molecule. NO-mediated vasodilation is impaired in patients with acquired GH deficiency. Reduced GH-stimulated NO secretion may have important implications in the pathogenesis of heart failure associated with GH deficiency, as it contributes to peripheral vasoconstriction and, thereby, increases afterload. Baseline NO elaboration in patients with adult-onset GH deficiency is reduced compared with that in healthy controls. In GH-deficient patients, chronic substitution of recombinant human GH (rhGH) results in increased rates of synthesis of NO and decreased peripheral arterial resistance. Recent evidence also suggests that GH secretion is reduced in severe heart failure. In addition, GH resistance has been reported in patients with cardiomyopathy, as suggested by an elevated GH/IGF-I ratio. This may contribute to the progression of cardiac failure via a reduction in NO-mediated vasodilation. Clinical studies suggest that NO-mediated vasodilation is impaired in patients with heart failure. Treatment with rhGH may be beneficial in chronic heart failure via a dual action: improved myocardial performance, and peripheral vasodilation mediated via IGF-I/NO/cyclic guanosine monophosphate. This hypothesis deserves further investigation in clinical trials.