Clinical Relevance of the Nitric Oxide/Cyclic GMP Pathway

Alteration of nitric oxide (NO) production and/or nitric oxide bioavailability have been shown to occur in the setting of diverse disorders as hypertension, hypercholesterolemia, aging, cigarette smoking, diabetes, erectile dysfunction, and heart failure.

Given the clinical relevance of deficiencies in nitric oxide production in several disorders, important amount of research has been devoted in order to counteract these abnormalities.

L-Arginine

L-Arginine (substrate for nitric oxide synthesis) has often been tested in experimental animals and in humans with good results in hypercholesterolemia, hypertension and diabetes. Even oral feeding of L-arginine, which only doubles plasma levels, appears to have beneficial effects.

Although in general positive, the reason for the effectiveness of the administration of this aminoacid is not completely understood. In all these clinical disorders the main alteration is supposed to occur at the endothelial level. Endothelial cells recover the interior of blood vessels and regulate nutrient exchange between plasma and tissues. In these cells, when studied in vitro, nitric oxide production is not altered by increasing L-arginine concentration. L-Arginine concentration inside the cell seems to be high enough to allow maximal activity of nitric oxide synthase (NOS) and, in addition, these cells are able to resynthesize this aminoacid from L-citrulline (co-product in the synthesis of nitric oxide).

Suggested mechanisms for this apparent paradox have been for example that an excess of L-arginine may allow nitric oxide synthesis not mediated by enzyme activity, that can occur at high concentrations of this aminoacid, or may compensate for the inhibitory effect of the endogenous inhibitor of nitric oxide synthase, asymmetric dimethyl arginine (ADMA).

Natriuretic peptides

Other substances related with this transduction pathway that have been administered with good results in patients are natriuretic factors. These compounds are endogenous peptides that activate membrane guanylyl cyclases and in consequence stimulate intracellular formation of cyclic GMP. Both nitric oxide and natriuretic peptides, through different ways (different enzymes), elicite increases in cyclic GMP synthesis.

The best known function of these peptides is their diuretic action. Apart from this renal action, natriuretic factors have important actions on the Cardiovascular System (reduce peripheral vascular resistance and lower blood pressure) and in the Central Nervous System (inhibition of vasopressin secretion and regulation of salt appetite and water drinking).

In accordance with these functions, the efficacy of natriuretic factors have been tested in disorders like hypertension, renal insufficiency, and congestive heart failure. Administration of these peptides reduces blood pressure and promotes sodium excretion in patients with essential hypertension. It also lowers blood pressure and improves central hemodynamics in patients with chronic heart failure.

Viagra

Recently, an inhibitor of one of the enzymes that degrade cyclic GMP (viagra or sildenafil, inhibitor of the cyclic nucleotide phosphodiesterase type V) has started to be amply used to treat erectile dysfunction. This compound allows that the same chemical impulses elicit much more cyclic GMP accumulation, since its degradation has been inhibited, and in consequence it improves vasodilation and final erection.